TUMOR MARKERS IN OVARIAN CANCER

Abstract

tures methods of diagnosing and prognosticating ovarian tumors by detecting increased expression of an ovarian tumor marker gene in a subject or in a sample from a subject. Also featured are kits for the aforementioned diagnostic and prognostic methods. In addition, the invention features methods of treating and preventing ovarian tumors, and methods of inhibiting the growth or metastasis of ovarian tumors, by modulating the production or activity of an ovarian tumor marker polypeptide. Further featured are methods of inhibiting the growth or metastasis of an ovarian tumor by contacting an ovarian tumor cell with an antibody that specifically binds an ovarian tumor marker polypeptide.

Description

[0001]This application is a continuation of U.S. application Ser. No. 11/895,326, filed Aug. 24, 2007, which is a continuation of U.S. application Ser. No. 10/257,021, filed Oct. 3, 2002 (now U.S. Pat. No. 7,279,294, issued Oct. 9, 2007), which is the national stage of PCT International Application No. PCT/US01/10947, filed on Apr. 3, 2001, which claims the benefit of U.S. Provisional Application 60/194,336, filed on Apr. 3, 2000, all of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0003]This invention relates generally to the identification of ovarian tumor markers and diagnostic, prognostic, and therapeutic methods for their use, as well as kits for use in the aforementioned methods.

BACKGROUND OF THE INVENTION

[0004]Ovarian cancer is one of the most common forms of neoplasia in women. Early diagnosis and treatment of any cancer ordinarily improves the likelihood of survival. However, ovarian cancer is difficult to detect in its early stages, and remains the leading cause of death among women with cancer of the female reproductive tract.

[0005]The low survival rate of ovarian cancer patients is in part due to the lack of good diagnostic markers for the detection of early stage neoplasms, and in part due to a deficit in the general understanding of ovarian cancer biology, which would facilitate the development of effective anti-tumor therapies. The present invention overcomes these shortcomings by providing much-needed improvements for the diagnosis, treatment, and prevention of ovarian tumors, based on the identification of a series of ovarian tumor marker genes that are highly expressed in ovarian epithelial tumor cells and are minimally expressed in normal ovarian epithelial cells. Over 75% of all ovarian tumors, and about 95% of all malignant ovarian tumors, arise from the ovarian surface epithelium (OSE). Because the tumor marker genes are broadly expressed in various types of ovarian epithelial tumors, the present invention should greatly improve the diagnosis and treatment of most ovarian cancers.

SUMMARY OF THE INVENTION

[0006]In a first aspect, the invention features a method of detecting an ovarian tumor in a subject. The method includes the step of measuring the expression level of an ovarian tumor marker gene in the subject, wherein an increase in the expression level of the ovarian tumor marker gene in the subject, relative to the expression level of the ovarian tumor marker gene in a reference subject not having an ovarian tumor, detects an ovarian tumor in the subject.

[0007]In a second aspect, the invention features a method of identifying a subject at increased risk for developing ovarian cancer. The method includes the step of measuring the expression level of an ovarian tumor marker gene in the subject, wherein an increase in the expression level of the ovarian tumor marker gene in the subject, relative to the expression level of the ovarian tumor marker gene in a reference subject not at increased risk for developing ovarian cancer, identifies an individual at increased risk for developing ovarian cancer.

[0008]In a preferred embodiment of the second aspect of the invention, the expression level of the ovarian tumor marker gene in the subject is compared to the expression level of the tumor marker gene in a reference subject that is identified as having an increased risk for developing ovarian cancer.

[0009]In a third aspect, the invention features a method of determining the effectiveness of an ovarian cancer treatment in a subject. The method includes the step of measuring the expression level of an ovarian tumor marker gene in the subject after treatment of the subject, wherein a modulation in the expression level of the ovarian tumor marker gene in the subject, relative to the expression level of the ovarian tumor marker gene in the subject prior to treatment, indicates an effective ovarian cancer treatment in the subject.

[0010]In a preferred embodiment of the first three aspects of the invention, the expression level of the ovarian tumor marker gene is determined in the subject by measuring the expression level of the tumor marker gene in a sample from the subject. The sample may be, for example, a tissue biopsy, ovarian epithelial cell scrapings, peritoneal fluid, blood, urine, or serum. In another preferred embodiment of the first three aspects of the invention, the expression level of the tumor marker gene is measured in vivo in the subject.

[0011]In yet another preferred embodiment of the first three aspects of the invention, the expression level of more than one ovarian tumor marker gene is measured. For example, the expression level of two, three, four, five, or more tumor marker genes may be measured.

[0012]In various other embodiments of the first three aspects of the invention, the expression level of the tumor marker gene may be determined by measuring the level of ovarian tumor marker mRNA. For example, the level of ovarian tumor marker mRNA may be measured using RT-PCR, Northern hybridization, dot-blotting, or in situ hybridization. In addition, or alternatively, the expression level of the ovarian tumor marker gene may be determined by measuring the level of ovarian tumor marker polypeptide encoded by the ovarian tumor marker gene. For example, the level of ovarian tumor marker polypeptide may be measured by ELISA, immunoblotting, or immunohistochemistry. The level of ovarian tumor marker polypeptide may also be measured in vivo in the subject using an antibody that specifically binds an ovarian tumor marker polypeptide, coupled to a paramagnetic label or other label used for in vivo imaging, and visualizing the distribution of the labeled antibody within the subject using an appropriate in vivo imaging method, such as magnetic resonance imaging.

[0013]In still another embodiment of the first three aspects of the invention, the expression level of the tumor marker gene may be compared to the expression level of the tumor marker gene in a reference subject diagnosed with ovarian cancer.

[0014]In a fourth aspect, the invention features a method of identifying a tumor as an ovarian tumor. The method includes the step of measuring the expression level of an ovarian tumor marker gene in a tumor cell from the tumor, wherein an increase in the expression level of the ovarian tumor marker gene in the tumor cell, relative to the expression level of the ovarian tumor marker gene in a noncancerous ovarian cell, identifies the tumor as an ovarian tumor.

[0015]In a fifth aspect, the invention features a method of treating or preventing an ovarian tumor in a subject. The method includes the step of modulating production or activity of a polypeptide encoded by an ovarian tumor marker gene in an ovarian epithelial cell in the subject.

[0016]In a sixth aspect, the invention features a method of inhibiting the growth or metastasis of an ovarian tumor cell in a subject. The method includes the step of modulating production or activity of a polypeptide encoded by an ovarian tumor marker gene in the ovarian tumor cell in the subject.

[0017]In a seventh aspect, the invention features a method of inhibiting the growth or metastasis of an ovarian tumor in a subject. The method includes the step of contacting an ovarian tumor cell with an antibody that specifically binds an ovarian tumor marker polypeptide encoded by an ovarian tumor marker gene, wherein the binding of the antibody to the ovarian tumor marker polypeptide inhibits the growth or metastasis of the ovarian tumor in the subject.

[0018]In various preferred embodiments of the seventh aspect of the invention, the ovarian tumor marker polypeptide may be on the surface of the ovarian tumor cell, and the antibody may be coupled to a radioisotope or to a toxic compound.

[0019]In an eighth aspect, the invention features a kit including an antibody for measuring the expression level of an ovarian tumor marker gene in a subject.

[0020]In a ninth aspect, the invention features a kit including a nucleic acid for measuring the expression level of an ovarian tumor marker gene in a subject.

[0021]In a tenth aspect, the invention features a method of diagnosing ovarian cancer in a subject. The method includes the step of measuring the amount of an ovarian tumor marker polypeptide in the subject, wherein an amount of ovarian tumor marker polypeptide that is greater than the amount of ovarian tumor marker polypeptide measured in a subject not having ovarian cancer diagnoses an ovarian cancer in the subject.

[0022]In various embodiments of the tenth aspect of the invention, the ovarian tumor marker polypeptide can be present at the surface of a cell (e.g., a cell-surface-localized polypeptide such as a cell adhesion molecule), or the ovarian tumor marker polypeptide may be in soluble form (e.g., secreted from a cell, released from a lysed cell, or otherwise detectable in a fluid-based assay).

[0023]In a preferred embodiment of all of the above aspects of the invention, the ovarian tumor may be an epithelial ovarian tumor. The epithelial ovarian tumor may be, for example, a serous cystadenoma, a borderline serous tumor, a serous cystadenocarcinoma, a mucinous cystadenoma, a borderline mucinous tumor, a mucinous cystadenocarcinoma, an endometrioid carcinoma, an undifferentiated carcinoma, a cystadenofibroma, an adenofibroma, or a Brenner tumor. The epithelial ovarian tumor may also be a clear cell adenocarcinoma.

[0024]In preferred embodiments of all of the above aspects of the invention, the ovarian tumor marker gene can be, but is not limited to, alpha prothymosin; beta polypeptide 2-like G protein subunit 1; tumor rejection antigen-1 (gp96)1; HSP90; Hepatoma-Derived Growth Factor (HGDF); DKFZp5860031; CD63 antigen (melanoma 1 antigen); protein kinase C substrate 80K-H; Polymerase II cofactor 4 (PC4); mitochondrial Tu translation elongation factor; hNRP H1; Solute carrier family 2; KIAA0591 protein; X-ray repair protein; DKFZP564M2423 protein; growth factor-regulated tyrosine kinase substrate; and eIF-2-associated p67. The ovarian tumor marker gene may also be HSP60 or Lutheran blood group (B-CAM). In other preferred embodiments of all aspects of the invention, the ovarian tumor marker gene may also be HLA-DR alpha chain; cysteine-rich protein 1; claudin 4; claudin 3; ceruloplasmin (ferroxidase); glutathione perroxidase 3; secretory leukocyte protease inhibitor; HOST-1 (FLJ14303 fis); interferon-induced transmembrane protein 1; apolipoprotein J/clusterin; serine protease inhibitor, Kunitz type 2; apoplipoprotein E; complement component 1, r subcomponent; G1P3/IFI-6-16; Lutheran blood group (BCAM); collagen type III, alpha-1; Mal (T cell differentiation protein); collagen type I, alpha-2; HLA-DPB1; bone marrow stroma antigen 2 (BST-2); or HLA-Cw.

[0025]The ovarian tumor marker gene may also be HOST-3 (Claudin-16) (e.g., Genbank® Accession No. XM_--003150; SEQ ID NOs: 141 and 142); HOST-4 (e.g., a gene that comprises SEQ ID NO: 144); or HOST-5 (sodium dependent transporter isoform NaPi-Iib) (e.g., Genbank® Accession No. AF146796; SEQ ID NOs: 146 and 147).

[0026]In other preferred embodiments of all aspects of the invention, the ovarian tumor marker gene comprises a nucleotide sequence set forth in one of SEQ ID NOs: 84-102.

[0027]In still other preferred embodiments of all aspects of the invention, the ovarian tumor marker gene comprises a nucleotide sequence set forth in one of SEQ ID NOs: 103-129.

[0028]In yet other preferred embodiments of all aspects of the invention, the ovarian tumor marker gene comprises a nucleotide sequence set forth in one of SEQ ID NOs: 141, 143, or 145.

[0029]Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

[0030]The low survival rate of ovarian cancer patients is in part due to the lack of good diagnostic markers allowing early detection of the disease. Further compounding this difficulty in early diagnosis is the lack of effective treatments for ovarian cancer, development of which has been impeded by a deficit in the general understanding of ovarian cancer biology. The present invention overcomes these deficits in the art by providing ovarian tumor markers that are expressed at elevated levels in ovarian epithelial tumor cells, relative to their expression in normal ovarian epithelial cells.

[0031]To identify marker genes that are up-regulated in ovarian tumor cells, SAGE (Serial Analysis of Gene Expression; Velculescu et al., Science 270:484-487, 1995) was employed to obtain global gene expression profiles of three ovarian tumors, five ovarian tumor cell lines of various histological types, a pool of ten ovarian tumor cell lines of various histological types, and normal human ovarian surface epithelium (HOSE). The expression patterns were generated by acquiring thousands of short sequence tags that contain sufficient information to uniquely identify transcripts due to the unique position of each tag within the transcript. Comparing the SAGE-generated expression profiles between ovarian cancer and HOSE revealed an abundance of genes that are expressed at elevated levels in ovarian tumor cells, relative to their expression in normal HOSE.

[0032]Selected SAGE results were further validated through immunohistochemical analysis of archival ovarian serous carcinoma samples. Ovarian tumor marker genes implicated in immune response pathways, regulation of cell proliferation, and protein folding were identified, many of which are membrane-localized or secreted. The ovarian tumor marker genes identified from these SAGE profiles are useful both as diagnostic and prognostic markers to detect and monitor a broad variety of ovarian cancers, and as therapeutic targets for the treatment of such ovarian cancers.

DEFINITIONS

[0033]In this specification and in the claims that follow, reference is made to a number of terms that shall be defined to have the following meanings.

[0034]As used in the specification and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a cell" can mean a single cell or more than one cell.

[0035]By "ovarian cell" is meant a cell that is of ovarian origin or that is a descendent of a cell of ovarian origin (e.g., a metastatic tumor cell in the liver that is derived from a tumor originating in the ovary), irrespective of whether the cell is physically within the ovary at the time at which it is subjected to a diagnostic test or an anti-tumor treatment. For example, the ovarian cell may be a normal ovarian cell or an ovarian tumor cell, either within the ovary or at another location within the body. The ovarian cell may also be outside the body (for example, in a tissue biopsy). A preferred ovarian cell is an ovarian cell of epithelial origin.

[0036]By "ovarian tumor marker gene" is meant a gene of the invention, for which expression is increased (as described below) in ovarian tumor cells relative to normal ovarian cells. Preferably, an ovarian tumor marker gene has been observed to display increased expression in at least two ovarian tumor SAGE libraries (relative to a HOSE library), more preferably in at least three SAGE libraries, and most preferably in at least four SAGE libraries (relative to a HOSE library). Examples of ovarian tumor marker genes are provided in Tables 2 and 4 hereinbelow.

[0037]By "ovarian tumor marker polypeptide" is meant a polypeptide that is encoded by an ovarian tumor marker gene and is produced at an increased level in an ovarian tumor cell due to the increased expression of the ovarian tumor marker gene that encodes the polypeptide.

[0038]By "sample" is meant any body fluid (e.g., but not limited to, blood, serum, urine, cerebrospinal fluid, semen, sputum, saliva, tears, joint fluids, body cavity fluids (e.g., peritoneal fluid), or washings), tissue, or organ obtained from a subject; a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a lysate (or lysate fraction) or extract derived from a cell; or a molecule derived from a cell or cellular material.

[0039]By "modulate" is meant to alter, by increase or decrease.

[0040]By "increase in gene expression level," "expressed at an increased level," "increased expression," and similar phrases is meant a rise in the relative amount of mRNA or protein, e.g., on account of an increase in transcription, translation, mRNA stability, or protein stability, such that the overall amount of a product of the gene, i.e., an mRNA or polypeptide, is augmented. Preferably the increase is by at least about 3-fold, more preferably, by at least about: 4-fold, 5-fold, 7-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 70-fold, or more. For example, as described herein, the expression level of the ovarian tumor marker genes of the invention is generally increased by at least 3-fold in ovarian tumor cells, relative to normal ovarian surface epithelial cells.

[0041]By "decrease in gene expression level" is meant a reduction in the relative amount of mRNA or protein transcription, translation, mRNA stability, or protein stability, such that the overall amount of a product of the gene, i.e., an mRNA or polypeptide, is reduced. Preferably the decrease is by at least about 20%-25%, more preferably by at least about 26%-50%, still more preferably by at least about 51%-75%, even more preferably by at least about 76%-95%, and most preferably, by about 96%-100%.

[0042]By "about" is meant ±10% of a recited value.

[0043]By "modulating production or activity of a polypeptide encoded by an ovarian tumor marker gene" is meant to increase or decrease gene expression level, as described above, or to stimulate or inhibit the ability of an ovarian tumor marker polypeptide to perform its intrinsic biological function (examples of such functions include, but are not limited to, enzymatic activity, e.g., kinase activity or GTPase activity; cell-signaling activity, e.g., activation of a growth factor receptor; or cell adhesion activity. The modulation may be an increase in the amount of the polypeptide produced or an increase in the activity of the polypeptide, of at least about: 2-fold, 4-fold, 6-fold, or 10-fold, or the modulation may be a decrease in the amount of the polypeptide produced or a decrease in the activity of the polypeptide, of at least about: 20%-25%, 26%-50%, 51%-75%, 76%-95%, or 96%-100%. These increases and/or decreases are compared with the amount of production and/or activity in a normal cell, sample, or subject.

[0044]By "effective amount" of a compound as provided herein is meant a nontoxic but sufficient amount of the compound to provide the desired effect, e.g., modulation of ovarian tumor marker gene expression or modulation of ovarian tumor marker polypeptide activity. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity and type of disease that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact "effective amount." However, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation.

[0045]By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with a molecule or compound of the invention (e.g., an antibody or nucleic acid molecule) without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0046]By "having an increased risk" is meant a subject that is identified as having a higher than normal chance of developing an ovarian tumor, compared to the general population. Such subjects include, for example, women that have a hereditary disposition to develop ovarian cancer, for example, those identified as harboring one or more genetic mutations (e.g., a mutation in the BRCA-1 gene) that are known indicators of a greater than normal chance of developing ovarian cancer, or who have a familial history of ovarian cancer. In addition, a subject who has had, or who currently has, an ovarian tumor is a subject who has an increased risk for developing an ovarian tumor, as such a subject may continue to develop new tumors. Subjects who currently have, or who have had, an ovarian tumor also have an increased risk for ovarian tumor metastases.

[0047]By "treat" is meant to administer a compound or molecule of the invention to a subject in order to: eliminate an ovarian tumor or reduce the size of an ovarian tumor or the number of ovarian tumors in a subject; arrest or slow the growth of an ovarian tumor in a subject; inhibit or slow the development of a new ovarian tumor or an ovarian tumor metastasis in a subject; or decrease the frequency or severity of symptoms and/or recurrences in a subject who currently has or who previously has had an ovarian tumor.

[0048]By "prevent" is meant to minimize the chance that a subject will develop an ovarian tumor or to delay the development of an ovarian tumor. For example, a woman at increased risk for an ovarian tumor, as described above, would be a candidate for therapy to prevent an ovarian tumor.

[0049]By "specifically binds" is meant that an antibody recognizes and physically interacts with its cognate antigen and does not significantly recognize and interact with other antigens.

[0050]By "probe," "primer," or "oligonucleotide" is meant a single-stranded DNA or RNA molecule of defined sequence that can base-pair to a second DNA or RNA molecule that contains a complementary sequence (the "target"). The stability of the resulting hybrid depends upon the extent of the base-pairing that occurs. The extent of base-pairing is affected by parameters such as the degree of complementarity between the probe and target molecules, and the degree of stringency of the hybridization conditions. The degree of hybridization stringency is affected by parameters such as temperature, salt concentration, and the concentration of organic molecules such as formamide, and is determined by methods known to one skilled in the art. Probes or primers specific for ovarian tumor marker nucleic acids (e.g., genes and/or mRNAs) preferably have at least 50%-55% sequence complementarity, more preferably at least 60%-75% sequence complementarity, even more preferably at least 80%-90% sequence complementarity, yet more preferably at least 91%-99% sequence complementarity, and most preferably 100% sequence complementarity to the ovarian tumor marker nucleic acid to be detected. Probes, primers, and oligonucleotides may be detectably-labeled, either radioactively, or non-radioactively, by methods well-known to those skilled in the art. Probes, primers, and oligonucleotides are used for methods involving nucleic acid hybridization, such as: nucleic acid sequencing, reverse transcription and/or nucleic acid amplification by the polymerase chain reaction, single stranded conformational polymorphism (SSCP) analysis, restriction fragment polymorphism (RFLP) analysis, Southern hybridization, Northern hybridization, in situ hybridization, electrophoretic mobility shift assay (EMSA).

[0051]By "specifically hybridizes" is meant that a probe, primer, or oligonucleotide recognizes and physically interacts (i.e., base-pairs) with a substantially complementary nucleic acid (e.g., an ovarian tumor marker mRNA of the invention) under high stringency conditions, and does not substantially base pair with other nucleic acids.

[0052]By "high stringency conditions" is meant conditions that allow hybridization comparable with the hybridization that occurs using a DNA probe of at least 500 nucleotides in length, in a buffer containing 0.5 M NaHPO₄, pH 7.2, 7% SDS, 1 mM EDTA, and 1% BSA (fraction V), at a temperature of 65° C., or a buffer containing 48% formamide, 4.8×SSC, 0.2 M Tris-Cl, pH 7.6, 1×Denhardt's solution, 10% dextran sulfate, and 0.1% SDS, at a temperature of 42° C. (these are typical conditions for high stringency Northern or Southern hybridizations). High stringency hybridization is relied upon for the success of numerous techniques routinely performed by molecular biologists, such as high stringency PCR, DNA sequencing, single strand conformational polymorphism analysis, and in situ hybridization. In contrast to Northern and Southern hybridizations, these techniques are usually performed with relatively short probes (e.g., usually 16 nucleotides or longer for PCR or sequencing, and 40 nucleotides or longer for in situ hybridization). The high stringency conditions used in these techniques are well known to those skilled in the art of molecular biology, and may be found, for example, in F. Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., 1997, herein incorporated by reference.

Examples of Ovarian Tumor Marker Genes

[0053]Examples of ovarian tumor marker genes of the invention include alpha prothymosin (e.g., Genbank® Accession No. M14483; SEQ ID NOs: 1 and 2); beta polypeptide 2-like G protein subunit 1 (e.g., Genbank® Accession No. M24194; SEQ ID NOs: 3 and 4); tumor rejection antigen-1 (gp96)1 (e.g., Genbank® Accession No. NM_--003299; SEQ ID NOs: 7 and 8); HSP90 (e.g., Genbank® Accession No. AA071048; SEQ ID NOs: 9 and 10); Hepatoma-Derived Growth Factor (HGDF) (e.g., Genbank® Accession No. D16431; SEQ ID NOs: 13 and 14); DKFZp5860031 (e.g., Genbank® Accession No. AL117237; SEQ ID NOs: 15 and 16); CD63 antigen (melanoma 1 antigen) (e.g., Genbank® Accession No. AA041408; SEQ ID NOs: 17 and 18); protein kinase C substrate 80K-H (e.g., Genbank® Accession No. J03075; SEQ ID NOs: 19 and 20); Polymerase II cofactor 4 (PC4) (e.g., Genbank® Accession No. X79805; SEQ ID NOs: 21 and 22); mitochondrial Tu translation elongation factor (e.g., Genbank® Accession No. L38995; SEQ ID NOs: 23 and 24); hNRP H1 (e.g., Genbank® Accession No. L22009; SEQ ID NOs: 25 and 26); Solute carrier family 2 (e.g., Genbank® Accession No. AF070544; SEQ ID NOs: 27 and 28); KIAA0591 protein (e.g., Genbank® Accession No. AB011163; SEQ ID NOs: 29 and 30); X-ray repair protein (e.g., Genbank® Accession No. AF035587; SEQ ID Nos: 31 and 32); DKFZP564M2423 protein (e.g., Genbank® Accession No. BC003049; SEQ ID NOs: 35 and 139); growth factor-regulated tyrosine kinase substrate (e.g., Genbank®Accession No. D84064; SEQ ID NOs: 36 and 37); and/or eIF-2-associated p67 (e.g., Genbank® Accession No. U29607; SEQ ID NOs: 38 and 39). The ovarian tumor marker gene may also be HSP60 (e.g., Genbank® Accession No. M22382; SEQ ID NOs: 11 and 12) and Lutheran blood group protein (B-CAM) (e.g., Genbank® Accession No. NM_--005581; SEQ ID NOs: 5 and 6).

[0054]Other examples of ovarian tumor marker genes of the invention include HLA-DR alpha chain (e.g., Genbank® Accession No. K01171; SEQ ID NOs: 40 and 41); cysteine-rich protein 1 (e.g., Genbank® Accession No. NM_--001311; SEQ ID NOs: 42 and 43); claudin 4 (e.g., Genbank® Accession No. NM_--001305; SEQ ID NOs: 44 and 45); HOST-2 (e.g., SEQ ID NO: 46); claudin 3 (e.g., Genbank® Accession No. NM_--001306; SEQ ID NOs: 47 and 48); ceruloplasmin (ferroxidase) (e.g., Genbank® Accession No. M13699; SEQ ID NOs: 49 and 50); glutathione perroxidase 3 (e.g., Genbank® Accession No. D00632; SEQ ID NOs: 51 and 52); secretory leukocyte protease inhibitor (e.g., Genbank® Accession No. AF114471; SEQ ID NOs: 53 and 54); HOST-1 (FLJ14303 fis) (e.g., Genbank® Accession No. AK024365; SEQ ID NOs: 55 and 56); interferon-induced transmembrane protein 1 (e.g., Genbank® Accession No. J04164; SEQ ID NOs: 57 and 58); apolipoprotein J/clusterin (e.g., Genbank® Accession No. J02908; SEQ ID NOs: 59 and 60); serine protease inhibitor, Kunitz type 2 (e.g., Genbank® Accession No. AF027205; SEQ ID NOs: 61 and 62); apoplipoprotein E (e.g., Genbank® Accession No. BC003557; SEQ ID NOs: 63 and 64); complement component 1, r subcomponent (e.g., Genbank® Accession No. M14058; SEQ ID NOs: 65 and 66); G1P3/IFI-6-16 (e.g., Genbank® Accession No. X02492; SEQ ID NOs: 67 and 68); Lutheran blood group (BCAM) (e.g., Genbank® Accession No. X83425; SEQ ID NOs: 69 and 70); collagen type III, alpha-1 (e.g., Genbank® Accession No. X14420; SEQ ID NOs: 71 and 72); Mal (T cell differentiation protein) (e.g., Genbank® Accession No. M15800; SEQ ID NOs: 73 and 74); collagen type I, alpha-2 (e.g., Genbank® Accession No. J03464; SEQ ID NOs: 75 and 76); HLA-DPB1 (e.g., Genbank® Accession No. J03041; SEQ ID NOs: 77 and 78); bone marrow stroma antigen 2 (BST-2) (e.g., Genbank® Accession No. D28137; SEQ ID NOs: 79 and 80); and HLA-Cw (e.g., Genbank® Accession No. X17093; SEQ ID NOs: 81 and 82).

[0055]Still other examples of ovarian tumor marker genes of the invention include HOST-3 (Claudin-16) (e.g., Genbank® Accession No. XM_--003150; SEQ ID NOs: 141 and 142); HOST-4 (e.g., a gene that comprises SEQ ID NO: 144); or HOST-5 (sodium dependent transporter isoform NaPi-Iib) (e.g., Genbank® Accession No. AF146796; SEQ ID NOs: 146 and 147).

[0056]Ovarian tumor marker genes of the invention may also be described by SAGE tags, as disclosed herein. For example, an ovarian tumor marker genes of the invention can include a nucleotide sequence set forth in one of SEQ ID NOs: 84-102; 103-129; or 141, 143, or 145.

Diagnostic Uses of Ovarian Tumor Marker Genes and Polypeptides

[0057]The ovarian tumor marker genes of the invention are overexpressed in a broad variety of ovarian epithelial tumor cells, relative to normal ovarian epithelial cells. This differential expression can be exploited in diagnostic tests for ovarian cancer, in prognostic tests for assessing the relative severity of ovarian cancer, in tests for monitoring a subject in remission from ovarian cancer, and in tests for monitoring disease status in a subject being treated for ovarian cancer. Increased expression of an ovarian tumor marker gene, i.e., detection of elevated levels of ovarian tumor marker mRNA and/or protein in a subject or in a sample from a subject (i.e., levels at least three-fold higher than in a normal subject or in an equivalent sample, e.g., blood, cells, or tissue from a normal subject) is diagnostic of ovarian cancer.

[0058]One of ordinary skill in the art will understand that in some instances, higher expression of a given ovarian tumor marker gene will indicate a worse prognosis for a subject having ovarian cancer. For example, relatively higher levels of ovarian tumor marker gene expression may indicate a relative large primary tumor, a higher tumor burden (e.g., more metastases), or a relatively more malignant tumor phenotype.

[0059]The diagnostic and prognostic methods of the invention involve using known methods, e.g., antibody-based methods to detect ovarian tumor marker polypeptides and nucleic acid hybridization- and/or amplification-based methods to detect ovarian tumor marker mRNA. One of ordinary skill in the art will understand how to choose the most appropriate method for measuring ovarian tumor marker expression, based upon the combination of the particular ovarian tumor marker to be measured, the information desired, and the particular type of diagnostic test to be used. For example, immunological tests such as enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), and Western blots may be used to measure the level of an ovarian tumor marker polypeptide in a body fluid sample (such as blood, serum, sputum, urine, or peritoneal fluid). Biopsies, tissue samples, and cell samples (such as ovaries, lymph nodes, ovarian surface epithelial cell scrapings, lung biopsies, liver biopsies, and any fluid sample containing cells (such as peritoneal fluid, sputum, and pleural effusions) may be tested by disaggregating and/or solubilizing the tissue or cell sample and subjecting it to an immunoassay for polypeptide detection, such as ELISA, RIA, or Western blotting. Such cell or tissue samples may also be analyzed by nucleic acid-based methods, e.g., reverse transcription-polymerase chain reaction (RT-PCR) amplification, Northern hybridization, or slot- or dot-blotting. To visualize the three-dimensional distribution of tumor cells within a tissue sample, diagnostic tests that preserve the tissue structure of a sample, e.g., immunohistological staining, in situ RNA hybridization, or in situ RT-PCR may be employed to detect ovarian tumor marker polypeptide or mRNA, respectively. For in vivo localization of tumor masses, imaging tests such as magnetic resonance imaging (MRI) may be employed by introducing into the subject an antibody that specifically binds an ovarian tumor marker polypeptide (particularly a cell surface-localized polypeptide), wherein the antibody is conjugated or otherwise coupled to a paramagnetic tracer (or other appropriate detectable moiety, depending upon the imaging method used); alternatively, localization of an unlabeled tumor marker-specific antibody may be detected using a secondary antibody coupled to a detectable moiety.

[0060]The skilled artisan will understand that selection of a particular ovarian tumor marker polypeptide as the target for detection in any diagnostic test and selection of the particular test to be employed will depend upon the type of sample to be tested. For example, measurement of ovarian tumor marker polypeptides that are secreted from a cell (e.g., HDGF) may be preferred for serological tests. Moreover, ovarian tumor marker polypeptides that are not normally actively secreted from cells (e.g., intracellular or membrane-associated polypeptides), but that are found in blood and other fluid samples (e.g., peritoneal fluid or washings) at detectable levels in subjects having tumors (e.g., due to tumor cell lysis) are considered to be soluble ovarian tumor marker polypeptides that may be used in serological and other diagnostic assays of body fluids.

[0061]A fluid sample (such as blood, peritoneal fluid, sputum, or pleural effusions) from a subject with ovarian cancer, particularly metastatic cancer, may contain one or more ovarian tumor cells or ovarian tumor cell fragments. The presence of such cells or fragments allows detection of a tumor mRNA using an RT-PCR assay, e.g., but not limited to, real-time quantitative RT-PCR using the Taqman method (Heid and Stevens, Genome Res. 6:986-94, 1996).

[0062]In addition, since rapid tumor cell destruction often results in autoantibody generation, the ovarian tumor markers of the invention may be used in serological assays (e.g., an ELISA test of a subject's serum) to detect autoantibodies against ovarian tumor markers in a subject. Ovarian tumor marker polypeptide-specific autoantibody levels that are at least about 3-fold higher (and preferably at least 5-fold or 7-fold higher, most preferably at least 10-fold or 20-fold higher) than in a control sample are indicative of ovarian cancer.

[0063]Cell-surface localized, intracellular, and secreted ovarian tumor marker polypeptides may all be employed for analysis of biopsies, e.g., tissue or cell samples (including cells obtained from liquid samples such as peritoneal cavity fluid) to identify a tissue or cell biopsy as containing ovarian tumor cells. A biopsy may be analyzed as an intact tissue or as a whole-cell sample, or the tissue or cell sample may be disaggregated and/or solubilized as necessary for the particular type of diagnostic test to be used. For example, biopsies or samples may be subjected to whole-tissue or whole-cell analysis of ovarian tumor marker polypeptide or mRNA levels in situ, e.g., using immunohistochemistry, in situ mRNA hybridization, or in situ RT-PCR. The skilled artisan will know how to process tissues or cells for analysis of polypeptide or mRNA levels using immunological methods such as ELISA, immunoblotting, or equivalent methods, or analysis of mRNA levels by nucleic acid-based analytical methods such as RT-PCR, Northern hybridization, or slot- or dot-blotting.

[0064]All of the above methods are well-known in the art. For example, generation of antibodies against a given protein, ELISA, immunoblotting, selection of nucleic acid primers for PCR, RT-PCR, Northern hybridization, in situ hybridization, in situ RT-PCR, and slot- or dot-blotting are all well-described in Current Protocols in Molecular Biology (Ausubel et al., eds.), John Wiley and Sons, Inc., 1996.

Kits for Measuring Expression Levels of Ovarian Tumor Marker Genes

[0065]The present invention provides kits for detecting an increased expression level of an ovarian tumor marker gene in a subject. A kit for detecting ovarian tumor marker polypeptide will contain an antibody that specifically binds a chosen ovarian tumor marker polypeptide. A kit for detecting ovarian tumor marker mRNA will contain one or more nucleic acids (e.g., one or more oligonucleotide primers or probes, DNA probes, RNA probes, or templates for generating RNA probes) that specifically hybridize with a chosen ovarian tumor marker mRNA.

[0066]Particularly, the antibody-based kit can be used to detect the presence of, and/or measure the level of, an ovarian tumor marker polypeptide that is specifically bound by the antibody or an immunoreactive fragment thereof. The kit can include an antibody reactive with the antigen and a reagent for detecting a reaction of the antibody with the antigen. Such a kit can be an ELISA kit and can contain a control (e.g., a specified amount of a particular ovarian tumor marker polypeptide), primary and secondary antibodies when appropriate, and any other necessary reagents such as detectable moieties, enzyme substrates and color reagents as described above. The diagnostic kit can, alternatively, be an immunoblot kit generally comprising the components and reagents described herein.

[0067]A nucleic acid-based kit can be used to detect and/or measure the expression level of an ovarian tumor marker gene by detecting and/or measuring the amount of ovarian tumor marker mRNA in a sample, such as a tissue or cell biopsy (e.g., an ovary, ovarian cell scrapings, a bone marrow biopsy, a lung biopsy or lung aspiration, etc.). For example, an RT-PCR kit for detection of elevated expression of an ovarian tumor marker gene will contain oligonucleotide primers sufficient to perform reverse transcription of ovarian tumor marker mRNA to cDNA and PCR amplification of ovarian tumor marker cDNA, and will preferably also contain control PCR template molecules and primers to perform appropriate negative and positive controls, and internal controls for quantitation. One of ordinary skill in the art will understand how to select the appropriate primers to perform the reverse transcription and PCR reactions, and the appropriate control reactions to be performed. Such guidance is found, for example, in F. Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., 1997. Numerous variations of RT-PCR are known in the art. One example of a quantitative RT-PCR assay is the real-time quantitative RT-PCR assay described by Heid and Stevens (Genome Res. 6:986-94, 1996), in which the primers are labeled by a fluorescent tag, and the amount of amplification product may be measured in a Taqman® apparatus (Perkin-Elmer; Norwal, Conn.).

Targeted Delivery of Immunotoxins to Ovarian Tumor Cells

[0068]The tumor marker genes of the invention can be employed as therapeutic targets for the treatment or prevention of ovarian cancer. For example, an antibody molecule that specifically binds a cell surface-localized ovarian tumor marker polypeptide can be Conjugated to a radioisotope or other toxic compound. Antibody conjugates are administered to the subject such that the binding of the antibody to its cognate ovarian tumor marker polypeptide results in the targeted delivery of the therapeutic compound to ovarian tumor cells, thereby treating an ovarian cancer.

[0069]The therapeutic moiety can be a toxin, radioisotope, drug, chemical, or a protein (see, e.g., Bera et al. "Pharmacokinetics and antitumor activity of a bivalent disultide-stabilized Fv immunotoxin with improved antigen binding to erbB2" Cancer Res. 59:4018-4022 (1999)). For example, the antibody can be linked or conjugated to a bacterial toxin (e.g., diptheria toxin, pseudomonas exotoxin A, cholera toxin) or plant toxin (e.g., ricin toxin) for targeted delivery of the toxin to a cell expressing the ovarian tumor marker. This immunotoxin can be delivered to a cell and upon binding the cell surface-localized ovarian tumor marker polypeptide, the toxin conjugated to the ovarian tumor marker-specific antibody will be delivered to the cell.

[0070]In addition, for any ovarian tumor polypeptide for which there is a specific ligand (e.g., a ligand that binds a cell surface-localized protein), the ligand can be used in place of an antibody to target a toxic compound to an ovarian tumor cell, as described above.

Antibodies that Specifically Bind Ovarian Tumor Marker Polypeptides

[0071]The term "antibodies" is used herein in a broad sense and includes both polyclonal and monoclonal antibodies. In addition to intact immunoglobulin molecules, also included in the term "antibodies" are fragments or polymers of those immunoglobulin molecules and humanized versions of immunoglobulin molecules, so long as they exhibit any of the desired properties (e.g., specific binding of an ovarian tumor marker polypeptide, delivery of a toxin to an ovarian tumor cell expressing an ovarian tumor marker gene at an increased level, and/or inhibiting the activity of an ovarian tumor marker polypeptide) described herein.

[0072]Whenever possible, the antibodies of the invention may be purchased from commercial sources. The antibodies of the invention may also be generated using well-known methods. The skilled artisan will understand that either full length ovarian tumor marker polypeptides or fragments thereof may be used to generate the antibodies of the invention. A polypeptide to be used for generating an antibody of the invention may be partially or fully purified from a natural source, or may be produced using recombinant DNA techniques. For example, a cDNA encoding an ovarian tumor marker polypeptide, or a fragment thereof, can be expressed in prokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast, insect, or mammalian cells), after which the recombinant protein can be purified and used to generate a monoclonal or polyclonal antibody preparation that specifically bind the ovarian tumor marker polypeptide used to generate the antibody.

[0073]In addition, one of skill in the art will know how to choose an antigenic peptide for the generation of monoclonal or polyclonal antibodies that specifically bind ovarian tumor antigen polypeptides. Antigenic peptides for use in generating the antibodies of the invention are chosen from non-helical regions of the protein that are hydrophilic. The PredictProtein Server or an analogous program may be used to select antigenic peptides to generate the antibodies of the invention. In one example, a peptide of about fifteen amino acids may be chosen and a peptide-antibody package may be obtained from a commercial source such as Anaspec (San Jose, Calif.). One of skill in the art will know that the generation of two or more different sets of monoclonal or polyclonal antibodies maximizes the likelihood of obtaining an antibody with the specificity and affinity required for its intended use (e.g., ELISA, immunohistochemistry, in vivo imaging, immunotoxin therapy). The antibodies are tested for their desired activity by known methods, in accordance with the purpose for which the antibodies are to be used (e.g., ELISA, immunohistochemistry, immunotherapy, etc.; for further guidance on the generation and testing of antibodies, see, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988). For example, the antibodies may be tested in ELISA assays, Western blots, immunohistochemical staining of formalin-fixed ovarian cancers or frozen tissue sections. After their initial in vitro characterization, antibodies intended for therapeutic or in vivo diagnostic use are tested according to known clinical testing methods.

[0074]The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. The monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired antagonistic activity (See, U.S. Pat. No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

[0075]Monoclonal antibodies of the invention may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro.

[0076]The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).

[0077]In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art. For instance, digestion can be performed using papain. Examples of papain digestion are described in WO 94/29348 published Dec. 22, 1994 and U.S. Pat. No. 4,342,566. Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual Fc fragment. Pepsin treatment yields a fragment that has two antigen combining sites and is still capable of cross-linking antigen.

[0078]The antibody fragments, whether attached to other sequences or not, can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the nonmodified antibody or antibody fragment. These modifications can provide for some additional property, such as to remove/add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In any case, the antibody fragment must possess a bioactive property, such as binding activity, regulation of binding at the binding domain, etc. Functional or active regions of the antibody may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide. Such methods are readily apparent to a skilled practitioner in the art and can include site-specific mutagenesis of the nucleic acid encoding the antibody fragment. (Zoller, M. J. Curr. Opin. Biotechnol. 3:348-354, 1992).

[0079]The antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab' or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., Nature, 321:522-525 (1986), Reichmann et al., Nature, 332:323-327 (1988), and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)).

[0080]Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be essentially performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986), Riechmann et al., Nature, 332:323-327 (1988), Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

[0081]Transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production can be employed. For example, it has been described that the homozygous deletion of the antibody heavy chain joining region (J(H)) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551-255 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggermann et al., Year in Immuno., 7:33 (1993)). Human antibodies can also be produced in phage display libraries (Hoogenboom et al., J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). The techniques of Cote et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)].

Administration of Therapeutic and Diagnostic Antibodies

[0082]Antibodies of the invention are preferably administered to a subject in a pharmaceutically acceptable carrier. Suitable carriers and their formulations are described in Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Co., edited by Oslo et al. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of antibody being administered.

[0083]The antibodies can be administered to the subject, patient, or cell by injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular), or by other methods such as infusion that ensure its delivery to the bloodstream in an effective form. The antibodies may also be administered by intratumoral or peritumoral routes, to exert local as well as systemic therapeutic effects. Local or intravenous injection is preferred.

[0084]Effective dosages and schedules for administering the antibodies may be determined empirically, and making such determinations is within the skill in the art. Those skilled in the art will understand that the dosage of antibodies that must be administered will vary depending on, for example, the subject that will receive the antibody, the route of administration, the particular type of antibody used and other drugs being administered. Guidance in selecting appropriate doses for antibodies is found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365-389. A typical daily dosage of the antibody used alone might range from about 1 μg/kg to up to 100 mg/kg of body weight or more per day, depending on the factors mentioned above.

[0085]Following administration of an antibody for treating ovarian cancer, the efficacy of the therapeutic antibody can be assessed in various ways well known to the skilled practitioner. For instance, the size, number, and/or distribution of ovarian tumors in a subject receiving treatment may be monitored using standard tumor imaging techniques. A therapeutically-administered antibody that arrests tumor growth, results in tumor shrinkage, and/or prevents the development of new tumors, compared to the disease course that would occurs in the absence of antibody administration, is an efficacious antibody for treatment of ovarian cancer.

Antisense and Gene Therapy Approaches for Inhibiting Ovarian Tumor Marker Gene Function

[0086]Because the ovarian tumor marker genes of the invention are highly expressed in ovarian tumor cells and are expressed at extremely low levels in normal ovarian cells, inhibition of ovarian tumor marker expression or polypeptide activity may be integrated into any therapeutic strategy for treating or preventing ovarian cancer.

[0087]The principle of antisense therapy is based on the hypothesis that sequence-specific suppression of gene expression (via transcription or translation) may be achieved by intracellular hybridization between genomic DNA or mRNA and a complementary antisense species. The formation of such a hybrid nucleic acid duplex interferes with transcription of the target tumor antigen-encoding genomic DNA, or processing/transport/translation and/or stability of the target tumor antigen mRNA.

[0088]Antisense nucleic acids can be delivered by a variety of approaches. For example, antisense oligonucleotides or antisense RNA can be directly administered (e.g., by intravenous injection) to a subject in a form that allows uptake into tumor cells. Alternatively, viral or plasmid vectors that encode antisense RNA (or RNA fragments) can be introduced into cells in vivo. Antisense effects can also be induced by sense sequences; however, the extent of phenotypic changes are highly variable. Phenotypic changes induced by effective antisense therapy are assessed according to changes in, e.g., target mRNA levels, target protein levels, and/or target protein activity levels.

[0089]In a specific example, inhibition of ovarian tumor marker function by antisense gene therapy may be accomplished by direct administration of antisense ovarian tumor marker RNA to a subject. The antisense tumor marker RNA may be produced and isolated by any standard technique, but is most readily produced by in vitro transcription using an antisense tumor marker cDNA under the control of a high efficiency promoter (e.g., the T7 promoter). Administration of antisense tumor marker RNA to cells can be carried out by any of the methods for direct nucleic acid administration described below.

[0090]An alternative strategy for inhibiting ovarian tumor marker polypeptide function using gene therapy involves intracellular expression of an anti-ovarian tumor marker antibody or a portion of an anti-ovarian tumor marker antibody. For example, the gene (or gene fragment) encoding a monoclonal antibody that specifically binds to an ovarian tumor marker polypeptide and inhibits its biological activity is placed under the transcriptional control of a specific (e.g., tissue- or tumor-specific) gene regulatory sequence, within a nucleic acid expression vector. The vector is then administered to the subject such that it is taken up by ovarian tumor cells or other cells, which then secrete the anti-ovarian tumor marker antibody and thereby block biological activity of the ovarian tumor marker polypeptide. Preferably, the ovarian tumor marker polypeptide is present at the extracellular surface of ovarian tumor cells.

Nucleic Acid Delivery

[0091]In the methods described above which include the administration and uptake of exogenous DNA into the cells of a subject (i.e., gene transduction or transfection), the nucleic acids of the present invention can be in the form of naked DNA or the nucleic acids can be in a vector for delivering the nucleic acids to the cells for inhibition of ovarian tumor marker protein expression. The vector can be a commercially available preparation, such as an adenovirus vector (Quantum Biotechnologies, Inc. (Laval, Quebec, Canada). Delivery of the nucleic acid or vector to cells can be via a variety of mechanisms. As one example, delivery can be via a liposome, using commercially available liposome preparations such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECTAM (Promega Biotec, Inc., Madison, Wis.), as well as other liposomes developed according to procedures standard in the art. In addition, the nucleic acid or vector of this invention can be delivered in vivo by electroporation, the technology for which is available from Genetronics, Inc. (San Diego, Calif.) as well as by means of a SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, Ariz.).

[0092]As one example, vector delivery can be via a viral system, such as a retroviral vector system which can package a recombinant retroviral genome (see e.g., Pastan et al., Proc. Natl. Acad. Sci. U.S.A. 85:4486, 1988; Miller et al., Mol. Cell. Biol. 6:2895, 1986). The recombinant retrovirus can then be used to infect and thereby deliver to the infected cells antisense nucleic acid that inhibits expression of an ovarian tumor marker gene. The exact method of introducing the altered nucleic acid into mammalian cells is, of course, not limited to the use of retroviral vectors. Other techniques are widely available for this procedure including the use of adenoviral vectors (Mitani et al., Hum. Gene Ther. 5:941-948, 1994), adeno-associated viral (AAV) vectors (Goodman et al., Blood 84:1492-1500, 1994), lentiviral vectors (Naidini et al., Science 272:263-267, 1996), pseudotyped retroviral vectors (Agrawal et al., Exper. Hematol. 24:738-747, 1996). Physical transduction techniques can also be used, such as liposome delivery and receptor-mediated and other endocytosis mechanisms (see, for example, Schwartzenberger et al., Blood 87:472-478, 1996). This invention can be used in conjunction with any of these or other commonly used gene transfer methods.

[0093]As one example, if the antisense nucleic acid of this invention is delivered to the cells of a subject in an adenovirus vector, the dosage for administration of adenovirus to humans can range from about 10⁷ to 10⁹ plaque forming units (pfu) per injection but can be as high as 10¹² pfu per injection (Crystal, Hum. Gene Ther. 8:985-1001, 1997; Alvarez and Curiel, Hum. Gene Ther. 8:597-613, 1997). Ideally, a subject will receive a single injection. If additional injections are necessary, they can be repeated at six month intervals for an indefinite period and/or until the efficacy of the treatment has been established.

[0094]Parenteral administration of the nucleic acid or vector of the present invention, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Pat. No. 3,610,795, which is incorporated by reference herein. For additional discussion of suitable formulations and various routes of administration of therapeutic compounds, see, e.g., Remington: The Science and Practice of Pharmacy (19th ed.) ed. A. R. Gennaro, Mack Publishing Company, Easton, Pa. 1995.

Example I

Identification of Ovarian Tumor Marker Genes Using SAGE

[0095]Serial Analysis of Gene Expression is a method that enables the global analysis of gene expression from a tissue of interest (Velculescu et al., Science 270:484-487, 1995; Zhang et al., Science 276:1268-72, 1997). The advantages of SAGE over cDNA arrays, another method for the global analysis of gene expression, include: 1) the possibility of identifying novel genes, 2) determination of absolute levels of gene expression, which is difficult in hybridization-based techniques, and, 3) examination of gene expression as a whole instead of as a subset of genes.

[0096]Construction and Screening of SAGE Libraries

[0097]The SAGE technique has been described in detail (Velculescu et al., Science 270:484-487, 1995). The SAGE libraries disclosed herein were made as described by Velculescu, supra. First, total RNA was purified from the cells. Poly A+ RNA was then isolated and reverse transcription was performed using a biotinylated poly dT primer for first strand synthesis. The cDNA mixture was cut with NlaIII and the biotinylated 3' fragments were collected using streptavidin beads. The beads were divided into two aliquots (A and B) and linkers containing PCR primer sites and a site for class II restriction enzyme BsmFI were ligated to the DNA fragments attached to the beads from samples A and B. The mixture was treated with the restriction enzyme BsmFI, which recognizes the site in the linker but cuts 14 by downstream. The resulting fragments contained the linker and 10 by of "cDNA sequence" that is referred to as "tag". The tags from samples A and B were ligated together to form ditags, which were then amplified by PCR. Any repeated ditag (tags containing the same two individual tags) are an indication of PCR bias and were eliminated by the SAGE software (Velculescu et al., Science 270:484-487, 1995; Zhang et al., Science 276:1268-72, 1997). The tags were concatemerized and cloned into a sequencing vector. Sequencing revealed the identity and frequency of the different tags. As described above, the 10 by tag is sufficient to identify cDNA and the frequency of a particular tag represents the frequency of a particular message in the population. The SAGE software developed in the laboratories of Bert Vogelstein and Kenneth Kinzler at Johns Hopkins extracts the tags from the raw sequencing data, matches the tags to the corresponding genes (present in Genbank®) and makes frequency comparisons between the tags from an individual library or other libraries.

[0098]Verification of Ovarian Tumor Marker Genes Identified by SAGE

[0099]The most promising candidates are selected and verified by any expression analysis method, e.g., Northern analysis or reverse transcription-polymerase chain reaction (RT-PCR). For Northern analysis, radioactive probes are generated from expressed sequence tags (ESTs) corresponding to the candidate genes and are used to hybridize to membranes containing total RNA from various ovarian cancers and controls. The candidates may also be verified by real-time PCR using the Taqman® method (Heid and Stevens, Genome Res. 6:986-94, 1996). Amplification primers and fluorescent probes are synthesized according to instructions from the manufacturer (Perkin-Elmer; Norwalk, Conn.). Quantitative PCR is performed using a PE 5700 apparatus or an analogous instrument.

[0100]Sources of RNA for SAGE Library Construction

[0101]Eleven SAGE libraries were constructed, as shown in Table 1. The human ovarian surface epithelial cell (HOSE) library was constructed using RNA from HOSE cells that were obtained by gently scraping the ovarian surface from a hysterectomy patient followed by short-term in vitro culture (three passages) of the cells. Three of the ovarian tumor libraries (designated OVT6, OVT7, and OVT8) were constructed using RNA from one of three primary high grade serous adenocarcinomas. Libraries from individual ovarian tumor cell lines were generated using RNA from OV1063 (derived from an ovarian papillary adenocarcinoma; obtained from the American Type Culture Collection (ATCC; Manassas, Va.; CRL-2183)); ES-2 (derived from a clear cell adenocarcinoma; from the ATCC; CRL-1978); A2780 (derived from an ovarian cancer; obtained from Dr. Vilhelm Bohr, Baltimore, Md.); OVCA432 (derived from an ovarian serous cystadenocarcinoma; Bast et al., J. Clin. Invest. 68:1331-1337, 1981); ML10 (derived from an ovarian cystadenoma; Luo et al. Gyn. Oncol., 67:277-284, 1997); or IOSE29 (simian virus 40-immortalized OSE cells; Auersperg et al., Proc. Natl. Acad. Sci. USA 96:6249-6254, 1999).

[0102]The pooled library was generated using RNA from a pool of 10 cell lines: A2780; BG-1 (poorly differentiated ovarian cancer; obtained from Dr. Carl Barrett, Durham, N.C.); ES-2; OVCA432; MDAH 2774 (endometrioid adenocarcinoma; obtained from the ATCC); and five cell lines obtained from Dr. Michael Birrer (Rockville, Md.): AD10 (an adriamycin-resistant derivative of A2780); A222 (ovarian carcinoma); UCI101 (papillary ovarian adenocarcinoma); UCI107 (papillary ovarian adenocarcinoma); and A224 (ovarian carcinoma).

TABLE-US-00001 TABLE 1 Library Seq Tags (raw) Tags Genes At least 2 HOSE 2,290 49,394 47,881 16,034 4,532 OVT6 2,104 43,891 41,620 18,476 4,799 OVT7 2,089 57,725 53,898 19,523 5,669 OVT8 2,076 36,813 32,494 16,363 3,815 OV1063 2,146 41,131 37,862 15,231 4,746 ES-2 1,775 36,430 35,352 14,739 3,952 A2780 ** 475 9,269 8,246 5,179 1,021 OVCA432 384 3,011 2,824 1,940 310 Pool 2,201 10,952 10,554 5,956 1,627 ML10 1,935 61,083 55,700 18,727 6,637 IOSE29 * * * * * TOTAL 17,475 349,699 326,431 75,056 25,071 * To be sequenced ** Incomplete

[0103]Results of SAGE

[0104]Eleven ovarian SAGE libraries were constructed, ten of which have been sequenced to date. The overall data are summarized in Table 1 above. For each SAGE library, Table 1 shows the number of SAGE library clones sequenced, the number of raw tags sequenced, the number of tags obtained after correction for PCR bias, the total number of genes that are represented by the corrected pool of tags, and the number of genes that were represented at least twice in the corrected pool of tags. For most libraries, 35,000-61,000 tags were obtained, yielding anywhere from 14,000-20,000 genes. In total, 75,056 genes were identified.

[0105]In order to identify genes that are up-regulated in ovarian tumors and that may serve as diagnostic markers and therapeutic targets, we compared gene expression between the normal ovarian cells (HOSE) and the cancer cells (OVT6, OVT7, OVT8, OV1063, ES2, A2780, Pool). OVCA432 was not included in this analysis because of the poor number of tags obtained from this library. We looked for genes for which expression was absent or low (frequency smaller or equal to 2 tags per 100,000) in HOSE and at least 7- to 10-fold up-regulated in the majority of the tumor libraries, and detected a number of genes matching these criteria. Table 2 shows the libraries that were screened, the SAGE tags that were identified in the library screens, along with their corresponding genes and Genbank® accession numbers, and the relative expression of each gene in each library. Any one of these ovarian tumor marker genes may be used in the diagnostic and/or therapeutic methods of the invention.

TABLE-US-00002 TABLE 2 SEQ.ID NO.(Tag) Tag OVT8 OVT7 PVT6 A2780 OV1063 ES2 Pool HOSE Gene Product Genbank® 83 TCAGACGCAG 52 149 91 97 49 214 82 2 Prothymosin, alpha M14483 84 TTATGGGATC 57 80 57 140 83 126 274 2 G protein, beta polypeptide 2-like M24194 1 85 CCCGCCCCCG 136 166 52 22 7 0 146 2 Lutheran blood group (B-CAM) NM_005581 86 GAGGAAGAAG 14 38 57 76 53 80 100 2 Tumor rejection antigen-1 (gp96) 1 NM_003299 87 GAAGCTTTGC 27 43 43 22 27 66 73 2 HSP90 AA071048 88 TACCAGTGTA 30 16 14 140 22 30 100 2 HSP60 M22382 89 TCTTCTCCCT 8 42 32 22 27 25 46 2 Hepatoma-Derived Growth Factor D16431 (HDGF) 90 TTGGCTTTTC 14 12 71 32 10 22 18 0 DKFZp5860031 AL117237 91 GGAAGGGAGG 30 14 16 11 12 44 55 2 CD63 antigen (melanoma 1 antigen) AA041408 92 AAGCCAGCCC 19 17 36 22 17 27 18 2 Protein kinase C substrate 80K-H J03075 93 TTTCAGATTG 16 26 25 32 22 19 18 0 Polymerase II cofactor 4 (PC4) X79805 94 GCATAGGCTG 11 24 25 22 12 27 9 2 Tu translation elong. factor L38995 (mitochondrial) 95 TTTGTTAATT 30 16 16 43 17 19 18 2 hNRP H1 L22009 96 GAGACTCCTG 11 23 23 22 12 3 64 2 Solute carrier family 2 AF070544 97 CCTGTAATTC 19 10 27 32 15 8 27 2 KIAA0591 protein AB011163 98 GTGGTGCGTG 16 10 21 11 15 19 27 2 X-ray repair protein AF035587 99 TTGGACGTGG 11 19 9 11 27 16 18 2 ATP synthase (delta subunit) AA524164 100 CTTAAGGATT 11 12 18 11 15 27 9 0 DKFZP564M2423 protein BC003049 101 GTCTGTGAGA 8 17 9 22 12 22 18 0 Growth factor-regul. tyr kinase D84064 substrate 102 GAAACTGAAG 16 10 14 32 12 3 9 2 eIF-2-associated p67 U29607

Example II

Identification of Additional Ovarian Tumor Marker Genes Using SAGE

[0106]Serial Analysis of Gene Expression (SAGE) was used to generate global gene expression profiles from various ovarian cell lines and tissues, including primary cancers, ovarian surface epithelial (OSE) cells and cystadenoma cells. The profiles were used to compare overall patterns of gene expression and identify differentially expressed genes. We have sequenced a total of 385,000 tags, yielding over 56,000 genes expressed in ten different libraries derived from ovarian tissues.

[0107]In general, ovarian cancer cell lines showed relatively high levels of similarity to libraries from other cancer cell lines, regardless of the tissue of origin (ovarian or colon), indicating that these lines had lost many of their tissue specific expression patterns. In contrast, immortalized OSE (IOSE) and ovarian cystadenoma cells showed much higher similarity to primary ovarian carcinomas as compared to primary colon carcinomas. Primary tissue specimens therefore appeared to be a better model for gene expression analyses. Using the expression profiles described above and stringent selection criteria, we have identified a number of genes highly differentially expressed between non-transformed ovarian epithelia and ovarian carcinomas. Some of the genes identified are already known to be overexpressed in ovarian cancer but several represent novel candidates. Many of the genes up-regulated in ovarian cancer represent surface or secreted proteins such as Claudin-3 and -4, HE4, Mucin-1, Ep-CAM and Mesothelin. The genes encoding apolipoprotein E (ApoE) and apolipoprotein J (ApoJ), two proteins involved in lipid homeostasis are among the genes highly up-regulated in ovarian cancer. Selected SAGE results were further validated through immunohistochemical analysis of ApoJ, Claudin-3, Claudin-4 and Ep-CAM in archival material. These experiments provided additional evidence of the relevance of our findings in vivo.

A) Methods

[0108]Cell Culture and Tissue Samples

[0109]Ovarian cancer cell lines OV1063, ES2, and MDAH 2774 were obtained from the American Type Culture Collection (Manassas, Va.). Cell lines A222, AD10, UCI101 and UCI107 were obtained from Dr. Michael Birrer (Rockville, Md.). Cell line A2780 was obtained from Dr. Vilhelm Bohr (Baltimore, Md.). The SV40-immortalized cell lines IOSE29 (Auersperg, N., et al. Proc. Natl Acad. Sci. USA, 96:6249-6254, 1999) and ML10 (Luo, M. P., et al. Gynecol. Oncol. 67:277-284, 1997) were kindly provided by Dr. Nelly Auersperg (British Columbia, Canada) and Dr. Louis Dubeau (Los Angeles, Calif.), respectively. Except for IOSE29, ML-10 and HOSE-4, all cell lines were cultured in McCoy's 5A growth medium (Life Technologies, Inc, Gaithersburg, Md.) supplemented with 10% fetal bovine serum (FBS) and antibiotics (100 U/ml of Penicillin and 100 ug/ml Streptomycin). IOSE29 was cultivated in Medium 199 (Life Technologies, Inc, Gaithersburg, Md.) supplemented with 5% newborn calf serum (NCS). ML10 was cultivated in MEM (Life Technologies, Inc, Gaithersburg, Md.) supplemented with 10% FBS and antibiotics as above.

[0110]Three high-grade serous ovarian cancer specimens, OVT6, OVT7, and OVT8, composed of at least 80% tumor cells as determined by histopathology, were chosen for SAGE. The ovarian tumor samples were frozen immediately after surgical resection and were obtained form the Johns Hopkins gynecological tumor bank in accordance with institutional guidelines on the use of human tissue. Normal human ovarian surface epithelial (HOSE-4) cells were cultured from the right ovary of a patient undergoing hysterectomy and bilateral salpingo-oophorectomy for benign disease. The OSE cells were obtained by gently scraping the surface of the ovary with a cytobrush and grown for 2 passages in RPMI 1640 medium supplemented with 10% FBS and 10 ug/ml insulin-like growth factor (IGF).

[0111]Serial Analysis of Gene Expression (SAGE)

[0112]Total RNA was obtained from guanidinium isothiocyanate cell lysates by centrifugation on CsCl. Polyadenylated mRNA was purified from total RNA using the Messagemaker® kit (Life Technologies, Gaithersburg, Md.) and the cDNA generated using the cDNA Synthesis System (Life Technologies, Gaithersburg, Md.). For the "Pool" library, 100 ug of total RNA from each of 10 ovarian cancer cell lines (A222, A2780, AD10, BG-1, ES-2, MDAH 2774, OVCA432, OV1063, UCI101 and UCI107) were combined and mRNA purified. SAGE was performed essentially as described (Velculescu, V. E., et al. Science 270:484-487, 1995) for all the libraries except HOSE. To create the HOSE library, MicroSAGE, a modified SAGE technique developed for limited sample sizes (Datson, N. A., et al. Nucleic Acids Res. 27:1300-1307, 1999), was used. Approximately 1×10⁶ OSE cells in short-term culture were lysed and the mRNA purified directly using Oligo (dT)₂₅ Dynabeads® (Dynal, Norway). As part of the Cancer Genome Anatomy Project (CGAP) SAGE consortium, the SAGE libraries were arrayed at the Lawrence Livermore National Laboratories and sequenced at the Washington University Human Genome Center or NISC (NIH, Bethesda, Md.). The data has been posted on the CGAP website as part of the SAGEmap database (Lal, A., et al. Cancer Res. 59:5403-5407, 1999.).

[0113]Sequence data from each library were analyzed by the SAGE software (Velculescu, V. E., et al. Science 270:484-487, 1995.) to quantify tags and identify their corresponding transcripts. The data for the colon libraries NC1, NC2, Tu98, Tu102, HCT116 and SW837 were obtained from the SAGEmap database and analyzed in the same way. Because the different libraries contained various numbers of total tags, normalization (to 100,000 tags) was performed to allow meaningful comparisons. The 10,000 most highly expressed genes in each of the 16 SAGE libraries of interest were formatted in a Microsoft Excel spreadsheet and Pearson correlation coefficients were calculated for each pair-wise comparison using normalized tag values for each library. The value for the Pearson correlation coefficient (r) represents the degree of similarity (the strength of the relationship) between two libraries and is calculated using the following equation:

r = n ( xy ) - ( x ) ( y ) { n x 2 - ( x ) 2 ] { n y 2 - ( y ) 2 ##EQU00001##

where, x_i=number of tags per 100,000 for tag i in the first library and y_i=number of tags per 100,000 for tag i in the second library. For our purposes n equals 10,000 since 10,000 tags are compared. A dendrogram representing the hierarchical relationships between samples was then generated using hierarchical cluster analysis as described (Eisen, M. B., et al. Proc. Natl Acad. Sci. USA 95:14863-14868, 1998). In addition, the identification of differentially expressed genes was also done using this subset of the SAGE data.

[0114]Immunohistochemistry

[0115]Deparafinized 5-um sections of formalin-fixed ovarian cancer specimens were submitted to heat-induced antigen retrieval and processed using the LSAB2 system (DAKO, Carpinteria, Calif.) with 3,3'-diaminobenzidine as the chromatogen and a hematoxylin counterstain. Monoclonal antibody against ApoJ/Clusterin (Clone CLI-9) was obtained from Alexis Corporation (San Diego, Calif.) and used at a 1:500 Dilution. Monoclonal antibody against Ep-CAM (Clone 323/A3) from NeoMarkers® (Fremont, Calif.) was used at a 1:500 dilution. Polyclonal antibodies against Claudin-3 and 4 were a generous gift from Drs. M. Furuse and S. Tsukita (Kyoto, Japan) and were used at a dilution of 1:1000.

B) Results

[0116]Ovarian SAGE Library Construction and Analysis

[0117]Gene expression alterations that arise during malignant transformation can be identified a number of ways. We chose the unbiased, comprehensive method SAGE to create global gene expression profiles from ten different ovarian sources. The expression patterns are generated by sequencing thousands of short sequence tags that contain sufficient information to uniquely identify the corresponding transcripts (Velculescu, V. E., et al. Science 270:484-487, 1995). Ten different SAGE libraries were constructed and sequenced for this study (Table 3). Our libraries included two derived from OSE cells (IOSE29 and HOSE-4), one derived from immortalized cystadenoma cells (ML-10), three primary tumors (OVT-6, -7, -8) and four libraries derived from ovarian cancer cell lines (OV-1063, ES-2, A2780 and a pool of cell lines). Almost 20,000 sequencing reactions were performed yielding a total of 384,497 tags, of which, 82,533 were unique. Accounting for a SAGE tag error rate of 6.8% (due to sequencing errors; see Zhang, L., et al., Science 276:1268-1272, 1997), we estimate that we have identified a total of 56,387 genes expressed in ovarian tissues. Except for the A2780 cell line and the pooled lines (POOL) samples, a minimum of 12,000 genes were obtained from every library. Typically, for each library, 10% of the genes were expressed at levels of at least 0.01% and, collectively, these genes accounted for more than 50% of all the tags sequenced. Among the tags that appeared more than once, up to 95% matched to known sequences in the current Genbank® nr database. For example, of the 6637 tags that appeared more than once in ML10, only 311 had no matches in the current database, excluding the EST databases.

TABLE-US-00003 TABLE 3 Summary of SAGE library analyses Library ^a Sequence Tags ^b Unique tags ^c Genes ^d ≧2 tags ^e HOSE 2,290 47,881 16,034 12,778 4,532 IOSE 1,912 47,549 18,004 14,771 5,681 ML10 1,935 55,700 18,727 14,939 6,637 OVT6 2,104 41,620 18,476 15,646 4,799 OVT7 2,089 53,898 19,523 15,858 5,669 OVT8 2,076 32,494 16,363 14,153 3,815 OV1063 2,146 37,862 15,231 12,656 4,746 A2780 1,332 21,587 10,717 9,249 2,761 ES2 1,775 35,352 14,739 12,335 3,952 POOL 2,201 10,554 5,956 5,238 1,627 TOTAL 19,860 384,497 82,533 56,387 28,219 ^a The libraries are: HOSE, human ovarian surface epithelium from short term culture; IOSE, SV40-immortalized ovarian surface epithelium; ML10, SV40-immortalized benign cystadenoma; OVT6, OVT7, and OVT8, primary ovarian serous adenocarcinomas; OV1063, A2780, and ES2, ovarian cancer cell lines; POOL, a pool of ten ovarian cancer cell lines. ^b Tag numbers after elimination of linker-based tags and duplicate ditags. ^c The number of unique tags identified in each library. ^d The number of genes identified after correction for sequencing errors. ^e The number of genes represented at least twice.

[0118]Comparisons of Global Gene Expression Between Ovarian Tissue Samples

[0119]Although progression to malignancy requires a number of gene expression changes, the transcript levels from the vast majority of genes remain unaltered (Zhang, L., et al., Science 276:1268-1272, 1997; and Alon, U., et al., Proc. Natl Acad. Sci. USA 96:6745-6750, 1999). Similarities between the global expression profiles of two given samples can be readily visualized using scatterplots and quantitated through the calculation of Pearson correlation coefficients. Scatterplots of global gene expression analysis in IOSE (ovarian) vs. ML10 (ovarian), OVT6 (ovarian), or Tu98 (colon) cells were generated using the Spotfire® Pro 4.0 software (Cambridge, Mass.) and the Pearson correlation coefficients for each pair-wise comparison of the 16 ovarian and colon SAGE libraries were calculated.

[0120]As expected, the immortalized IOSE29 and ovarian cystadenoma strain ML10 are much more similar to ovarian tumors than to colon tumors (average correlation coefficients of 0.70 vs. 0.51, respectively). In addition, IOSE29 and ML10 are very similar to each other, with a correlation coefficient of 0.82. The primary culture of OSE cells (HOSE-4) exhibited higher similarities to the ovarian tumors than to the colon tumors, although the similarity levels were much lower than those observed for IOSE29. Interestingly, HOSE-4 and IOSE29 appear to be much more distantly related than expected considering the fact that they were both derived from "normal" OSE cells. The differences in gene expression between these cells may be due to a number of factors. The age of the patient, the pathological state of the ovaries, the presence of non-epithelial cells in the culture and the fact that IOSE29 is SV40-immortalized may all contribute to the gene expression differences observed. However, it is unlikely that the main differences are due to SV40-immortalization since IOSE29 is much more similar to normal colon (a non SV40-immortalized epithelium) than HOSE-4. It is, of course, possible that the lower degree of similarity between HOSE-4 and the ovarian tumors compared to IOSE29 and ML-10 reflects the fact that HOSE-4 represents a better approximation of the normal in vivo OSE cell.

[0121]Three dendrograms were created from hierarchical cluster analysis of all colon and ovarian SAGE libraries, ovarian samples only, and non-malignant ovarian and colon epithelia as well as ovarian and colon primary tumors, using Cluster software (Eisen, M. B., et al. Proc. Natl Acad. Sci. USA 95:14863-14868, 1998). When all the samples were included in the hierarchical clustering analysis, the primary colon tumors clustered with the normal colon epithelium, but colon cell lines clustered with the ovarian specimens. Clearly, the tissue clustering that was readily apparent when comparing primary tissues or immortalized lines was lost when including carcinoma cell lines. For example, A2780, a widely used ovarian cancer cell line was just as similar to colon cancer cell lines as it was to ovarian cancer cell lines. This observation supports the idea that in the process of establishment, cell lines may lose many of the gene expression characteristics of their tissue of origin, although tissue specific expression is clearly not completely lost in cancer cell lines (Ross, D. T., et al. Nat. Genet. 24:227-235, 2000).

[0122]It is widely believed that epithelial ovarian cancer and benign ovarian cysts, while not necessarily part of a progression sequence toward malignancy, are both derived from the ovarian surface epithelium (Scully, R. E. J. Cell Biochem. 23, Suppl.:208-218, 1995). OSE cells themselves are mesodermal in origin and are believed to undergo metaplasia before progressing to neoplasia (Scully, R. E. J. Cell Biochem. 23 Suppl.:208-218, 1995; and Maines-Bandiera, S. L. and Auersperg, N. Int. J. Gynecol. Pathol. 16:250-255, 1997). On the other hand, it has also been argued that ovarian cancers are not derived from OSE but rather from the secondary Mullerian system, structures lined by Mullerian epithelium but located outside the uterus, cervix and fallopian tubes (Schink, J. C. Semin. Oncol. 26 Suppl. 1: 2-7, 1999). This hypothesis would explain some of the shortcomings of the OSE model, such as the requirement for metaplasia and the lack of well-defined precursors in the ovary. While not wishing to be bound by theory, our results are consistent with the widely accepted dogma of the OSE origin of ovarian cancer. Indeed, IOSE29 showed high degrees of similarity to the ovarian tumors and both IOSE29 and HOSE were much more closely related to ovarian than colon primary cancers.

[0123]E-cadherin expression has been proposed to be a major determinant in the formation of metaplastic OSE (Auersperg, N., et al. Proc. Natl Acad. Sci. USA, 96:6249-6254, 1999; and Maines-Bandiera, S. L. and Auersperg, N. Int. J. Gynecol. Pathol. 16:250-255, 1997). Consistent with this hypothesis, E-cadherin was absent in IOSE29, HOSE and ML10 but was expressed in all three ovarian tumors (Table 4). Other cadherins are also shown for comparison. Interestingly, VE-cadherin is absent in most libraries except in two of the pre-neoplastic ovarian samples, again suggesting metaplasia. As expected, LI-Cadherin was expressed exclusively in the colon-derived libraries. Interestingly, vimentin, a mesenchymal marker, was present in essentially all the ovarian libraries but very low in the colon specimens. Although the specificity of vimentin as a mesenchymal marker has been questioned, this suggests that OSE may retain some of their mesenchymal characteristics, even after turning on the expression of E-cadherin.

[0124]The cytokeratins (CKs) and carcinoembryonic antigen (CEA) have been used to differentiate between colon cancer and ovarian cancer (Lagendijk, J. H., et al. Hum. Pathol. 29:491-497, 1998; and Berezowski, K., et al. Mod. Pathol. 9:426-429, 1996). Typically, colon cancer expresses CK20 and CEA while ovarian cancer expresses CK7. The expression patterns in our libraries were consistent with previously reported observations: CK20 and CEA were found in normal colon and colon tumors but absent from all of our ovarian samples (Table 4). Conversely, CK7 was expressed in all three primary ovarian tumors and, while not absent, was much lower in the colon samples. Examination of the differential expression patterns of a variety of established ovarian cancer markers thus provided validation of the SAGE database and cluster analysis.

[0125]Differential Gene Expression

[0126]The ultimate goal of comparing SAGE libraries is to identify differentially expressed genes. Criteria for differential expression can be determined for each comparison and transcripts within the determined range selected for study. We found a large number of genes that were up-regulated in only one or two of the three tumors on which SAGE was performed. For example, a total of 444 genes were up-regulated more than 10-fold in at least one of the three ovarian primary cancers compared to IOSE29. However, only 45 genes were overexpressed more than 10-fold in all three ovarian tumors analyzed compared to IOSE29.

[0127]Our analysis of three different primary ovarian cancers allowed us to reduce the number of candidates by looking for consistency between samples. In order to identify genes that are very likely to be frequently up-regulated during ovarian tumorigenesis we set the following conservative criteria for our analysis. First, the fold induction was calculated by adding the number of normalized tags from the three primary tumors and dividing this number by the total normalized tags in the three non-malignant specimens. Cell lines were not included here for reasons described above. In addition, although HOSE-4 appeared more distantly related to the other non-transformed specimens, we believe that the inclusion of HOSE-4, while possibly eliminating real candidates makes our analysis more conservative and more likely to identify truly overexpressed genes in ovarian cancer. Second, all three primary tumors were required to consistently show elevated levels (>12 tags/100,000) of the gene in question. This eliminated genes that may be very highly overexpressed in one tumor but not in others. Finally, the candidate genes were required to be expressed in at least one ovarian cell line at a level greater than 3 tags/100,000. This last criterion was used to reduce the possibility of identifying genes because of their high level of expression in inflammatory cells or in the stroma of the primary tumors. Using these criteria, the genes that exhibited more than 10-fold overexpression were identified and are shown in Table 4.

[0128]Two members of the Claudin family of tight junction proteins, Claudin-3 and -4 were found among the top six differentially expressed genes and likely represent transmembrane receptors. In addition, Apolipoprotein J (ApoJ) and Apolipoprotein E (ApoE) were both overexpressed in ovarian cancer.

[0129]Of the 27 overexpressed genes shown in Table 4, ten were relatively specific for the ovary (HLA-DR, two different ESTs, GA733-1, ceruloplasmin, glutathione peroxidase-3, the secretory leukocyte protease inhibitor, ApoJ, ApoE and mesothelin) while the others were also expressed in colon tissues. In any event, it is significant that MUC1, HE4, Ep-CAM and mesothelin, four genes already known to be up-regulated in epithelial ovarian cancer, were identified in this study. This fact validates our approach as well as our set of criteria used to determine the genes differentially expressed.

[0130]Similarly, stringent criteria were used to identify genes down-regulated in ovarian tumors compared to IOSE29, HOSE-4 and ML10. Again, the fold difference was calculated by adding tag frequency for all three "normal" specimens and dividing by the total number of tags in the three ovarian tumors. A candidate was required to be expressed at a level of 12 tags/100,000 or greater in all three normal samples. The genes found elevated more than ten-fold in normal tissue compared to tumors are shown in Table 4.

TABLE-US-00004 TABLE 4 A subset of genes differentially expressed in ovarian tumors compared to non-malignant ovarian samples SEQ ID EXPRESSION^c NO. OSE Ovarian Colon Colon (TAG) TAG GENE Fold ML10 Tumors Epithelium Tumors FUNCTION up-regulated^a 103 GGGCATCTCT HLA-DR α chain 289 - ++ - - Major histocompatibility complex, class II/ antigen presentation 104 TTTGGGCCTA Cysteine-rich 123 - ++ + - LIM/double zinc finger protein 1 105 ATCGTGGCGG Claudin 4 109 - + ++ + Tight junction barrier function 106 TATTATGGTA ESTs (HOST-2) 101 - + - - Unknown 107 GCCTACCCGA Surface marker 93 - + - - Tumor Ag/Ca²+ signal 1/GA733-1/TROP2 transducer 108 CTCGCGCTGG Claudin 3 83 - + ++ + Tight junction barrier function 109 TTGCTTGCCA Ceruloplasmin 79 - + - - Secreted metalloprotein/ (ferroxidase) antioxidant 110 CCTGCTTGTC HE4 72 - ++ + - Secreted protease inhibitor 111 AGGGAGGGGC Glutathione 69 - + - - Secreted selenoprotein/ peroxidase 3 (plasma) peroxidase 112 TGTGGGAAAT Secretory leukocyte 60 - ++ - - Secreted seine protease protease inhibitor inhibitor 113 CCTGATCTGC ESTs (HOST-1) 56 - + - - Unknown 114 ACCATTGGAT Interferon-induced 49 - ++ - + Receptor for interferon transmembrane protein 1 signaling 115 AGTTTGTTAG Ep-CAM/EGP2/ 48 - + ++ + Tumor Ag/Ca²+ 1-independent TROP1/GA733-2 CAM/proliferation 116 CCTGGGAAGT Mucin 1 43 - ++ + + Tumor Ag/Type-I membrane glycoprotein 117 CAACTAATTC Apolipoprotein 39 - ++ - - Secreted chaperone/ J/clusterin cytoprotection 118 GCCTGCAGTC Serine protease 34 - ++ ++ + Transmembrane/protease inhibitor, Kunitz inhibitor type, 2 119 CGACCCCACG Apolipoprotein E 34 - ++ - - Lipoprotein particle binding, internalization and catabolism 120 TTCTGTGCTG Complement component 24 - + - - Serine protease of 1, r subcomponent complement system/ autoimmune diseases 121 CGCCGACGAT G1P3/1FI-6-16 24 - ++ + + Interferon primary response/α IFN-inducible 122 CCGCCCCCCG Lutheran blood group 17 - ++ - - Possible cell surface protein/BCAM receptor/immunoglobulin superfamily 123 GATCAGGCCA Collagen Type III, 16 - ++ - + Unknown alpha-1 124 GTGGAAGACG Mal (T cell 16 - + - - Trans-Golgi membrane differentiation protein (epithelial cells)/ protein) T-cell differentiation 125 GATGAGGAGA ESTs (Collagen Type 13 + ++ - + Unknown I, alpha-2 126 TTCCCTTCTT HLA-DPB1 13 - + - - Major histocompatibility complex, class II/antigen presentation 127 CCCCCTGCAG Mesothelin 12 - ++ - - GPI-anchored/mesothelioma and ovarian cancer antigen/ cell adhesion 128 TGCTGCCTGT Bone marrow stroma 12 - ++ - + Type II transmembrane antigen 2/BST-2 protein/pre-B-cell growth 129 TGCAGCACGA HLA-Cw 10 - ++ ++ + Major histocompatibility complex, class I/antigen presentation down-regulated^b 130 GGTTATTTTG Unknown 99 + - - - Unknown 131 TGTCATCACA Lysyl oxidase-like 2 73 + - - - Secreted/collagen and elastin crosslinker 132 AAAATAAACA Chloride 29 + - - - Ion transport intracellular channel 4 like 133 TAAAAATGTT Plasminogen activator 26 ++ - - - Serine protease inhibitor inhibitor, type 1 family/tPA inhibitor 134 GAGCTTTTGA EST 14 + - - - Unknown 135 GGCTGATGTG Glycine t-RNA 13 + - - - Protein synthesis synthetase 136 CGACGAGGAG Epithelial membrane 13 + - - - Proliferation, protein-3 differentiation, and apoptosis 137 GCCCCCAATA Galectin-1 10 ++ + - - β-galactoside binding lectin/ECM interaction and proliferation 138 GCAACTTGGA Vinexin β 10 + - - - Cell-adhesion and cytoarchitecture ^aCandidates up-regulated at least 30-fold in tumors ^bCandidates down-regulated at least 10-fold in tumors ^cExpression is defined as: -, 0-9 tags/100,000; +, 10-49 tags/100,000; ++, >49 tags/100,000

[0131]In order to validate the candidates identified by SAGE, we performed immunohistochemical analysis of thirteen cases of serous cancer of the ovary using antibodies against four of the genes identified as up-regulated in ovarian cancer (Table 5). This was particularly important since the SAGE analysis was initially performed from primary ovarian cancers, which contain a mixture of cell types. Ep-CAM exhibited diffuse, strong staining of tumor cell membranes in all thirteen tumors, without blood cell or stromal staining. Importantly, only one of six samples of the ovarian surface epithelium present in the cases showed weak focal staining, and the rest were negative. The strong immunoreactivity of all thirteen ovarian tumors confirms the validity of our approach to identify genes highly and consistently up-regulated in ovarian cancer. Similarly, ApoJ was found to be expressed in ovarian cancer cells and absent from the surface epithelium. While some expression was detected in non-tumor stroma and inflammatory cells, most of the immuno-reactivity was in tumor cells, and a majority (nine out of thirteen) of the cases showed staining. This observation represents the first report of ApoJ expression in ovarian cancer and provides a novel target for diagnosis or therapy. Claudin-3 and -4 also exhibited staining limited to the tumor component of the specimens. Most tumor cells showed strong membrane staining with weak cytoplasmic reactivity. Some tumors specimens showed decreased membrane staining with strong cytoplasmic reactivity. The normal surface epithelial component (or mesothelial cells) examined did not stain or only stained weakly with the Claudin-4 antibody, while the determination of Claudin-3 levels in normal epithelium was complicated by a low background reactivity with this antibody.

Incorporation by Reference

[0132]Throughout this application, various publications, patents, and/or patent applications are referenced in order to more fully describe the state of the art to which this invention pertains. The disclosures of these publications, patents, and/or patent applications are herein incorporated by reference in their entireties to the same extent as if each independent publication, patent, and/or patent application was specifically and individually indicated to be incorporated by reference.

Other Embodiments

[0133]It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Sequence CWU 1

1471490DNAHomo sapiens 1tccttgcccg ccgcagtcgc ctccgccgcg cgcctcctcc gccgccgcgg actccggcag 60ctttatcgcc agagtccctg aactctcgct ttctttttaa tcccctgcat cggatcaccg 120gcgtgcccca ccatgtcaga cgcagccgta gacaccagct ccgaaatcac caccaaggac 180ttaaaggaga agaaggaagt tgtggaagag gcagaaaatg gaagagacgc ccctgctaac 240gggaatgcta atgaggaaaa cggggagcag gaggctgaca atgaggtaga cgaagaagag 300gaagaaggtg gggaggaaga ggaggaggaa gaagaaggtg atggtgagga agaggatgga 360gatgaagatg aggaagctga gtcagctacg ggcaagcggg cagctgaaga tgatgaggat 420gacgatgtcg ataccaagaa gcagaagacc gacgaggatg actagacagc aaaaaaggaa 480aagttaaact 4902110PRTHomo sapiens 2Met Ser Asp Ala Ala Val Asp Thr Ser Ser Glu Ile Thr Thr Lys Asp 1 5 10 15Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Gly Arg Asp 20 25 30Ala Pro Ala Asn Gly Asn Ala Asn Glu Glu Asn Gly Glu Gln Glu Ala 35 40 45Asp Asn Glu Val Asp Glu Glu Glu Glu Glu Gly Gly Glu Glu Glu Glu 50 55 60Glu Glu Glu Glu Gly Asp Gly Glu Glu Glu Asp Gly Asp Glu Asp Glu65 70 75 80Glu Ala Glu Ser Ala Thr Gly Lys Arg Ala Ala Glu Asp Asp Glu Asp 85 90 95Asp Asp Val Asp Thr Lys Lys Gln Lys Thr Asp Glu Asp Asp 100 105 11031093DNAHomo sapiens 3ctgcaaggcg gcggcaggag aggttgtggt gctagtttct ctaagccatc cagtgccatc 60ctcgtcgctg cagcgacacc gctctcgccg ccgccatgac tgagcagatg acccttcgtg 120gcaccctcaa gggccacaac ggctgggtaa cccagatcgc tactaccccg cagttcccgg 180acatgatcct ctccgcctct cgagataaga ccatcatcat gtggaaactg accagggatg 240agaccaacta tggaattcca cagcgtgctc tgcggggtca ctcccacttt gttagtgatg 300tggttatctc ctcagatggc cagtttgccc tctcaggctc ctgggatgga accctgcgcc 360tctgggatct cacaacgggc accaccacga ggcgatttgt gggccatacc aaggatgtgc 420tgagtgtggc cttctcctct gacaaccggc agattgtctc tggatctcga gataaaacca 480tcaagctatg gaataccctg ggtgtgtgca aatacactgt ccaggatgag agccactcag 540agtgggtgtc ttgtgtccgc ttctcgccca acagcagcaa ccctatcatc gtctcctgtg 600gctgggacaa gctggtcaag gtatggaacc tggctaactg caagctgaag accaaccaca 660ttggccacac aggctatctg aacacggtga ctgtctctcc agatggatcc ctctgtgctt 720ctggaggcaa ggatggccag gccatgttat gggatctcaa cgaaggcaaa cacctttaca 780cgctagatgg tggggacatc atcaacgccc tgtgcttcag ccctaaccgc tactggctgt 840gtgctgccac aggccccagc atcaagatct gggatttaga gggaaagatc attgtagatg 900aactgaagca agaagttatc agtaccagca gcaaggcaga accaccccag tgcacttccc 960tggcctggtc tgctgatggc cagactctgt ttgctggcta cacggacaac ctggtgcgag 1020tgtggcaggt gaccattggc acacgctaga agtttatggc agagctttac aaataaaaaa 1080aaaatggctt ttc 10934317PRTHomo sapiens 4Met Thr Glu Gln Met Thr Leu Arg Gly Thr Leu Lys Gly His Asn Gly 1 5 10 15Trp Val Thr Gln Ile Ala Thr Thr Pro Gln Phe Pro Asp Met Ile Leu 20 25 30Ser Ala Ser Arg Asp Lys Thr Ile Ile Met Trp Lys Leu Thr Arg Asp 35 40 45Glu Thr Asn Tyr Gly Ile Pro Gln Arg Ala Leu Arg Gly His Ser His 50 55 60Phe Val Ser Asp Val Val Ile Ser Ser Asp Gly Gln Phe Ala Leu Ser65 70 75 80Gly Ser Trp Asp Gly Thr Leu Arg Leu Trp Asp Leu Thr Thr Gly Thr 85 90 95Thr Thr Arg Arg Phe Val Gly His Thr Lys Asp Val Leu Ser Val Ala 100 105 110Phe Ser Ser Asp Asn Arg Gln Ile Val Ser Gly Ser Arg Asp Lys Thr 115 120 125Ile Lys Leu Trp Asn Thr Leu Gly Val Cys Lys Tyr Thr Val Gln Asp 130 135 140Glu Ser His Ser Glu Trp Val Ser Cys Val Arg Phe Ser Pro Asn Ser145 150 155 160Ser Asn Pro Ile Ile Val Ser Cys Gly Trp Asp Lys Leu Val Lys Val 165 170 175Trp Asn Leu Ala Asn Cys Lys Leu Lys Thr Asn His Ile Gly His Thr 180 185 190Gly Tyr Leu Asn Thr Val Thr Val Ser Pro Asp Gly Ser Leu Cys Ala 195 200 205Ser Gly Gly Lys Asp Gly Gln Ala Met Leu Trp Asp Leu Asn Glu Gly 210 215 220Lys His Leu Tyr Thr Leu Asp Gly Gly Asp Ile Ile Asn Ala Leu Cys225 230 235 240Phe Ser Pro Asn Arg Tyr Trp Leu Cys Ala Ala Thr Gly Pro Ser Ile 245 250 255Lys Ile Trp Asp Leu Glu Gly Lys Ile Ile Val Asp Glu Leu Lys Gln 260 265 270Glu Val Ile Ser Thr Ser Ser Lys Ala Glu Pro Pro Gln Cys Thr Ser 275 280 285Leu Ala Trp Ser Ala Asp Gly Gln Thr Leu Phe Ala Gly Tyr Thr Asp 290 295 300Asn Leu Val Arg Val Trp Gln Val Thr Ile Gly Thr Arg305 310 31552402DNAHomo sapiens 5agtctccgcc gccgccgtga acatggagcc cccggacgca ccggcccagg cgcgcggggc 60cccgcggctg ctgttgctcg cagtcctgct ggcggcgcac ccagatgccc aggcggaggt 120gcgcttgtct gtacccccgc tggtggaggt gatgcgagga aagtctgtca ttctggactg 180cacccctacg ggaacccacg accattatat gctggaatgg ttccttaccg accgctcggg 240agctcgcccc cgcctagcct cggctgagat gcagggctct gagctccagg tcacaatgca 300cgacacccgg ggccgcagtc ccccatacca gctggactcc caggggcgcc tggtgctggc 360tgaggcccag gtgggcgacg agcgagacta cgtgtgcgtg gtgagggcag gggcggcagg 420cactgctgag gccactgcgc ggctcaacgt gtttgcaaag ccagaggcca ctgaggtctc 480ccccaacaaa gggacactgt ctgtgatgga ggactctgcc caggagatcg ccacctgcaa 540cagccggaac gggaacccgg cccccaagat cacgtggtat cgcaacgggc agcgcctgga 600ggtgcccgta gagatgaacc cagagggcta catgaccagc cgcacggtcc gggaggcctc 660gggcctgctc tccctcacca gcaccctcta cctgcggctc cgcaaggatg accgagacgc 720cagcttccac tgcgccgccc actacagcct gcccgagggc cgccacggcc gcctggacag 780ccccaccttc cacctcaccc tgcactatcc cacggagcac gtgcagttct gggtgggcag 840cccgtccacc ccagcaggct gggtacgcga gggtgacact gtccagctgc tctgccgggg 900ggacggcagc cccagcccgg agtatacgct tttccgcctt caggatgagc aggaggaagt 960gctgaatgtg aatctcgagg ggaacttgac cctggaggga gtgacccggg gccagagcgg 1020gacctatggc tgcagagtgg aggattacga cgcggcagat gacgtgcagc tctccaagac 1080gctggagctg cgcgtggcct atctggaccc cctggagctc agcgagggga aggtgctttc 1140cttacctcta aacagcagtg cagtcgtgaa ctgctccgtg cacggcctgc ccacccctgc 1200cctacgctgg accaaggact ccactcccct gggcgatggc cccatgctgt cgctcagttc 1260tatcaccttc gattccaatg gcacctacgt atgtgaggcc tccctgccca cagtcccggt 1320cctcagccgc acccagaact tcacgctgct ggtccaaggc tcgccagagc taaagacagc 1380ggaaatagag cccaaggcag atggcagctg gagggaagga gacgaagtca cactcatctg 1440ctctgcccgc ggccatccag accccaaact cagctggagc caattggggg gcagccccgc 1500agagccaatc cccggacggc agggttgggt gagcagctct ctgaccctga aagtgaccag 1560cgccctgagc cgcgatggca tctcctgtga agcctccaac ccccacggga acaagcgcca 1620tgtcttccac ttcggcgccg tgagccccca gacctcccag gctggagtgg ccgtcatggc 1680cgtggccgtc agcgtgggcc tcctgctcct cgtcgttgct gtcttctact gcgtgagacg 1740caaagggggc ccctgctgcc gccagcggcg ggagaagggg gctccgccgc caggggagcc 1800agggctgagc cactcggggt cggagcaacc agagcagacc ggccttctca tgggaggtgc 1860ctccggagga gccaggggtg gcagcggggg cttcggagac gagtgctgag ccaagaacct 1920cctagaggct gtccctggac ctggagctgc aggcatcaga gaaccagccc tgctcacgcc 1980atgcccgccc ccgccttccc tcttccctct tccctctccc tgcccagccc tcccttcctt 2040cctctgccgg caaggcaggg acccacagtg gctgcctgcc tccgggaggg aaggagaggg 2100agggtgggtg ggtgggaggg ggccttcctc cagggaatgt gactctccca ggccccagaa 2160tagctcctgg acccaagccc aaggcccagc ctgggacaag gctccgaggg tcggctggcc 2220ggagctattt ttacctcccg cctcccctgc tggtcccccc acctgacgtc ttgctgcaga 2280gtctgacact ggattccccc ccctcacccc gcccctggtc ccactcctgc ccccgcccta 2340cctccgcccc accccatcat ctgtggacac tggagtctgg aataaatgct gtttgtcaca 2400tc 24026628PRTHomo sapiens 6Met Glu Pro Pro Asp Ala Pro Ala Gln Ala Arg Gly Ala Pro Arg Leu 1 5 10 15Leu Leu Leu Ala Val Leu Leu Ala Ala His Pro Asp Ala Gln Ala Glu 20 25 30Val Arg Leu Ser Val Pro Pro Leu Val Glu Val Met Arg Gly Lys Ser 35 40 45Val Ile Leu Asp Cys Thr Pro Thr Gly Thr His Asp His Tyr Met Leu 50 55 60Glu Trp Phe Leu Thr Asp Arg Ser Gly Ala Arg Pro Arg Leu Ala Ser65 70 75 80Ala Glu Met Gln Gly Ser Glu Leu Gln Val Thr Met His Asp Thr Arg 85 90 95Gly Arg Ser Pro Pro Tyr Gln Leu Asp Ser Gln Gly Arg Leu Val Leu 100 105 110Ala Glu Ala Gln Val Gly Asp Glu Arg Asp Tyr Val Cys Val Val Arg 115 120 125Ala Gly Ala Ala Gly Thr Ala Glu Ala Thr Ala Arg Leu Asn Val Phe 130 135 140Ala Lys Pro Glu Ala Thr Glu Val Ser Pro Asn Lys Gly Thr Leu Ser145 150 155 160Val Met Glu Asp Ser Ala Gln Glu Ile Ala Thr Cys Asn Ser Arg Asn 165 170 175Gly Asn Pro Ala Pro Lys Ile Thr Trp Tyr Arg Asn Gly Gln Arg Leu 180 185 190Glu Val Pro Val Glu Met Asn Pro Glu Gly Tyr Met Thr Ser Arg Thr 195 200 205Val Arg Glu Ala Ser Gly Leu Leu Ser Leu Thr Ser Thr Leu Tyr Leu 210 215 220Arg Leu Arg Lys Asp Asp Arg Asp Ala Ser Phe His Cys Ala Ala His225 230 235 240Tyr Ser Leu Pro Glu Gly Arg His Gly Arg Leu Asp Ser Pro Thr Phe 245 250 255His Leu Thr Leu His Tyr Pro Thr Glu His Val Gln Phe Trp Val Gly 260 265 270Ser Pro Ser Thr Pro Ala Gly Trp Val Arg Glu Gly Asp Thr Val Gln 275 280 285Leu Leu Cys Arg Gly Asp Gly Ser Pro Ser Pro Glu Tyr Thr Leu Phe 290 295 300Arg Leu Gln Asp Glu Gln Glu Glu Val Leu Asn Val Asn Leu Glu Gly305 310 315 320Asn Leu Thr Leu Glu Gly Val Thr Arg Gly Gln Ser Gly Thr Tyr Gly 325 330 335Cys Arg Val Glu Asp Tyr Asp Ala Ala Asp Asp Val Gln Leu Ser Lys 340 345 350Thr Leu Glu Leu Arg Val Ala Tyr Leu Asp Pro Leu Glu Leu Ser Glu 355 360 365Gly Lys Val Leu Ser Leu Pro Leu Asn Ser Ser Ala Val Val Asn Cys 370 375 380Ser Val His Gly Leu Pro Thr Pro Ala Leu Arg Trp Thr Lys Asp Ser385 390 395 400Thr Pro Leu Gly Asp Gly Pro Met Leu Ser Leu Ser Ser Ile Thr Phe 405 410 415Asp Ser Asn Gly Thr Tyr Val Cys Glu Ala Ser Leu Pro Thr Val Pro 420 425 430Val Leu Ser Arg Thr Gln Asn Phe Thr Leu Leu Val Gln Gly Ser Pro 435 440 445Glu Leu Lys Thr Ala Glu Ile Glu Pro Lys Ala Asp Gly Ser Trp Arg 450 455 460Glu Gly Asp Glu Val Thr Leu Ile Cys Ser Ala Arg Gly His Pro Asp465 470 475 480Pro Lys Leu Ser Trp Ser Gln Leu Gly Gly Ser Pro Ala Glu Pro Ile 485 490 495Pro Gly Arg Gln Gly Trp Val Ser Ser Ser Leu Thr Leu Lys Val Thr 500 505 510Ser Ala Leu Ser Arg Asp Gly Ile Ser Cys Glu Ala Ser Asn Pro His 515 520 525Gly Asn Lys Arg His Val Phe His Phe Gly Ala Val Ser Pro Gln Thr 530 535 540Ser Gln Ala Gly Val Ala Val Met Ala Val Ala Val Ser Val Gly Leu545 550 555 560Leu Leu Leu Val Val Ala Val Phe Tyr Cys Val Arg Arg Lys Gly Gly 565 570 575Pro Cys Cys Arg Gln Arg Arg Glu Lys Gly Ala Pro Pro Pro Gly Glu 580 585 590Pro Gly Leu Ser His Ser Gly Ser Glu Gln Pro Glu Gln Thr Gly Leu 595 600 605Leu Met Gly Gly Ala Ser Gly Gly Ala Arg Gly Gly Ser Gly Gly Phe 610 615 620Gly Asp Glu Cys62572780DNAHomo sapiens 7gtgggcggac cgcgcggctg gaggtgtgag gatccgaacc caggggtggg gggtggaggc 60ggctcctgcg atcgaagggg acttgagact caccggccgc acgccatgag ggccctgtgg 120gtgctgggcc tctgctgcgt cctgctgacc ttcgggtcgg tcagagctga cgatgaagtt 180gatgtggatg gtacagtaga agaggatctg ggtaaaagta gagaaggatc aaggacggat 240gatgaagtag tacagagaga ggaagaagct attcagttgg atggattaaa tgcatcacaa 300ataagagaac ttagagagaa gtcggaaaag tttgccttcc aagccgaagt taacagaatg 360atgaaactta tcatcaattc attgtataaa aataaagaga ttttcctgag agaactgatt 420tcaaatgctt ctgatgcttt agataagata aggctaatat cactgactga tgaaaatgct 480ctttctggaa atgaggaact aacagtcaaa attaagtgtg ataaggagaa gaacctgctg 540catgtcacag acaccggtgt aggaatgacc agagaagagt tggttaaaaa ccttggtacc 600atagccaaat ctgggacaag cgagttttta aacaaaatga ctgaagcaca ggaagatggc 660cagtcaactt ctgaattgat tggccagttt ggtgtcggtt tctattccgc cttccttgta 720gcagataagg ttattgtcac ttcaaaacac aacaacgata cccagcacat ctgggagtct 780gactccaatg aattttctgt aattgctgac ccaagaggaa acactctagg acggggaacg 840acaattaccc ttgtcttaaa agaagaagca tctgattacc ttgaattgga tacaattaaa 900aatctcgtca aaaaatattc acagttcata aactttccta tttatgtatg gagcagcaag 960actgaaactg ttgaggagcc catggaggaa gaagaagcag ccaaagaaga gaaagaagaa 1020tctgatgatg aagctgcagt agaggaagaa gaagaagaaa agaaaccaaa gactaaaaaa 1080gttgaaaaaa ctgtctggga ctgggaactt atgaatgata tcaaaccaat atggcagaga 1140ccatcaaaag aagtagaaga agatgaatac aaagctttct acaaatcatt ttcaaaggaa 1200agtgatgacc ccatggctta tattcacttt actgctgaag gggaagttac cttcaaatca 1260attttatttg tacccacatc tgctccacgt ggtctgtttg acgaatatgg atctaaaaag 1320agcgattaca ttaagctcta tgtgcgccgt gtattcatca cagacgactt ccatgatatg 1380atgcctaaat acctcaattt tgtcaagggt gtggtggact cagatgatct ccccttgaat 1440gtttcccgcg agactcttca gcaacataaa ctgcttaagg tgattaggaa gaagcttgtt 1500cgtaaaacgc tggacatgat caagaagatt gctgatgata aatacaatga tactttttgg 1560aaagaatttg gtaccaacat caagcttggt gtgattgaag accactcgaa tcgaacacgt 1620cttgctaaac ttcttaggtt ccagtcttct catcatccaa ctgacattac tagcctagac 1680cagtatgtgg aaagaatgaa ggaaaaacaa gacaaaatct acttcatggc tgggtccagc 1740agaaaagagg ctgaatcttc tccatttgtt gagcgacttc tgaaaaaggg ctatgaagtt 1800atttacctca cagaacctgt ggatgaatac tgtattcagg cccttcccga atttgatggg 1860aagaggttcc agaatgttgc caaggaagga gtgaagttcg atgaaagtga gaaaactaag 1920gagagtcgtg aagcagttga gaaagaattt gagcctctgc tgaattggat gaaagataaa 1980gcccttaagg acaagattga aaaggctgtg gtgtctcagc gcctgacaga atctccgtgt 2040gctttggtgg ccagccagta cggatggtct ggcaacatgg agagaatcat gaaagcacaa 2100gcgtaccaaa cgggcaagga catctctaca aattactatg cgagtcagaa gaaaacattt 2160gaaattaatc ccagacaccc gctgatcaga gacatgcttc gacgaattaa ggaagatgaa 2220gatgataaaa cagttttgga tcttgctgtg gttttgtttg aaacagcaac gcttcggtca 2280gggtatcttt taccagacac taaagcatat ggagatagaa tagaaagaat gcttcgcctc 2340agtttgaaca ttgaccctga tgcaaaggtg gaagaagagc ccgaagaaga acctgaagag 2400acagcagaag acacaacaga agacacagag caagacgaag atgaagaaat ggatgtggga 2460acagatgaag aagaagaaac agcaaaggaa tctacagctg aaaaagatga attgtaaatt 2520atactctcac catttggatc ctgtgtggag agggaatgtg aaatttacat catttctttt 2580tgggagagac ttgttttgga tgccccctaa tccccttctc ccctgcactg taaaatgtgg 2640gattatgggt cacaggaaaa agtgggtttt ttagttgaat tttttttaac attcctcatg 2700aatgtaaatt tgtactattt aactgactat tcttgatgta aaatcttgtc atgtgtataa 2760aaataaaaaa gatcccaaat 27808838PRTHomo sapiens 8Val Gly Gly Pro Arg Gly Trp Arg Cys Glu Asp Pro Asn Pro Gly Val 1 5 10 15Gly Gly Gly Gly Gly Ser Cys Asp Arg Arg Gly Leu Glu Thr His Arg 20 25 30Pro His Ala Met Arg Ala Leu Trp Val Leu Gly Leu Cys Cys Val Leu 35 40 45Leu Thr Phe Gly Ser Val Arg Ala Asp Asp Glu Val Asp Val Asp Gly 50 55 60Thr Val Glu Glu Asp Leu Gly Lys Ser Arg Glu Gly Ser Arg Thr Asp65 70 75 80Asp Glu Val Val Gln Arg Glu Glu Glu Ala Ile Gln Leu Asp Gly Leu 85 90 95Asn Ala Ser Gln Ile Arg Glu Leu Arg Glu Lys Ser Glu Lys Phe Ala 100 105 110Phe Gln Ala Glu Val Asn Arg Met Met Lys Leu Ile Ile Asn Ser Leu 115 120 125Tyr Lys Asn Lys Glu Ile Phe Leu Arg Glu Leu Ile Ser Asn Ala Ser 130 135 140Asp Ala Leu Asp Lys Ile Arg Leu Ile Ser Leu Thr Asp Glu Asn Ala145 150 155 160Leu Ser Gly Asn Glu Glu Leu Thr Val Lys Ile Lys Cys Asp Lys Glu 165 170 175Lys Asn Leu Leu His Val Thr Asp Thr Gly Val Gly Met Thr Arg Glu 180 185 190Glu Leu Val Lys Asn Leu Gly Thr Ile Ala Lys Ser Gly Thr Ser Glu 195 200 205Phe Leu Asn Lys Met Thr Glu Ala Gln Glu Asp Gly Gln Ser Thr Ser 210 215 220Glu Leu Ile Gly Gln Phe Gly Val Gly Phe Tyr Ser Ala Phe Leu Val225 230 235 240Ala Asp Lys Val Ile Val Thr Ser Lys His Asn Asn Asp Thr Gln His 245

250 255Ile Trp Glu Ser Asp Ser Asn Glu Phe Ser Val Ile Ala Asp Pro Arg 260 265 270Gly Asn Thr Leu Gly Arg Gly Thr Thr Ile Thr Leu Val Leu Lys Glu 275 280 285Glu Ala Ser Asp Tyr Leu Glu Leu Asp Thr Ile Lys Asn Leu Val Lys 290 295 300Lys Tyr Ser Gln Phe Ile Asn Phe Pro Ile Tyr Val Trp Ser Ser Lys305 310 315 320Thr Glu Thr Val Glu Glu Pro Met Glu Glu Glu Glu Ala Ala Lys Glu 325 330 335Glu Lys Glu Glu Ser Asp Asp Glu Ala Ala Val Glu Glu Glu Glu Glu 340 345 350Glu Lys Lys Pro Lys Thr Lys Lys Val Glu Lys Thr Val Trp Asp Trp 355 360 365Glu Leu Met Asn Asp Ile Lys Pro Ile Trp Gln Arg Pro Ser Lys Glu 370 375 380Val Glu Glu Asp Glu Tyr Lys Ala Phe Tyr Lys Ser Phe Ser Lys Glu385 390 395 400Ser Asp Asp Pro Met Ala Tyr Ile His Phe Thr Ala Glu Gly Glu Val 405 410 415Thr Phe Lys Ser Ile Leu Phe Val Pro Thr Ser Ala Pro Arg Gly Leu 420 425 430Phe Asp Glu Tyr Gly Ser Lys Lys Ser Asp Tyr Ile Lys Leu Tyr Val 435 440 445Arg Arg Val Phe Ile Thr Asp Asp Phe His Asp Met Met Pro Lys Tyr 450 455 460Leu Asn Phe Val Lys Gly Val Val Asp Ser Asp Asp Leu Pro Leu Asn465 470 475 480Val Ser Arg Glu Thr Leu Gln Gln His Lys Leu Leu Lys Val Ile Arg 485 490 495Lys Lys Leu Val Arg Lys Thr Leu Asp Met Ile Lys Lys Ile Ala Asp 500 505 510Asp Lys Tyr Asn Asp Thr Phe Trp Lys Glu Phe Gly Thr Asn Ile Lys 515 520 525Leu Gly Val Ile Glu Asp His Ser Asn Arg Thr Arg Leu Ala Lys Leu 530 535 540Leu Arg Phe Gln Ser Ser His His Pro Thr Asp Ile Thr Ser Leu Asp545 550 555 560Gln Tyr Val Glu Arg Met Lys Glu Lys Gln Asp Lys Ile Tyr Phe Met 565 570 575Ala Gly Ser Ser Arg Lys Glu Ala Glu Ser Ser Pro Phe Val Glu Arg 580 585 590Leu Leu Lys Lys Gly Tyr Glu Val Ile Tyr Leu Thr Glu Pro Val Asp 595 600 605Glu Tyr Cys Ile Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln 610 615 620Asn Val Ala Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys625 630 635 640Glu Ser Arg Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp 645 650 655Met Lys Asp Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser 660 665 670Gln Arg Leu Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly 675 680 685Trp Ser Gly Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr 690 695 700Gly Lys Asp Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe705 710 715 720Glu Ile Asn Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile 725 730 735Lys Glu Asp Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu 740 745 750Phe Glu Thr Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys 755 760 765Ala Tyr Gly Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile 770 775 780Asp Pro Asp Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu785 790 795 800Thr Ala Glu Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu Glu 805 810 815Met Asp Val Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr 820 825 830Ala Glu Lys Asp Glu Leu 83592912DNAHomo sapiens 9cagttgcttc agcgtcccgg tgtggctgtg ccgttggtcc tgtgcggtca cttagccaag 60atgcctgagg aaacccagac ccaagaccaa ccgatggagg aggaggaggt tgagacgttc 120gcctttcagg cagaaattgc ccagttgatg tcattgatca tcaatacttt ctactcgaac 180aaagagatct ttctgagaga gctcatttca aattcatcag atgcattgga caaaatccgg 240tatgaaactt tgacagatcc cagtaaatta gactctggga aagagctgca tattaacctt 300ataccgaaca aacaagatcg aactctcact attgtggata ctggaattgg aatgaccaag 360gctgacttga tcaataacct tggtactatc gccaagtctg ggaccaaagc gttcatggaa 420gctttgcagg ctggtgcaga tatctctatg attggccagt tcggtgttgg tttttattct 480gcttatttgg ttgctgagaa agtaactgtg atcaccaaac ataacgatga tgagcagtac 540gcttgggagt cctcagcagg gggatcattc acagtgagga cagacacagg tgaacctatg 600ggtcgtggaa caaaagttat cctacacctg aaagaagacc aaactgagta cttggaggaa 660cgaagaataa aggagattgt gaagaaacat tctcagttta ttggatatcc cattactctt 720tttgtggaga aggaacgtga taaagaagta agcgatgatg aggctgaaga aaaggaagac 780aaagaagaag aaaaagaaaa agaagagaaa gagtcggaag acaaacctga aattgaagat 840gttggttctg atgaggaaga agaaaagaag gatggtgaca agaagaagaa gaagaagatt 900aaggaaaagt acatcgatca agaagagctc aacaaaacaa agcccatctg gaccagaaat 960cccgacgata ttactaatga ggagtacgga gaattctata agagcttgac caatgactgg 1020gaagatcact tggcagtgaa gcatttttca gttgaaggac agttggaatt cagagccctt 1080ctatttgtcc cacgacgtgc tccttttgat ctgtttgaaa acagaaagaa aaagaacaat 1140atcaaattgt atgtacgcag agttttcatc atggataact gtgaggagct aatccctgaa 1200tatctgaact tcattagagg ggtggtagac tcggaggatc tccctctaaa catatcccgt 1260gagatgttgc aacaaagcaa aattttgaaa gttatcagga agaatttggt caaaaaatgc 1320ttagaactct ttactgaact ggcggaagat aaagagaact acaagaaatt ctatgagcag 1380ttctctaaaa acataaagct tggaatacac gaagactctc aaaatcggaa gaagctttca 1440gagctgttaa ggtactacac atctgcctct ggtgatgaga tggtttctct caaggactac 1500tgcaccagaa tgaaggagaa ccagaaacat atctattata tcacaggtga gaccaaggac 1560caggtagcta actcagcctt tgtggaacgt cttcggaaac atggcttaga agtgatctat 1620atgattgagc ccattgatga gtactgtgtc caacagctga aggaatttga ggggaagact 1680ttagtgtcag tcaccaaaga aggcctggaa cttccagagg atgaagaaga gaaaaagaag 1740caggaagaga aaaaaacaaa gtttgagaac ctctgcaaaa tcatgaaaga catattggag 1800aaaaaagttg aaaaggtggt tgtgtcaaac cgattggtga catctccatg ctgtattgtc 1860acaagcacat atggctggac agcaaacatg gagagaatca tgaaagctca agccctaaga 1920gacaactcaa caatgggtta catggcagca aagaaacacc tggagataaa ccctgaccat 1980tccattattg agaccttaag gcaaaaggca gaggctgata agaacgacaa gtctgtgaag 2040gatctggtca tcttgcttta tgaaactgcg ctcctgtctt ctggcttcag tctggaagat 2100ccccagacac atgctaacag gatctacagg atgatcaaac ttggtctggg tattgatgaa 2160gatgacccta ctgctgatga taccagtgct gctgtaactg aagaaatgcc accccttgaa 2220ggagatgacg acacatcacg catggaagaa gtagactaat ctctggctga gggatgactt 2280acctgttcag tactctacaa ttcctctgat aatatatttt caaggatgtt tttctttatt 2340tttgttaata ttaaaaagtc tgtatggcat gacaactact ttaaggggaa gataagattt 2400ctgtctacta agtgatgctg tgatacctta ggcactaaag cagagctagt aatgcttttt 2460gagtttcatg ttggttcttt cacagatggg gtaacgtgca ctgtaagacg tatgtaacat 2520gatgttaact ttgtgtggtc taaagtgttt agctgtcaag ccggatgcct aagtagacca 2580aatcttgtta ttgaagtgtt ctgagctgta tcttgatgtt tagaaaagta ttcgttacat 2640cttgtaggat ctactttttg aacttttcat tccctgtagt tgacaattct gcatgtacta 2700gtcctctaga aataggttaa actgaagcaa cttgatggaa ggatctctcc acagggcttg 2760ttttccaaag aaaagtattg tttggaggag caaagttaaa agcctaccta agcatatcgt 2820aaagctgttc aaatactcga gcccagtctt gtggatggaa atgtagtgct cgagtcacat 2880tctgcttaaa gttgtaacaa atacagatga gt 291210732PRTHomo sapiens 10Met Pro Glu Glu Thr Gln Thr Gln Asp Gln Pro Met Glu Glu Glu Glu 1 5 10 15Val Glu Thr Phe Ala Phe Gln Ala Glu Ile Ala Gln Leu Met Ser Leu 20 25 30Ile Ile Asn Thr Phe Tyr Ser Asn Lys Glu Ile Phe Leu Arg Glu Leu 35 40 45Ile Ser Asn Ser Ser Asp Ala Leu Asp Lys Ile Arg Tyr Glu Thr Leu 50 55 60Thr Asp Pro Ser Lys Leu Asp Ser Gly Lys Glu Leu His Ile Asn Leu65 70 75 80Ile Pro Asn Lys Gln Asp Arg Thr Leu Thr Ile Val Asp Thr Gly Ile 85 90 95Gly Met Thr Lys Ala Asp Leu Ile Asn Asn Leu Gly Thr Ile Ala Lys 100 105 110Ser Gly Thr Lys Ala Phe Met Glu Ala Leu Gln Ala Gly Ala Asp Ile 115 120 125Ser Met Ile Gly Gln Phe Gly Val Gly Phe Tyr Ser Ala Tyr Leu Val 130 135 140Ala Glu Lys Val Thr Val Ile Thr Lys His Asn Asp Asp Glu Gln Tyr145 150 155 160Ala Trp Glu Ser Ser Ala Gly Gly Ser Phe Thr Val Arg Thr Asp Thr 165 170 175Gly Glu Pro Met Gly Arg Gly Thr Lys Val Ile Leu His Leu Lys Glu 180 185 190Asp Gln Thr Glu Tyr Leu Glu Glu Arg Arg Ile Lys Glu Ile Val Lys 195 200 205Lys His Ser Gln Phe Ile Gly Tyr Pro Ile Thr Leu Phe Val Glu Lys 210 215 220Glu Arg Asp Lys Glu Val Ser Asp Asp Glu Ala Glu Glu Lys Glu Asp225 230 235 240Lys Glu Glu Glu Lys Glu Lys Glu Glu Lys Glu Ser Glu Asp Lys Pro 245 250 255Glu Ile Glu Asp Val Gly Ser Asp Glu Glu Glu Glu Lys Lys Asp Gly 260 265 270Asp Lys Lys Lys Lys Lys Lys Ile Lys Glu Lys Tyr Ile Asp Gln Glu 275 280 285Glu Leu Asn Lys Thr Lys Pro Ile Trp Thr Arg Asn Pro Asp Asp Ile 290 295 300Thr Asn Glu Glu Tyr Gly Glu Phe Tyr Lys Ser Leu Thr Asn Asp Trp305 310 315 320Glu Asp His Leu Ala Val Lys His Phe Ser Val Glu Gly Gln Leu Glu 325 330 335Phe Arg Ala Leu Leu Phe Val Pro Arg Arg Ala Pro Phe Asp Leu Phe 340 345 350Glu Asn Arg Lys Lys Lys Asn Asn Ile Lys Leu Tyr Val Arg Arg Val 355 360 365Phe Ile Met Asp Asn Cys Glu Glu Leu Ile Pro Glu Tyr Leu Asn Phe 370 375 380Ile Arg Gly Val Val Asp Ser Glu Asp Leu Pro Leu Asn Ile Ser Arg385 390 395 400Glu Met Leu Gln Gln Ser Lys Ile Leu Lys Val Ile Arg Lys Asn Leu 405 410 415Val Lys Lys Cys Leu Glu Leu Phe Thr Glu Leu Ala Glu Asp Lys Glu 420 425 430Asn Tyr Lys Lys Phe Tyr Glu Gln Phe Ser Lys Asn Ile Lys Leu Gly 435 440 445Ile His Glu Asp Ser Gln Asn Arg Lys Lys Leu Ser Glu Leu Leu Arg 450 455 460Tyr Tyr Thr Ser Ala Ser Gly Asp Glu Met Val Ser Leu Lys Asp Tyr465 470 475 480Cys Thr Arg Met Lys Glu Asn Gln Lys His Ile Tyr Tyr Ile Thr Gly 485 490 495Glu Thr Lys Asp Gln Val Ala Asn Ser Ala Phe Val Glu Arg Leu Arg 500 505 510Lys His Gly Leu Glu Val Ile Tyr Met Ile Glu Pro Ile Asp Glu Tyr 515 520 525Cys Val Gln Gln Leu Lys Glu Phe Glu Gly Lys Thr Leu Val Ser Val 530 535 540Thr Lys Glu Gly Leu Glu Leu Pro Glu Asp Glu Glu Glu Lys Lys Lys545 550 555 560Gln Glu Glu Lys Lys Thr Lys Phe Glu Asn Leu Cys Lys Ile Met Lys 565 570 575Asp Ile Leu Glu Lys Lys Val Glu Lys Val Val Val Ser Asn Arg Leu 580 585 590Val Thr Ser Pro Cys Cys Ile Val Thr Ser Thr Tyr Gly Trp Thr Ala 595 600 605Asn Met Glu Arg Ile Met Lys Ala Gln Ala Leu Arg Asp Asn Ser Thr 610 615 620Met Gly Tyr Met Ala Ala Lys Lys His Leu Glu Ile Asn Pro Asp His625 630 635 640Ser Ile Ile Glu Thr Leu Arg Gln Lys Ala Glu Ala Asp Lys Asn Asp 645 650 655Lys Ser Val Lys Asp Leu Val Ile Leu Leu Tyr Glu Thr Ala Leu Leu 660 665 670Ser Ser Gly Phe Ser Leu Glu Asp Pro Gln Thr His Ala Asn Arg Ile 675 680 685Tyr Arg Met Ile Lys Leu Gly Leu Gly Ile Asp Glu Asp Asp Pro Thr 690 695 700Ala Asp Asp Thr Ser Ala Ala Val Thr Glu Glu Met Pro Pro Leu Glu705 710 715 720Gly Asp Asp Asp Thr Ser Arg Met Glu Glu Val Asp 725 730112227DNAHomo sapiens 11gacgacctgt ctcgccgagc gcacgcttgc cgccgccccg cagaaatgct tcggttaccc 60acagtctttc gccagatgag accggtgtcc agggtactgg ctcctcatct cactcgggct 120tatgccaaag atgtaaaatt tggtgcagat gcccgagcct taatgcttca aggtgtagac 180cttttagccg atgctgtggc cgttacaatg gggccaaagg gaagaacagt gattattgag 240cagagttggg gaagtcccaa agtaacaaaa gatggtgtga ctgttgcaaa gtcaattgac 300ttaaaagata aatacaagaa cattggagct aaacttgttc aagatgttgc caataacaca 360aatgaagaag ctggggatgg cactaccact gctactgtac tggcacgctc tatagccaag 420gaaggcttcg agaagattag caaaggtgct aatccagtgg aaatcaggag aggtgtgatg 480ttagctgttg atgctgtaat tgctgaactt aaaaagcagt ctaaacctgt gaccacccct 540gaagaaattg cacaggttgc tacgatttct gcaaacggag acaaagaaat tggcaatatc 600atctctgatg caatgaaaaa agttggaaga aagggtgtca tcacagtaaa ggatggaaaa 660acactgaatg atgaattaga aattattgaa ggcatgaagt ttgatcgagg ctatatttct 720ccatacttta ttaatacatc aaaaggtcag aaatgtgaat tccaggatgc ctatgttctg 780ttgagtgaaa agaaaatttc tagtatccag tccattgtac ctgctcttga aattgccaat 840gctcaccgta agcctttggt cataatcgct gaagatgttg atggagaagc tctaagtaca 900ctcgtcttga ataggctaaa ggttggtctt caggttgtgg cagtcaaggc tccagggttt 960ggtgacaata gaaagaacca gcttaaagat atggctattg ctactggtgg tgcagtgttt 1020ggagaagagg gattgaccct gaatcttgaa gacgttcagc ctcatgactt aggaaaagtt 1080ggagaggtca ttgtgaccaa agacgatgcc atgctcttaa aaggaaaagg tgacaaggct 1140caaattgaaa aacgtattca agaaatcatt gagcagttag atgtcacaac tagtgaatat 1200gaaaaggaaa aactgaatga acggcttgca aaactttcag atggagtggc tgtgctgaag 1260gttggtggga caagtgatgt tgaagtgaat gaaaagaaag acagagttac agatgccctt 1320aatgctacaa gagctgctgt tgaagaaggc attgttttgg gagggggttg tgccctcctt 1380cgatgcattc cagccttgga ctcattgact ccagctaatg aagatcaaaa aattggtata 1440gaaattatta aaagaacact caaaattcca gcaatgacca ttgctaagaa tgcaggtgtt 1500gaaggatctt tgatagttga gaaaattatg caaagttcct cagaagttgg ttatgatgct 1560atggctggag attttgtgaa tatggtggaa aaaggaatca ttgacccaac aaaggttgtg 1620agaactgctt tattggatgc tgctggtgtg gcctctctgt taactacagc agaagttgta 1680gtcacagaaa ttcctaaaga agagaaggac cctggaatgg gtgcaatggg tggaatggga 1740ggtggtatgg gaggtggcat gttctaactc ctagactagt gctttacctt tattaatgaa 1800ctgtgacagg aagcccaagg cagtgttcct caccaataac ttcagagaag tcagttggag 1860aaaatgaaga aaaaggctgg ctgaaaatca ctataaccat cagttactgg tttcagttga 1920caaaatatat aatggtttac tgctgtcatt gtccatgcct acagataatt tattttgtat 1980ttttgaataa aaaacatttg tacattcctg atactgggta caagagccat gtaccagtgt 2040actgctttca acttaaatca ctgaggcatt tttactacta ttctgttaaa atcaggattt 2100tagtgcttgc caccaccaga tgagaagtta agcagccttt ctgtggagag tgagaataat 2160tgtgtacaaa gtagagaagt atccaattat gtgacaacct ttgtgtaata aaaatttgtt 2220taaagtt 222712573PRTHomo sapiens 12Met Leu Arg Leu Pro Thr Val Phe Arg Gln Met Arg Pro Val Ser Arg 1 5 10 15Val Leu Ala Pro His Leu Thr Arg Ala Tyr Ala Lys Asp Val Lys Phe 20 25 30Gly Ala Asp Ala Arg Ala Leu Met Leu Gln Gly Val Asp Leu Leu Ala 35 40 45Asp Ala Val Ala Val Thr Met Gly Pro Lys Gly Arg Thr Val Ile Ile 50 55 60Glu Gln Ser Trp Gly Ser Pro Lys Val Thr Lys Asp Gly Val Thr Val65 70 75 80Ala Lys Ser Ile Asp Leu Lys Asp Lys Tyr Lys Asn Ile Gly Ala Lys 85 90 95Leu Val Gln Asp Val Ala Asn Asn Thr Asn Glu Glu Ala Gly Asp Gly 100 105 110Thr Thr Thr Ala Thr Val Leu Ala Arg Ser Ile Ala Lys Glu Gly Phe 115 120 125Glu Lys Ile Ser Lys Gly Ala Asn Pro Val Glu Ile Arg Arg Gly Val 130 135 140Met Leu Ala Val Asp Ala Val Ile Ala Glu Leu Lys Lys Gln Ser Lys145 150 155 160Pro Val Thr Thr Pro Glu Glu Ile Ala Gln Val Ala Thr Ile Ser Ala 165 170 175Asn Gly Asp Lys Glu Ile Gly Asn Ile Ile Ser Asp Ala Met Lys Lys 180 185 190Val Gly Arg Lys Gly Val Ile Thr Val Lys Asp Gly Lys Thr Leu Asn 195 200 205Asp Glu Leu Glu Ile Ile Glu Gly Met Lys Phe Asp Arg Gly Tyr Ile 210 215 220Ser Pro Tyr Phe Ile Asn Thr Ser Lys Gly Gln Lys Cys Glu Phe Gln225 230 235 240Asp Ala Tyr Val Leu Leu Ser Glu Lys Lys Ile Ser Ser Ile Gln Ser 245 250 255Ile Val Pro Ala Leu Glu Ile Ala Asn Ala His Arg Lys Pro Leu Val 260 265 270Ile Ile Ala Glu Asp Val Asp Gly Glu Ala Leu Ser Thr Leu Val Leu 275 280 285Asn Arg

Leu Lys Val Gly Leu Gln Val Val Ala Val Lys Ala Pro Gly 290 295 300Phe Gly Asp Asn Arg Lys Asn Gln Leu Lys Asp Met Ala Ile Ala Thr305 310 315 320Gly Gly Ala Val Phe Gly Glu Glu Gly Leu Thr Leu Asn Leu Glu Asp 325 330 335Val Gln Pro His Asp Leu Gly Lys Val Gly Glu Val Ile Val Thr Lys 340 345 350Asp Asp Ala Met Leu Leu Lys Gly Lys Gly Asp Lys Ala Gln Ile Glu 355 360 365Lys Arg Ile Gln Glu Ile Ile Glu Gln Leu Asp Val Thr Thr Ser Glu 370 375 380Tyr Glu Lys Glu Lys Leu Asn Glu Arg Leu Ala Lys Leu Ser Asp Gly385 390 395 400Val Ala Val Leu Lys Val Gly Gly Thr Ser Asp Val Glu Val Asn Glu 405 410 415Lys Lys Asp Arg Val Thr Asp Ala Leu Asn Ala Thr Arg Ala Ala Val 420 425 430Glu Glu Gly Ile Val Leu Gly Gly Gly Cys Ala Leu Leu Arg Cys Ile 435 440 445Pro Ala Leu Asp Ser Leu Thr Pro Ala Asn Glu Asp Gln Lys Ile Gly 450 455 460Ile Glu Ile Ile Lys Arg Thr Leu Lys Ile Pro Ala Met Thr Ile Ala465 470 475 480Lys Asn Ala Gly Val Glu Gly Ser Leu Ile Val Glu Lys Ile Met Gln 485 490 495Ser Ser Ser Glu Val Gly Tyr Asp Ala Met Ala Gly Asp Phe Val Asn 500 505 510Met Val Glu Lys Gly Ile Ile Asp Pro Thr Lys Val Val Arg Thr Ala 515 520 525Leu Leu Asp Ala Ala Gly Val Ala Ser Leu Leu Thr Thr Ala Glu Val 530 535 540Val Val Thr Glu Ile Pro Lys Glu Glu Lys Asp Pro Gly Met Gly Ala545 550 555 560Met Gly Gly Met Gly Gly Gly Met Gly Gly Gly Met Phe 565 570132376DNAHomo sapiens 13gaggaggagt ggggaccggg cggggggtgg aggaagaggc ctcgcgcaga ggagggagca 60attgaatttc aaacacaaac aactcgacga gcgcgcaccc accgcgccgg agccttgccc 120cgatccgcgc ccgccccgtc cgtgcggcgc gcgggcggag acgccgtggc cgcgccggag 180ctcgggccgg gggccaccat cgaggcgggg gccgcgcgag ggccggagcg gagcggcgcc 240gccaccgccg cacgcgcaaa cttgggctcg cgcttcccgg cccggcgcgg agcccggggc 300gcccggagcc ccgccatgtc gcgatccaac cggcagaagg agtacaaatg cggggacctg 360gtgttcgcca agatgaaggg ctacccacac tggccggccc ggattgacga gatgcctgag 420gctgccgtga aatcaacagc caacaaatac caagtctttt ttttcgggac ccacgagacg 480gcattcctgg gccccaaaga cctcttccct tacgaggaat ccaaggagaa gtttggcaag 540cccaacaaga ggaaagggtt cagcgagggg ctgtgggaga tcgagaacaa ccctactgtc 600aaggcttccg gctatcagtc ctcccagaaa aagagctgtg tggaagagcc tgaaccagag 660cccgaagctg cagagggtga cggtgataag aaggggaatg cagagggcag cagcgacgag 720gaagggaagc tggtcattga tgagccagcc aaggagaaga acgagaaagg agcgttgaag 780aggagagcag gggacttgct ggaggactct cctaaacgtc ccaaggaggc agaaaaccct 840gaaggagagg agaaggaggc agccaccttg gaggttgaga ggccccttcc tatggaggtg 900gaaaagaata gcaccccctc tgagcccggc tctggccggg ggcctcccca agaggaagaa 960gaagaggagg atgaagagga agaggctacc aaggaagatg ctgaggcccc aggcatcaga 1020gatcatgaga gcctgtagcc accaatgttt caagaggagc ccccaccctg ttcctgctgc 1080tgtctgggtg ctactgggga aactggccat ggcctgcaaa ctgggaaccc ctttcccacc 1140ccaacctgct ctcctcttct actcactttt cccactccaa gcccagccca tggagattga 1200cctggatggg gcaggccacc tggctctcac ctctaggtcc ccatactcct atgatctgag 1260tcagagccat gtcttctccc tggaatgagt tgaggccact gtgttccttc cgcttggagc 1320tattttccag gcttctgctg gggcctggga caactgctcc cacctcctga cacccttctc 1380ccactctcct aggcattctg gacctctggg ttgggatcag gggtaggaat ggaaggatgg 1440agcatcaaca gcagggtggg cttgtggggc ctgggagggg caatcctcaa atgcggggtg 1500ggggcagcac aggagggcgg cctccttctg agctcctgtc ccctgctaca cctattatcc 1560cagctgccta gattcaggga aagtgggaca gcttgtaggg gaggggctcc tttccataaa 1620tccttgatga ttgacaacac ccatttttcc ttttgccgac cccaagagtt ttgggagttg 1680tagttaatca tcaagagaat ttggggcttc caagttgttc gggccaagga cctgagacct 1740gaagggttga ctttacccat ttgggtggga gtgttgagca tctgtccccc tttagatctc 1800tgaagccaca aataggatgc ttgggaagac tcctagctgt cctttttcct ctccacacag 1860tgctcaaggc cagcttatag tcatatatat cacccagaca taaaggaaaa gacacatttt 1920ttaggaaatg tttttaataa aagaaaatta caaaaaaaaa ttttaaagac ccctaaccct 1980ttgtgtgctc tccattctgc tccttcccca tcgttgcccc catttctgag gtgcactggg 2040aggctcccct tctatttggg gcttgatgac tttctttttg tagctggggc tttgatgttc 2100cttccagtgt catttctcat ccacataccc tgacctggcc ccctcagtgt tgtcaccaga 2160tctgatttgt aacccactga gaggacagag agaaataagt gccctctccc accctcttcc 2220tactggtctc tctatgcctc tctacagtct cgtctctttt accctggccc ctctcccttg 2280ggctctgatg aaaaattgct gactgtagct ttggaagttt agctctgaga accgtagatg 2340atttcagttc taggaaaata aaacccgttg attact 237614240PRTHomo sapiens 14Met Ser Arg Ser Asn Arg Gln Lys Glu Tyr Lys Cys Gly Asp Leu Val 1 5 10 15Phe Ala Lys Met Lys Gly Tyr Pro His Trp Pro Ala Arg Ile Asp Glu 20 25 30Met Pro Glu Ala Ala Val Lys Ser Thr Ala Asn Lys Tyr Gln Val Phe 35 40 45Phe Phe Gly Thr His Glu Thr Ala Phe Leu Gly Pro Lys Asp Leu Phe 50 55 60Pro Tyr Glu Glu Ser Lys Glu Lys Phe Gly Lys Pro Asn Lys Arg Lys65 70 75 80Gly Phe Ser Glu Gly Leu Trp Glu Ile Glu Asn Asn Pro Thr Val Lys 85 90 95Ala Ser Gly Tyr Gln Ser Ser Gln Lys Lys Ser Cys Val Glu Glu Pro 100 105 110Glu Pro Glu Pro Glu Ala Ala Glu Gly Asp Gly Asp Lys Lys Gly Asn 115 120 125Ala Glu Gly Ser Ser Asp Glu Glu Gly Lys Leu Val Ile Asp Glu Pro 130 135 140Ala Lys Glu Lys Asn Glu Lys Gly Ala Leu Lys Arg Arg Ala Gly Asp145 150 155 160Leu Leu Glu Asp Ser Pro Lys Arg Pro Lys Glu Ala Glu Asn Pro Glu 165 170 175Gly Glu Glu Lys Glu Ala Ala Thr Leu Glu Val Glu Arg Pro Leu Pro 180 185 190Met Glu Val Glu Lys Asn Ser Thr Pro Ser Glu Pro Gly Ser Gly Arg 195 200 205Gly Pro Pro Gln Glu Glu Glu Glu Glu Glu Asp Glu Glu Glu Glu Ala 210 215 220Thr Lys Glu Asp Ala Glu Ala Pro Gly Ile Arg Asp His Glu Ser Leu225 230 235 240153689DNAHomo sapiens 15aagatctcat aaaatctatg ctgaggaatg agcgacagtt caaggaggag aagcttgcag 60agcagctcaa gcaagctgag gagctcaggc aatataaagt cctggttcac gctcaggaac 120gagagctgac ccagttaagg gagaagttgc gggaagggag agatgcctcc cgctcattga 180atgagcatct ccaggccctc ctcactccgg atgagccgga caagtcccag gggcaggacc 240tccaagaaca gctggctgag gggtgtagac tggcacagca ccttgtccaa aagctcagcc 300cagaaaatga caacgatgac gatgaagatg ttcaagttga ggtggctgag aaagtgcaga 360aatcgtctgc ccccagggag atgcagaagg ctgaagaaaa ggaagtccct gaggactcac 420tggaggaatg tgccatcact tgttcaaata gccatggccc ttatgactcc aaccagccac 480ataggaaaac caaaatcaca tttgaggaag acaaagtcga ctcaactctc attggctcat 540cctctcatgt tgaatgggag gatgctgtac acattattcc agaaaatgaa agtgatgatg 600aggaagagga agaaaaagga ccagtgtctc ccaggaatct gcaggagtct gaagaggagg 660aagtccccca ggagtcctgg gatgaaggtt attcgactct ctcaattcct cctgaaatgt 720tggcctcgta caagtcttac agcagcacat ttcactcatt agaggaacag caagtctgca 780tggctgttga cataggcaga catcggtggg atcaagtgaa aaaggaggac cacgaggcaa 840caggtcccag gctcagcaga gagctgctgg atgagaaagg gcctgaagtc ttgcaggact 900cactggatag atgttattca actccttcag gttgtcttga actgactgac tcatgccagc 960cctacagaag tgccttttac gtattggagc aacagcgtgt tggcttggct gttaacatgg 1020atgaaattga aaagtaccaa gaagtggaag aagaccaaga cccatcatgc cccaggctca 1080gcagggagct gctggatgag aaagagcctg aagtcttgca ggactcactg ggtagatgtt 1140attcgactcc ttcaggttat cttgaactgc ctgacttagg ccagccctac agcagtgctg 1200tttactcatt ggaggaacag taccttggct tggctcttga cgtggacaga attaaaaagg 1260accaagaaga ggaagaagac caaggcccac catgccccag gctcagcagg gagctgctgg 1320aggtagtaga gcctgaagtc ttgcaggact cactggatag atgttattca actccttcca 1380gttgtcttga acagcctgac tcctgccagc cctatggaag ttccttttat gcattggagg 1440aaaagcatgt tggcttttct cttgacgtgg gagaaattga aaagaagggg aaggggaaga 1500aaagaagggg aagaagatca aagaaggaaa gaagaagggg aagaaaagaa ggggaagaag 1560atcaaaaccc accatgcccc aggctcagca gggagctgct ggatgagaaa gggcctgaag 1620tcttgcagga ctcactggat agatgttatt caactccttc aggttgtctt gaactgactg 1680actcatgcca gccctacaga agtgcctttt acatattgga gcaacagcgt gttggcttgg 1740ctgttgacat ggatgaaatt gaaaagtacc aagaagtgga agaagaccaa gacccatcat 1800gccccaggct cagcggggag ctgttggatg agaaagagcc tgaagtcttg caggagtcac 1860tggatagatg ctattcaact ccttcaggtt gtcttgaact gactgactca tgccagccct 1920acagaagtgc cttttacata ttggagcaac agcgtgttgg cttggctgtt gacatggatg 1980aaattgaaaa gtaccaagaa gtggaagaag accaagaccc atcatgcccc aggctcagca 2040gggagctgct ggatgagaaa gagcctgaag tcttgcagga ctcactgggt agatgttatt 2100cgactccttc aggttatctt gaactgcctg acttaggcca gccctacagc agtgctgttt 2160actcattgga ggaacagtac cttggcttgg ctcttgacgt ggacagaatt aaaaaggacc 2220aagaagagga agaagaccaa ggcccaccat gccccaggct cagcagggag ctgctggagg 2280tagtagagcc tgaagtcttg caggactcac tggatagatg ttattcaact ccttccagtt 2340gtcttgaaca gcctgactcc tgccagccct atggaagttc cttttatgca ttggaggaaa 2400aacatgttgg cttttctctt gacgtgggag aaattgaaaa gaaggggaag gggaagaaaa 2460gaaggggaag aagatcaaag aaggaaagaa gaaggggaag aaaagaaggg gaagaagatc 2520aaaacccacc atgccccagg ctcaacagca tgctgatgga agtggaagag cctgaagtct 2580tgcaggactc actggatata tgttattcga ctccgtcaat gtactttgaa ctacctgact 2640cattccagca ctacagaagt gtgttttact catttgagga agagcatatc agcttcgccc 2700tttacgtgga caataggttt tttactttga cggtgacaag tctccacctg gtgttccaga 2760tgggagtcat attcccacaa taagcagccc ttactaagcc gagaggtgtc attcctgcag 2820gcaggaccta taggcacgtg aagatttgaa tgaaagtaca gttccatttg gaagcccaga 2880cataggatgg gtcagtgggc atggctctat tcctattctc aaaccatgcc agtggcaacc 2940tgtgctcagt ctgaagacaa tggacccacg ttaggtgtga cacgttcaca taactgtgca 3000gcacatgccg ggagtgatca gtcagacatt ttaatttgaa ccacgtatct ctgggtagct 3060acaaaattcc tcagggatgt cattttgcag gcatgtctct gagcttctat acctgctcaa 3120ggtcattgtc atctttgtgt ttagctcatc caaaggtgtt accctggttt caatgaacct 3180aacctcattc tttgtgtctt cagtgttggc ttgttttagc tgatccatct gtaacacagg 3240agggatcctt ggctgaggat tgtatttcag aaccaccaac tgctcttgac aattgttaac 3300ccgctaggct cctttggtta gagaagccac agtccttcag cctccaattg gtgtcagtac 3360ttaggaagac cacagctaga tggacaaaca gcattgggag gccttagccc tgctcctctc 3420aattccatcc tgtagagaac aggagtcagg agccgctggc aggagacagc atgtcaccca 3480ggactctgcc ggtgcagaat atgagcaatg ccatgttctt gcagaaaacg cttaacctga 3540gtttcatagg aggtaatcac cagacaactg cagaatgtag aacactgagc aggacaactg 3600acctgtctcc ttcacatagt ccatatcacc acaaatcaca caacaaaaag gagaagagat 3660attttcggtt gaaaaaaagt aaaaagata 368916921PRTHomo sapiens 16Met Leu Arg Asn Glu Arg Gln Phe Lys Glu Glu Lys Leu Ala Glu Gln 1 5 10 15Leu Lys Gln Ala Glu Glu Leu Arg Gln Tyr Lys Val Leu Val His Ala 20 25 30Gln Glu Arg Glu Leu Thr Gln Leu Arg Glu Lys Leu Arg Glu Gly Arg 35 40 45Asp Ala Ser Arg Ser Leu Asn Glu His Leu Gln Ala Leu Leu Thr Pro 50 55 60Asp Glu Pro Asp Lys Ser Gln Gly Gln Asp Leu Gln Glu Gln Leu Ala65 70 75 80Glu Gly Cys Arg Leu Ala Gln His Leu Val Gln Lys Leu Ser Pro Glu 85 90 95Asn Asp Asn Asp Asp Asp Glu Asp Val Gln Val Glu Val Ala Glu Lys 100 105 110Val Gln Lys Ser Ser Ala Pro Arg Glu Met Gln Lys Ala Glu Glu Lys 115 120 125Glu Val Pro Glu Asp Ser Leu Glu Glu Cys Ala Ile Thr Cys Ser Asn 130 135 140Ser His Gly Pro Tyr Asp Ser Asn Gln Pro His Arg Lys Thr Lys Ile145 150 155 160Thr Phe Glu Glu Asp Lys Val Asp Ser Thr Leu Ile Gly Ser Ser Ser 165 170 175His Val Glu Trp Glu Asp Ala Val His Ile Ile Pro Glu Asn Glu Ser 180 185 190Asp Asp Glu Glu Glu Glu Glu Lys Gly Pro Val Ser Pro Arg Asn Leu 195 200 205Gln Glu Ser Glu Glu Glu Glu Val Pro Gln Glu Ser Trp Asp Glu Gly 210 215 220Tyr Ser Thr Leu Ser Ile Pro Pro Glu Met Leu Ala Ser Tyr Lys Ser225 230 235 240Tyr Ser Ser Thr Phe His Ser Leu Glu Glu Gln Gln Val Cys Met Ala 245 250 255Val Asp Ile Gly Arg His Arg Trp Asp Gln Val Lys Lys Glu Asp His 260 265 270Glu Ala Thr Gly Pro Arg Leu Ser Arg Glu Leu Leu Asp Glu Lys Gly 275 280 285Pro Glu Val Leu Gln Asp Ser Leu Asp Arg Cys Tyr Ser Thr Pro Ser 290 295 300Gly Cys Leu Glu Leu Thr Asp Ser Cys Gln Pro Tyr Arg Ser Ala Phe305 310 315 320Tyr Val Leu Glu Gln Gln Arg Val Gly Leu Ala Val Asn Met Asp Glu 325 330 335Ile Glu Lys Tyr Gln Glu Val Glu Glu Asp Gln Asp Pro Ser Cys Pro 340 345 350Arg Leu Ser Arg Glu Leu Leu Asp Glu Lys Glu Pro Glu Val Leu Gln 355 360 365Asp Ser Leu Gly Arg Cys Tyr Ser Thr Pro Ser Gly Tyr Leu Glu Leu 370 375 380Pro Asp Leu Gly Gln Pro Tyr Ser Ser Ala Val Tyr Ser Leu Glu Glu385 390 395 400Gln Tyr Leu Gly Leu Ala Leu Asp Val Asp Arg Ile Lys Lys Asp Gln 405 410 415Glu Glu Glu Glu Asp Gln Gly Pro Pro Cys Pro Arg Leu Ser Arg Glu 420 425 430Leu Leu Glu Val Val Glu Pro Glu Val Leu Gln Asp Ser Leu Asp Arg 435 440 445Cys Tyr Ser Thr Pro Ser Ser Cys Leu Glu Gln Pro Asp Ser Cys Gln 450 455 460Pro Tyr Gly Ser Ser Phe Tyr Ala Leu Glu Glu Lys His Val Gly Phe465 470 475 480Ser Leu Asp Val Gly Glu Ile Glu Lys Lys Gly Lys Gly Lys Lys Arg 485 490 495Arg Gly Arg Arg Ser Lys Lys Glu Arg Arg Arg Gly Arg Lys Glu Gly 500 505 510Glu Glu Asp Gln Asn Pro Pro Cys Pro Arg Leu Ser Arg Glu Leu Leu 515 520 525Asp Glu Lys Gly Pro Glu Val Leu Gln Asp Ser Leu Asp Arg Cys Tyr 530 535 540Ser Thr Pro Ser Gly Cys Leu Glu Leu Thr Asp Ser Cys Gln Pro Tyr545 550 555 560Arg Ser Ala Phe Tyr Ile Leu Glu Gln Gln Arg Val Gly Leu Ala Val 565 570 575Asp Met Asp Glu Ile Glu Lys Tyr Gln Glu Val Glu Glu Asp Gln Asp 580 585 590Pro Ser Cys Pro Arg Leu Ser Gly Glu Leu Leu Asp Glu Lys Glu Pro 595 600 605Glu Val Leu Gln Glu Ser Leu Asp Arg Cys Tyr Ser Thr Pro Ser Gly 610 615 620Cys Leu Glu Leu Thr Asp Ser Cys Gln Pro Tyr Arg Ser Ala Phe Tyr625 630 635 640Ile Leu Glu Gln Gln Arg Val Gly Leu Ala Val Asp Met Asp Glu Ile 645 650 655Glu Lys Tyr Gln Glu Val Glu Glu Asp Gln Asp Pro Ser Cys Pro Arg 660 665 670Leu Ser Arg Glu Leu Leu Asp Glu Lys Glu Pro Glu Val Leu Gln Asp 675 680 685Ser Leu Gly Arg Cys Tyr Ser Thr Pro Ser Gly Tyr Leu Glu Leu Pro 690 695 700Asp Leu Gly Gln Pro Tyr Ser Ser Ala Val Tyr Ser Leu Glu Glu Gln705 710 715 720Tyr Leu Gly Leu Ala Leu Asp Val Asp Arg Ile Lys Lys Asp Gln Glu 725 730 735Glu Glu Glu Asp Gln Gly Pro Pro Cys Pro Arg Leu Ser Arg Glu Leu 740 745 750Leu Glu Val Val Glu Pro Glu Val Leu Gln Asp Ser Leu Asp Arg Cys 755 760 765Tyr Ser Thr Pro Ser Ser Cys Leu Glu Gln Pro Asp Ser Cys Gln Pro 770 775 780Tyr Gly Ser Ser Phe Tyr Ala Leu Glu Glu Lys His Val Gly Phe Ser785 790 795 800Leu Asp Val Gly Glu Ile Glu Lys Lys Gly Lys Gly Lys Lys Arg Arg 805 810 815Gly Arg Arg Ser Lys Lys Glu Arg Arg Arg Gly Arg Lys Glu Gly Glu 820 825 830Glu Asp Gln Asn Pro Pro Cys Pro Arg Leu Asn Ser Met Leu Met Glu 835 840 845Val Glu Glu Pro Glu Val Leu Gln Asp Ser Leu Asp Ile Cys Tyr Ser 850 855 860Thr Pro Ser Met Tyr Phe Glu Leu Pro Asp Ser Phe Gln His Tyr Arg865 870 875 880Ser Val Phe Tyr Ser Phe Glu Glu Glu His Ile Ser Phe Ala Leu Tyr 885 890 895Val Asp Asn Arg Phe Phe Thr Leu Thr Val Thr Ser Leu His Leu Val 900 905 910Phe Gln Met Gly Val Ile Phe Pro Gln 915 92017664DNAHomo sapiens 17aacccaatga tcctgcagca gcccttgcag cgaggccccc

agggaggggc ccagcgcctc 60ccgcgggccg ccttgggggt gacttggggc ctggacgcca gctcccctct ccgaggagct 120gtgcccatga gcaccaagcg gcgcctggag gaggagcagg agcctctgcg caagcagttt 180ctgtctgagg agaacatggc cacccacttc tctcaactca gcctgcacaa tgaccacccc 240tactgcagcc cccccatgac cttctcccca gccctgcccc cactcaggag cccttgctct 300gagctgcttc tctggcgcta tcctggcagc ctcatccctg aggccctccg tctgctgagg 360ctgggggaca cccccagtcc cccctaccct gcaaccccag ctggggacat aatggagctc 420tgagtgctgg tggacagtgc ccctcccacc ttccttcttc cccacaacag aagagaccag 480cgactcccgc aaagggacaa ggttcctccc tctcctgcag agtaggcatc tgggcaccaa 540gaccttccct caacagagga cactgagccc aacggagttc tgggatggga ggggtgggag 600catgggaagg gaggcatccc acccccaaga agaactgaat aaagattgct gagcaaagga 660aggc 66418138PRTHomo sapiens 18Met Ile Leu Gln Gln Pro Leu Gln Arg Gly Pro Gln Gly Gly Ala Gln 1 5 10 15Arg Leu Pro Arg Ala Ala Leu Gly Val Thr Trp Gly Leu Asp Ala Ser 20 25 30Ser Pro Leu Arg Gly Ala Val Pro Met Ser Thr Lys Arg Arg Leu Glu 35 40 45Glu Glu Gln Glu Pro Leu Arg Lys Gln Phe Leu Ser Glu Glu Asn Met 50 55 60Ala Thr His Phe Ser Gln Leu Ser Leu His Asn Asp His Pro Tyr Cys65 70 75 80Ser Pro Pro Met Thr Phe Ser Pro Ala Leu Pro Pro Leu Arg Ser Pro 85 90 95Cys Ser Glu Leu Leu Leu Trp Arg Tyr Pro Gly Ser Leu Ile Pro Glu 100 105 110Ala Leu Arg Leu Leu Arg Leu Gly Asp Thr Pro Ser Pro Pro Tyr Pro 115 120 125Ala Thr Pro Ala Gly Asp Ile Met Glu Leu 130 135192056DNAHomo sapiens 19ggaaccgcgg ctgctggaca agaggggtgc ggtggatact gacctttgct ccggcctcgt 60cgtgaagaca cagcgcatct ccccgctgta ggcttctccc acagaacccg tttcgggcct 120cagagcgtct ggtgagatgc tgttgccgct gctgctgctg ctacccatgt gctgggccgt 180ggaggtcaag aggccccggg gcgtctccct caccaatcat cacttctacg atgagtccaa 240gcctttcacc tgcctggacg gttcggccac catcccattt gatcaggtca acgatgacta 300ttgcgactgc aaagatggct ctgacgagcc aggcacggct gcctgtccta atggcagctt 360ccactgcacc aacactggct ataagcccct gtatatcccc tccaaccggg tcaacgatgg 420tgtttgtgac tgctgcgatg gaacagacga gtacaacagc ggcgtcatct gtgagaacac 480ctgcaaagag aagggccgta aggagagaga gtccctgcag cagatggccg aggtcacccg 540cgaagggttc cgtctgaaga agatccttat tgaggactgg aagaaggcac gggaggagaa 600gcagaaaaag ctcattgagc tacaggctgg gaagaagtct ctggaagacc aggtggagat 660gctgcggaca gtgaaggagg aagctgagaa gccagagaga gaggccaaag agcagcacca 720gaagctgtgg gaagagcagc tggctgctgc caaggcccaa caggagcagg agctggcggc 780tgatgccttc aaggagctgg atgatgacat ggacgggacg gtctcggtga ctgagctgca 840gactcacccg gagctggaca cagatgggga tggggcgttg tcagaagcgg aagctcaggc 900cctcctcagt ggggacacac agacagacgc cacctctttc tacgaccgcg tctgggccgc 960catcagggac aagtaccggt ccgaggcact gcccaccgac cttccagcac cttctgcccc 1020tgacttgacg gagcccaagg aggagcagcc gccagtgccc tcgtcgccca cagaggagga 1080ggaggaggag gaggaggagg aagaagaggc tgaagaagag gaggaggagg aggattccga 1140ggaggcccca ccgccactgt cacccccgca gccggccagc cctgctgagg aagacaaaat 1200gccgccctac gacgagcaga cgcaggcctt catcgatgct gcccaggagg cccgcaacaa 1260gttcgaggag gccgagcggt cgctgaagga catggaggag tccatcagga acctggagca 1320agagatttct tttgactttg gccccaacgg ggagtttgct tacctgtaca gccagtgcta 1380cgagctcacc accaacgaat acgtctaccg cctctgcccc ttcaagcttg tctcgcagaa 1440acccaaactc gggggctctc ccaccagcct tggcacctgg ggctcatgga ttggccccga 1500ccacgacaag ttcagtgcca tgaagtatga gcaaggcacg ggctgctggc agggccccaa 1560ccgctccacc accgtgcgcc tcctgtgcgg gaaagagacc atggtgacca gcaccacaga 1620gcccagtcgc tgcgagtacc tcatggagct gatgacgcca gccgcctgcc cggagccacc 1680gcctgaagca cccaccgaag acgaccatga cgagctctag ctggatgggc gcagagaacc 1740tcaagaaggc atgaagccag cccctgcagt gccgtccacc cgcccctctg ggcctgcctg 1800tggctctgtt gccctcctct gtggcggcag gacctttgtg gggcttcgtg ccctgctctg 1860gggcccaggc ggggctggtc cacattccca ggccccaaca gcctccaaag atgggtaaag 1920gagcttgccc tccctgggcc ccccaccttg gtgactcgcc ccaccacccc cagccctgtc 1980cctgccaccc ctcctagtgg ggactagtga atgacttgac ctgtgacctc aatacaataa 2040atgtgatccc ccaccc 205620527PRTHomo sapiens 20Met Leu Leu Pro Leu Leu Leu Leu Leu Pro Met Cys Trp Ala Val Glu 1 5 10 15Val Lys Arg Pro Arg Gly Val Ser Leu Thr Asn His His Phe Tyr Asp 20 25 30Glu Ser Lys Pro Phe Thr Cys Leu Asp Gly Ser Ala Thr Ile Pro Phe 35 40 45Asp Gln Val Asn Asp Asp Tyr Cys Asp Cys Lys Asp Gly Ser Asp Glu 50 55 60Pro Gly Thr Ala Ala Cys Pro Asn Gly Ser Phe His Cys Thr Asn Thr65 70 75 80Gly Tyr Lys Pro Leu Tyr Ile Pro Ser Asn Arg Val Asn Asp Gly Val 85 90 95Cys Asp Cys Cys Asp Gly Thr Asp Glu Tyr Asn Ser Gly Val Ile Cys 100 105 110Glu Asn Thr Cys Lys Glu Lys Gly Arg Lys Glu Arg Glu Ser Leu Gln 115 120 125Gln Met Ala Glu Val Thr Arg Glu Gly Phe Arg Leu Lys Lys Ile Leu 130 135 140Ile Glu Asp Trp Lys Lys Ala Arg Glu Glu Lys Gln Lys Lys Leu Ile145 150 155 160Glu Leu Gln Ala Gly Lys Lys Ser Leu Glu Asp Gln Val Glu Met Leu 165 170 175Arg Thr Val Lys Glu Glu Ala Glu Lys Pro Glu Arg Glu Ala Lys Glu 180 185 190Gln His Gln Lys Leu Trp Glu Glu Gln Leu Ala Ala Ala Lys Ala Gln 195 200 205Gln Glu Gln Glu Leu Ala Ala Asp Ala Phe Lys Glu Leu Asp Asp Asp 210 215 220Met Asp Gly Thr Val Ser Val Thr Glu Leu Gln Thr His Pro Glu Leu225 230 235 240Asp Thr Asp Gly Asp Gly Ala Leu Ser Glu Ala Glu Ala Gln Ala Leu 245 250 255Leu Ser Gly Asp Thr Gln Thr Asp Ala Thr Ser Phe Tyr Asp Arg Val 260 265 270Trp Ala Ala Ile Arg Asp Lys Tyr Arg Ser Glu Ala Leu Pro Thr Asp 275 280 285Leu Pro Ala Pro Ser Ala Pro Asp Leu Thr Glu Pro Lys Glu Glu Gln 290 295 300Pro Pro Val Pro Ser Ser Pro Thr Glu Glu Glu Glu Glu Glu Glu Glu305 310 315 320Glu Glu Glu Glu Ala Glu Glu Glu Glu Glu Glu Glu Asp Ser Glu Glu 325 330 335Ala Pro Pro Pro Leu Ser Pro Pro Gln Pro Ala Ser Pro Ala Glu Glu 340 345 350Asp Lys Met Pro Pro Tyr Asp Glu Gln Thr Gln Ala Phe Ile Asp Ala 355 360 365Ala Gln Glu Ala Arg Asn Lys Phe Glu Glu Ala Glu Arg Ser Leu Lys 370 375 380Asp Met Glu Glu Ser Ile Arg Asn Leu Glu Gln Glu Ile Ser Phe Asp385 390 395 400Phe Gly Pro Asn Gly Glu Phe Ala Tyr Leu Tyr Ser Gln Cys Tyr Glu 405 410 415Leu Thr Thr Asn Glu Tyr Val Tyr Arg Leu Cys Pro Phe Lys Leu Val 420 425 430Ser Gln Lys Pro Lys Leu Gly Gly Ser Pro Thr Ser Leu Gly Thr Trp 435 440 445Gly Ser Trp Ile Gly Pro Asp His Asp Lys Phe Ser Ala Met Lys Tyr 450 455 460Glu Gln Gly Thr Gly Cys Trp Gln Gly Pro Asn Arg Ser Thr Thr Val465 470 475 480Arg Leu Leu Cys Gly Lys Glu Thr Met Val Thr Ser Thr Thr Glu Pro 485 490 495Ser Arg Cys Glu Tyr Leu Met Glu Leu Met Thr Pro Ala Ala Cys Pro 500 505 510Glu Pro Pro Pro Glu Ala Pro Thr Glu Asp Asp His Asp Glu Leu 515 520 52521384DNAHomo sapiens 21atgcctaaat caaaggaact tgtttcttca agctcttctg gcagtgattc tgacagtgag 60gttgacaaaa agttaaagag gaaaaagcaa gttgctccag aaaaacctgt aaagaaacaa 120aagacaggtg agacttcgag agccctgtca tcttctaaac agagcagcag cagcagagat 180gataacatgt ttcagattgg gaaaatgagg tacgttagtg ttcgcgattt taaaggcaaa 240gtgctaattg atattagaga atattggatg gatcctgaag gtgaaatgaa accaggaaga 300aaaggtattt ctttaaatcc agaacaatgg agccagctga aggaacagat ctctgatata 360gatgacgcag taagaaagct gtga 38422127PRTHomo sapiens 22Met Pro Lys Ser Lys Glu Leu Val Ser Ser Ser Ser Ser Gly Ser Asp 1 5 10 15Ser Asp Ser Glu Val Asp Lys Lys Leu Lys Arg Lys Lys Gln Val Ala 20 25 30Pro Glu Lys Pro Val Lys Lys Gln Lys Thr Gly Glu Thr Ser Arg Ala 35 40 45Leu Ser Ser Ser Lys Gln Ser Ser Ser Ser Arg Asp Asp Asn Met Phe 50 55 60Gln Ile Gly Lys Met Arg Tyr Val Ser Val Arg Asp Phe Lys Gly Lys65 70 75 80Val Leu Ile Asp Ile Arg Glu Tyr Trp Met Asp Pro Glu Gly Glu Met 85 90 95Lys Pro Gly Arg Lys Gly Ile Ser Leu Asn Pro Glu Gln Trp Ser Gln 100 105 110Leu Lys Glu Gln Ile Ser Asp Ile Asp Asp Ala Val Arg Lys Leu 115 120 125231554DNAHomo sapiens 23gaccacaatg gcggccgcca ccctgctgcg cgcgacgccc cacttcagcg gtctcgccgc 60cggccggacc ttcctgctgc agggtctgtt gcggctgctg aaagccccgg cattgcctct 120cttgtgccgc ggcctggccg tggaggccaa gaagacttac gtgcgcgaca agccacatgt 180gaatgtgggt accatcggcc atgtggacca cgggaagacc acgctgactg cagccatcac 240gaagattcta gctgagggag gtggggctaa gttcaagaag tacgaggaga ttgacaatgc 300cccggaggag cgagctcggg gtatcaccat caatgcggct catgtggagt atagcactgc 360cgcccgccac tacgcccaca cagactgccc gggtcatgca gattatgtta agaatatgat 420cacaggcact gcacccctcg acggctgcat cctggtggta gcagccaatg acggccccat 480gccccagacc cgagagcact tattactggc cagacagatt ggggtggagc atgtggtggt 540gtatgtgaac aaggctgacg ctgtccagga ctctgagatg gtggaactgg tggaactgga 600gatccgggag ctgctcaccg agtttggcta taaaggggag gagaccccag tcatcgtagg 660ctctgctctc tgtgcccttg agggtcggga ccctgagtta ggcctgaagt ctgtgcagaa 720gctactggat gctgtggaca cttacatccc agtgcccgcc cgggacctgg agaagccttt 780cctgctgcct gtggaggcgg tgtactccgt ccctggccgt ggcaccgtgg tgacaggtac 840actagagcgt ggcattttaa agaagggaga cgagtgtgag ctcctaggac atagcaagaa 900catccgcact gtggtgacag gcattgagat gttccacaag agcctggaga gggccgaggc 960cggagataac ctcggggccc tggtccgagg cttgaagcgg gaggacttgc ggcggggcct 1020ggtcatggtc aagccaggtt ccatcaagcc ccaccagaag gtggaggccc aggtttacat 1080cctcagcaag gaggaaggtg gccgccacaa gccctttgtg tcccacttca tgcctgtcat 1140gttctccctg acttggaaca tggcctgtcg gattatcctg cccccagaga aggagcttgc 1200catgcccggg gaggacctga agttcaacct aatcttgcgg cagccaatga tcttagagaa 1260aggccagcgt ttcaccctgc gagatggcaa ccggactatt ggcaccggtc tagtcaccaa 1320cacgctggcc atgactgagg aggagaagaa tatcaaatgg ggttgagtgt gcagatctct 1380gctcagcttc ccttgcgttt aaggcctgcc ctagccaggg ctccctcctg cttccagtac 1440cctctcatgg cataggctgc aacccagcag agggcagcta gatggacatt tcccctgctc 1500ggaagggttg gcctgcctgg ctggggaggt cagtaaactt tgaatagtaa gcca 155424452PRTHomo sapiens 24Met Ala Ala Ala Thr Leu Leu Arg Ala Thr Pro His Phe Ser Gly Leu 1 5 10 15Ala Ala Gly Arg Thr Phe Leu Leu Gln Gly Leu Leu Arg Leu Leu Lys 20 25 30Ala Pro Ala Leu Pro Leu Leu Cys Arg Gly Leu Ala Val Glu Ala Lys 35 40 45Lys Thr Tyr Val Arg Asp Lys Pro His Val Asn Val Gly Thr Ile Gly 50 55 60His Val Asp His Gly Lys Thr Thr Leu Thr Ala Ala Ile Thr Lys Ile65 70 75 80Leu Ala Glu Gly Gly Gly Ala Lys Phe Lys Lys Tyr Glu Glu Ile Asp 85 90 95Asn Ala Pro Glu Glu Arg Ala Arg Gly Ile Thr Ile Asn Ala Ala His 100 105 110Val Glu Tyr Ser Thr Ala Ala Arg His Tyr Ala His Thr Asp Cys Pro 115 120 125Gly His Ala Asp Tyr Val Lys Asn Met Ile Thr Gly Thr Ala Pro Leu 130 135 140Asp Gly Cys Ile Leu Val Val Ala Ala Asn Asp Gly Pro Met Pro Gln145 150 155 160Thr Arg Glu His Leu Leu Leu Ala Arg Gln Ile Gly Val Glu His Val 165 170 175Val Val Tyr Val Asn Lys Ala Asp Ala Val Gln Asp Ser Glu Met Val 180 185 190Glu Leu Val Glu Leu Glu Ile Arg Glu Leu Leu Thr Glu Phe Gly Tyr 195 200 205Lys Gly Glu Glu Thr Pro Val Ile Val Gly Ser Ala Leu Cys Ala Leu 210 215 220Glu Gly Arg Asp Pro Glu Leu Gly Leu Lys Ser Val Gln Lys Leu Leu225 230 235 240Asp Ala Val Asp Thr Tyr Ile Pro Val Pro Ala Arg Asp Leu Glu Lys 245 250 255Pro Phe Leu Leu Pro Val Glu Ala Val Tyr Ser Val Pro Gly Arg Gly 260 265 270Thr Val Val Thr Gly Thr Leu Glu Arg Gly Ile Leu Lys Lys Gly Asp 275 280 285Glu Cys Glu Leu Leu Gly His Ser Lys Asn Ile Arg Thr Val Val Thr 290 295 300Gly Ile Glu Met Phe His Lys Ser Leu Glu Arg Ala Glu Ala Gly Asp305 310 315 320Asn Leu Gly Ala Leu Val Arg Gly Leu Lys Arg Glu Asp Leu Arg Arg 325 330 335Gly Leu Val Met Val Lys Pro Gly Ser Ile Lys Pro His Gln Lys Val 340 345 350Glu Ala Gln Val Tyr Ile Leu Ser Lys Glu Glu Gly Gly Arg His Lys 355 360 365Pro Phe Val Ser His Phe Met Pro Val Met Phe Ser Leu Thr Trp Asn 370 375 380Met Ala Cys Arg Ile Ile Leu Pro Pro Glu Lys Glu Leu Ala Met Pro385 390 395 400Gly Glu Asp Leu Lys Phe Asn Leu Ile Leu Arg Gln Pro Met Ile Leu 405 410 415Glu Lys Gly Gln Arg Phe Thr Leu Arg Asp Gly Asn Arg Thr Ile Gly 420 425 430Thr Gly Leu Val Thr Asn Thr Leu Ala Met Thr Glu Glu Glu Lys Asn 435 440 445Ile Lys Trp Gly 450252201DNAHomo sapiens 25tttttttttt cgtcttagcc acgcagaagt cgcgtgtcta gtttgtttcg acgccggacc 60gcgtaagaga cgatgatgtt gggcacggaa ggtggagagg gattcgtggt gaaggtccgg 120ggcttgccct ggtcttgctc ggccgatgaa gtgcagaggt ttttttctga ctgcaaaatt 180caaaatgggg ctcaaggtat tcgtttcatc tacaccagag aaggcagacc aagtggcgag 240gcttttgttg aacttgaatc agaagatgaa gtcaaattgg ccctgaaaaa agacagagaa 300actatgggac acagatatgt tgaagtattc aagtcaaaca acgttgaaat ggattgggtg 360ttgaagcata ctggtccaaa tagtcctgac acggccaatg atggctttgt acggcttaga 420ggacttccct ttggatgtag caaggaagaa attgttcagt tcttctcagg gttggaaatc 480gtgccaaatg ggataacatt gccggtggac ttccagggga ggagtacggg ggaggccttc 540gtgcagtttg cttcacagga aatagctgaa aaggctctaa agaaacacaa ggaaagaata 600gggcacaggt atattgaaat ctttaagagc agtagagctg aagttagaac tcattatgat 660ccaccacgaa agcttatggc catgcagcgg ccaggtcctt atgacagacc tggggctggt 720agagggtata acagcattgg cagaggagct ggctttgaga ggatgaggcg tggtgcttat 780ggtggaggct atggaggcta tgatgattac aatggctata atgatggcta tggatttggg 840tcagatagat ttggaagaga cctcaattac tgtttttcag gaatgtctga tcacagatac 900ggggatggtg gctctacttt ccagagcaca acaggacact gtgtacacat gcggggatta 960ccttacagag ctactgagaa tgacatttat aatttttttt caccgctcaa ccctgtgaga 1020gtacacattg aaattggtcc tgatggcaga gtaactggtg aagcagatgt cgagttcgca 1080actcatgaag atgctgtggc agctatgtca aaagacaaag caaatatgca acacagatat 1140gtagaactct tcttgaattc tacagcagga gcaagcggtg gtgcttacga acacagatat 1200gtagaactct tcttgaattc tacagcagga gcaagcggtg gtgcttatgg tagccaaatg 1260atgggaggca tgggcttgtc aaaccagtcc agctacgggg gcccagccag ccagcagctg 1320agtgggggtt acggaggcgg ctacggtggc cagagcagca tgagtggata cgaccaagtt 1380ttacaggaaa actccagtga ttttcaatca aacattgcat aggtaaccaa ggagcagtga 1440acagcagcta ctacagtagt ggaagccgtg catctatggg cgtgaacgga atgggagggt 1500tgtctagcat gtccagtatg agtggtggat ggggaatgta attgatcgat cctgatcact 1560gactcttggt caaccttttt tttttttttt ttttctttaa gaaaacttca gtttaacagt 1620ttctgcaata caagcttgtg atttatgctt actctaagtg gaaatcagga ttgttatgaa 1680gacttaaggc ccagtatttt tgaatacaat actcatctag gatgtaacag tgaagctgag 1740taaactataa ctgttaaact taagttccag cttttctcaa gttagttata ggatgtactt 1800aagcagtaag cgtatttagg taaaagcagt tgaattatgt taaatgttgc cctttgccac 1860gttaaattga acactgtttt ggatgcatgt tgaaagacat gcttttattt tttttgtaaa 1920acaatatagg agctgtgtct actattaaaa gtgaaacatt ttggcatgtt tgttaattct 1980agtttcattt aataacctgt aaggcacgta agtttaagct tttttttttt ttaagttaat 2040gggaaaaatt tgagacgcaa taccaatact taggattttg gtcttggtgt ttgtatgaaa 2100ttctgaggcc ttgatttaaa tctttcattg tattgtgatt tccttttagg tatattgcgc 2160taagtgaaac ttgtcaaata aatcctcctt ttaaaaactg c 220126449PRTHomo sapiens 26Met Met Leu Gly Thr Glu Gly Gly Glu Gly Phe Val Val Lys Val Arg 1 5 10 15Gly Leu Pro Trp Ser Cys Ser Ala Asp Glu Val Gln Arg Phe Phe Ser 20 25 30Asp Cys Lys Ile Gln Asn Gly Ala Gln Gly Ile Arg Phe Ile Tyr Thr 35 40 45Arg Glu Gly Arg Pro Ser Gly Glu Ala Phe Val Glu Leu Glu Ser

Glu 50 55 60Asp Glu Val Lys Leu Ala Leu Lys Lys Asp Arg Glu Thr Met Gly His65 70 75 80Arg Tyr Val Glu Val Phe Lys Ser Asn Asn Val Glu Met Asp Trp Val 85 90 95Leu Lys His Thr Gly Pro Asn Ser Pro Asp Thr Ala Asn Asp Gly Phe 100 105 110Val Arg Leu Arg Gly Leu Pro Phe Gly Cys Ser Lys Glu Glu Ile Val 115 120 125Gln Phe Phe Ser Gly Leu Glu Ile Val Pro Asn Gly Ile Thr Leu Pro 130 135 140Val Asp Phe Gln Gly Arg Ser Thr Gly Glu Ala Phe Val Gln Phe Ala145 150 155 160Ser Gln Glu Ile Ala Glu Lys Ala Leu Lys Lys His Lys Glu Arg Ile 165 170 175Gly His Arg Tyr Ile Glu Ile Phe Lys Ser Ser Arg Ala Glu Val Arg 180 185 190Thr His Tyr Asp Pro Pro Arg Lys Leu Met Ala Met Gln Arg Pro Gly 195 200 205Pro Tyr Asp Arg Pro Gly Ala Gly Arg Gly Tyr Asn Ser Ile Gly Arg 210 215 220Gly Ala Gly Phe Glu Arg Met Arg Arg Gly Ala Tyr Gly Gly Gly Tyr225 230 235 240Gly Gly Tyr Asp Asp Tyr Asn Gly Tyr Asn Asp Gly Tyr Gly Phe Gly 245 250 255Ser Asp Arg Phe Gly Arg Asp Leu Asn Tyr Cys Phe Ser Gly Met Ser 260 265 270Asp His Arg Tyr Gly Asp Gly Gly Ser Thr Phe Gln Ser Thr Thr Gly 275 280 285His Cys Val His Met Arg Gly Leu Pro Tyr Arg Ala Thr Glu Asn Asp 290 295 300Ile Tyr Asn Phe Phe Ser Pro Leu Asn Pro Val Arg Val His Ile Glu305 310 315 320Ile Gly Pro Asp Gly Arg Val Thr Gly Glu Ala Asp Val Glu Phe Ala 325 330 335Thr His Glu Asp Ala Val Ala Ala Met Ser Lys Asp Lys Ala Asn Met 340 345 350Gln His Arg Tyr Val Glu Leu Phe Leu Asn Ser Thr Ala Gly Ala Ser 355 360 365Gly Gly Ala Tyr Glu His Arg Tyr Val Glu Leu Phe Leu Asn Ser Thr 370 375 380Ala Gly Ala Ser Gly Gly Ala Tyr Gly Ser Gln Met Met Gly Gly Met385 390 395 400Gly Leu Ser Asn Gln Ser Ser Tyr Gly Gly Pro Ala Ser Gln Gln Leu 405 410 415Ser Gly Gly Tyr Gly Gly Gly Tyr Gly Gly Gln Ser Ser Met Ser Gly 420 425 430Tyr Asp Gln Val Leu Gln Glu Asn Ser Ser Asp Phe Gln Ser Asn Ile 435 440 445Ala271852DNAHomo sapiens 27acagcccttc gtggggccct gggcaccctg caccagctgg gcatcgtcgt cggcatcctc 60atcgcccagg tgttcggcct ggactccatc atgggcaaca aggacctgtg gcccctgctg 120ctgagcatca tcttcatccc ggccctgctg cagtgcatcg tgctgccctt ctgccccgag 180agtccccgct tcctgctcat caaccgcaac gaggagaacc gggccaagag tgtgctaaag 240aagctgcgcg ggacagctga cgtgacccat gacctgcagg agatgaagga agagagtcgg 300cagatgatgc gggagaagaa ggtcaccatc ctggagctgt tccgctcccc cgcctaccgc 360cagcccatcc tcatcgctgt ggtgctgcag ctgtcccagc agctgtctgg catcaacgct 420gtcttctatt actccacgag catcttcgag aaggcggggg tgcagcagcc tgtgtatgcc 480accattggct ccggtatcgt caacacggcc ttcactgtcg tgtcgctgtt tgtggtggag 540cgagcaggcc ggcggaccct gcacctcata ggcctcgctg gcatggcggg ttgtgccata 600ctcatgacca tcgcgctagc actgctggag cagctaccct ggatgtccta tctgagcatc 660gtggccatct ttggctttgt ggccttcttt gaagtgggtc ctggccccat cccatggttc 720atcgtggctg aactcttcag ccagggtcca cgtccagctg ccattgccgt tgcaggcttc 780tccaactgga cctcaaattt cattgtgggc atgtgcttcc agtatgtgga gcaactgtgt 840ggtccctacg tcttcatcat cttcactgtg ctcctggttc tgttcttcat cttcacctac 900ttcaaagttc ctgagactaa aggccggacc ttcgatgaga tcgcttccgg cttccggcag 960gggggagcca gccaaagtga caagacaccc gaggagctgt tccatcccct gggggctgat 1020tcccaagtgt gagtcgcccc agatcaccag cccggcctgc tcccagcagc cctaaggatc 1080tctcaggagc acaggcagct ggatgagact tccaaacctg acagatgtca gccgagccgg 1140gcctggggct cctttctcca gccagcaatg atgtccagaa gaatattcag gacttaacgg 1200ctccaggatt ttaacaaaag caagactgtt gctcaaatct attcagacaa gcaacaggtt 1260ttataatttt tttattactg attttgttat ttttatatca gcctgagtct cctgtgccca 1320catcccaggc ttcaccctga atggttccat gcctgagggt ggagactaag ccctgtcgag 1380acacttgcct tcttcaccca gctaatctgt agggctggac ctatgtccta aggacacact 1440aatcgaacta tgaactacaa agcttctatc ccaggaggtg gctatggcca cccgttctgc 1500tggcctggat ctccccactc taggggtcag gctccattag gatttgcccc ttcccatctc 1560ttcctaccca accactcaaa ttaatctttc tttacctgag accagttggg agcactggag 1620tgcagggagg agaggggaag ggccagtctg ggctgccggg ttctagtctc ctttgcactg 1680agggccacac tattaccatg agaagagggc ctgtgggagc ctgcaaactc actgctcaag 1740aagacatgga gactcctgcc ctgttgtgta tagatgcaag atatttatat atatttttgg 1800ttgtcaatat taaatacaga cactaagtta tagtaaaaaa aaaaaaaaaa aa 185228343PRTHomo sapiens 28Thr Ala Leu Arg Gly Ala Leu Gly Thr Leu His Gln Leu Gly Ile Val 1 5 10 15Val Gly Ile Leu Ile Ala Gln Val Phe Gly Leu Asp Ser Ile Met Gly 20 25 30Asn Lys Asp Leu Trp Pro Leu Leu Leu Ser Ile Ile Phe Ile Pro Ala 35 40 45Leu Leu Gln Cys Ile Val Leu Pro Phe Cys Pro Glu Ser Pro Arg Phe 50 55 60Leu Leu Ile Asn Arg Asn Glu Glu Asn Arg Ala Lys Ser Val Leu Lys65 70 75 80Lys Leu Arg Gly Thr Ala Asp Val Thr His Asp Leu Gln Glu Met Lys 85 90 95Glu Glu Ser Arg Gln Met Met Arg Glu Lys Lys Val Thr Ile Leu Glu 100 105 110Leu Phe Arg Ser Pro Ala Tyr Arg Gln Pro Ile Leu Ile Ala Val Val 115 120 125Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn Ala Val Phe Tyr Tyr 130 135 140Ser Thr Ser Ile Phe Glu Lys Ala Gly Val Gln Gln Pro Val Tyr Ala145 150 155 160Thr Ile Gly Ser Gly Ile Val Asn Thr Ala Phe Thr Val Val Ser Leu 165 170 175Phe Val Val Glu Arg Ala Gly Arg Arg Thr Leu His Leu Ile Gly Leu 180 185 190Ala Gly Met Ala Gly Cys Ala Ile Leu Met Thr Ile Ala Leu Ala Leu 195 200 205Leu Glu Gln Leu Pro Trp Met Ser Tyr Leu Ser Ile Val Ala Ile Phe 210 215 220Gly Phe Val Ala Phe Phe Glu Val Gly Pro Gly Pro Ile Pro Trp Phe225 230 235 240Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg Pro Ala Ala Ile Ala 245 250 255Val Ala Gly Phe Ser Asn Trp Thr Ser Asn Phe Ile Val Gly Met Cys 260 265 270Phe Gln Tyr Val Glu Gln Leu Cys Gly Pro Tyr Val Phe Ile Ile Phe 275 280 285Thr Val Leu Leu Val Leu Phe Phe Ile Phe Thr Tyr Phe Lys Val Pro 290 295 300Glu Thr Lys Gly Arg Thr Phe Asp Glu Ile Ala Ser Gly Phe Arg Gln305 310 315 320Gly Gly Ala Ser Gln Ser Asp Lys Thr Pro Glu Glu Leu Phe His Pro 325 330 335Leu Gly Ala Asp Ser Gln Val 340295368DNAHomo sapiens 29ggaatcagag aagatcattg ctgagttgaa tgaaacttgg gaagagaagc ttcgtaaaac 60agaggccatc agaatggaga gagaggcttt gttggctgag atgggagttg ccattcggga 120agatggagga accctagggg ttttctcacc taaaaagacc ccacatcttg ttaacctcaa 180tgaagaccca ctaatgtctg agtgcctact ttattacatc aaagatggaa ttacaagggt 240tggccaagca gatgctgagc ggcgccagga catagtgctg agcggggctc acattaaaga 300agagcattgt atcttccgga gtgagagaag caacagcggg gaagttatcg tgaccttaga 360gccctgtgag cgctcagaaa cctacgtaaa tggcaagagg gtgtcccagc ctgttcagct 420gcgctcagga aaccgtatca tcatgggtaa aaaccatgtt ttccgcttta accacccgga 480acaagcacga gctgagcgag agaagactcc ttctgctgag accccctctg agcctgtgga 540ctggacattt gcccagaggg agcttctgga aaaacaagga attgatatga aacaagagat 600ggagaaaagg ctacaggaaa tggagatctt atacaaaaag gagaaggaag aagcagatct 660tcttttggag cagcagagac tggactatga gagtaaattg caggccttgc agaagcaggt 720tgaaacccga tctctggctg cagaaacaac tgaagaggag gaagaagagg aagaagttcc 780ttggacacag catgaatttg agttggccca atgggccttc cggaaatgga agtctcatca 840gtttacttca ttacgggact tactctgggg caatgccgtg tacctaaagg aggccaatgc 900catcagtgtg gaactgaaaa agaaggtgca gtttcagttt gttctgctga ctgacacact 960gtactcccct ttgcctcctg aattacttcc cactgagatg gaaaaaactc atgaggacag 1020gcctttccct cgcacagtgg tagcagtaga agtccaggat ttgaagaatg gagcaacaca 1080ctattggtct ttggagaaac tcaagcagag gctggatttg atgcgagaga tgtatgatag 1140ggcaggggag atggcctcca gtgcccaaga cgaaagcgaa accactgtga ctggcagcga 1200tcccttctat gatcggttcc actggttcaa acttgtgggg agctccccca ttttccacgg 1260ctgtgtgaac gagcgccttg ccgaccgcac accctccccc actttttcca cggccgattc 1320cgacatcact gagctggctg acgagcagca agatgagatg gaggattttg atgatgaggc 1380attcgtggat gacgccggct ctgacgcagg gacggaggag ggatcagatc tcttcagtga 1440cgggcatgac ccgttttacg accgatcccc ttggttcatt ttagtgggaa gggcatttgt 1500ttacctgagc aatctgctgt atcccgtgcc cctgatccac agggtggcca tcgtcagtga 1560gaaaggtgaa gtgcggggat ttctgcgtgt ggctgtacag gccatcgcag cggatgaaga 1620agctcctgat tatggctctg gaattcgaca gtcaggaaca gctaaaatat cttttgataa 1680tgaatacttt aatcagagtg acttttcgtc tgttgcaatg actcgttctg gtctgtcctt 1740ggaggagttg aggattgtgg aaggacaggg tcagagttct gaggtcatca ctcctccaga 1800agaaatcagt cgaattaatg acttggattt gaagtcaagc actttgctgg atggtaagat 1860ggtaatggaa gggttttctg aagagattgg caaccacctg aaactgggca gtgccttcac 1920tttccgagta acagtgttgc aggccagtgg aatcctccca gagtatgcag atatcttctg 1980tcagttcaac tttttgcatc gccatgatga agcattctcc acggagcccc tcaaaaacaa 2040tggcagagga agtcccctgg ccttttatca tgtgcagaat attgcagtgg agatcactga 2100atcatttgtg gattacatca aaaccaagcc tattgtattt gaagtctttg ggcattatca 2160gcagcaccca cttcatctgc aaggacagga gcttaacagt ccgcctcagc cgtgccgccg 2220attcttccct ccacccatgc cactgtccaa gccagttcca gccaccaagt taaacacgat 2280gagcaaaacc agccttggcc agagcatgag caagtatgac ctcctggttt ggtttgagat 2340cagtgaactg gagcctacag gagagtatat cccagctgtg gttgaccaca cagcaggctt 2400gccttgccag gggacatttt tgcttcatca gggcatccag cgaaggatca cagtgaccat 2460tatccatgag aaggggagcg agctccattg gaaagatgtt cgtgaactgg tggtaggtcg 2520tattcggaat aagcctgagg tggatgaagc tgcagttgat gccatcctct ccctaaatat 2580tatttctgcc aagtacctga agtcttccca caactctagc aggaccttct accgctttga 2640ggctgtgtgg gatagctctc tgcataactc ccttcttctg aaccgagtga caccctatgg 2700agaaaagatc tacatgacct tgtcggccta cctagagctg gatcattgca tccagccggc 2760tgtcatcacc aaggatgtgt gcatggtctt ctactcccga gatgccaaga tctcaccacc 2820acgctctctg cgtagcctct ttggcagcgg ctactcaaag tcaccagatt cgaatcgagt 2880cactggcatt tacgaactca gcttatgcaa aatgtcagac acaggtagtc caggtatgca 2940gagaaggaga agaaaaatct tagatacgtc agtggcatat gtgcggggag aagagaactt 3000agcaggctgg cggccccgtg gagacagcct catccttgag caccagtggg agctggagaa 3060gctggagctc ctacatgagg tggaaaaaac ccgccacttt ttgctgctgc gtgagagact 3120tggtgacagc atccccaaat ccctgagcga ctcgttatcc cccagcctca gcagtgggac 3180cctcagcacc tccaccagta tctcctctca gatctcaacc actacctttg aaagcgccat 3240cacacctagc gagagcagtg gctatgattc aggagacatc gaaagcctgg tggaccgaga 3300gaaagagctg gctaccaagt gcctgcaact tctcacccac actttcaaca gagaattcag 3360ccaggtgcac ggcagcgtca gtgactgtaa gttgtctgat atctctccaa ttggacggga 3420tccctctgag tccagtttca gcagtgccac cctcactccc tcctccacct gtccctctct 3480ggtagactct aggagcaact ctctggatca gaagacccca gaagccaatt cccgggcctc 3540tagtccctgc ccagaatttg aacagtttca gattgtccca gctgtggaaa caccatattt 3600ggcccgagca ggaaaaaacg aatttctcaa tcttgttcca gatattgaag aaattagacc 3660aagctcagtg gtctctaaga aaggatacct tcatttcaag gagcctcttt acagtaactg 3720ggctaaacat tttgttgtcg tccgtcggcc ttatgtcttc atctataaca gtgacaaaga 3780ccctgtggag cgtggaatca ttaacctgtc cacagcacag gtggagtaca gtgaggacca 3840gcaggccatg gtgaagacac caaacacctt tgctgtctgc acaaagcacc gtggggtcct 3900tttgcaggcc ctcaatgaca aagacatgaa cgactggttg tatgccttca acccacttct 3960agctggcaca atacggtcaa agctttcccg cagatgcccg agccagtcga aatactaagt 4020gactctgccg agtgccctca ctcgccttcg agagataaag aaagcgttac ctctcatttc 4080tctttgtgat tcttgacggt gactcttgta tgtaatcctg tggcttaact acttctccct 4140ccttgtccag cacttttcta gctctcccgt tccccatctc cattgctctg tactcttttc 4200ttttttcttg tgctgagaat ctcgttagta gcatgtggcc taacaaaagg aaaaaatgtt 4260tttaaacaca cacacacaca cacacacaca cacacacata cacagacaaa aacacaaaaa 4320ctctgagggg atctggtgaa tctccaaatt attgtgggtg tactttggct tccttttgta 4380tgataggtcc ccatcatgac cacctctgat gtctgtgctg ctgtcaccag gcacctttgt 4440ttttcaagac aacatacttt ttttttcttt tctctgtttg tgatatcact ttaatttttc 4500ttgggtggct tagagactaa gggaggagac atctggcctt tttagaacct gagaggaaaa 4560aaagagtctt tttttcccct ctgtctcttt ttgccatggc taatccctgc atttccattc 4620agggaaaagg tggtagtgag catagaactg caacagttat attctgagtc aaagttgggg 4680ctttttacgg cataattatg gaatttttat ttactggtag agaggagacg agaggctttt 4740tcagtgggcc tgggacagtg gctgctcttg actttgtgtg aagggaaatg ccaaggatgc 4800ttctggtgga cttcagggga ccccagggtt tggccgtggg ccgtgatggc agcaggcggt 4860gggatgcttg tagctcctca cagcaggatt cctgcccact gttttttctc tgttgggagg 4920gaagctcttt tctaggagtg tctcagttct gcttttggca ttagtgatgg tggtggtaca 4980gttggaatta gtgccatgtc atacacaaat gttccacaag gcgggagtgt ttcactttct 5040ggtgataaac ttgatggtca ttgttatgat taagataatg ccgggcaggc cgggcacagt 5100ggctcacgcc tgtaatccaa gcacttgggg aggccgaggc gggcagatca cgagatcagg 5160agttcaagac cagcctggcc aatgtgatga aaccccgtct ctactaaaaa tacaaaatta 5220gtcgggtatg gtggcacatg cctgtaattc cagctgcttg ggagcctgag gcaggagaac 5280tgcttgaacc caggaggcag aggttgcagt gagccaagat cgcgctattg cactccagcc 5340tgggtgacag agcaagactc tgcctcag 5368301338PRTHomo sapiens 30Glu Ser Glu Lys Ile Ile Ala Glu Leu Asn Glu Thr Trp Glu Glu Lys 1 5 10 15Leu Arg Lys Thr Glu Ala Ile Arg Met Glu Arg Glu Ala Leu Leu Ala 20 25 30Glu Met Gly Val Ala Ile Arg Glu Asp Gly Gly Thr Leu Gly Val Phe 35 40 45Ser Pro Lys Lys Thr Pro His Leu Val Asn Leu Asn Glu Asp Pro Leu 50 55 60Met Ser Glu Cys Leu Leu Tyr Tyr Ile Lys Asp Gly Ile Thr Arg Val65 70 75 80Gly Gln Ala Asp Ala Glu Arg Arg Gln Asp Ile Val Leu Ser Gly Ala 85 90 95His Ile Lys Glu Glu His Cys Ile Phe Arg Ser Glu Arg Ser Asn Ser 100 105 110Gly Glu Val Ile Val Thr Leu Glu Pro Cys Glu Arg Ser Glu Thr Tyr 115 120 125Val Asn Gly Lys Arg Val Ser Gln Pro Val Gln Leu Arg Ser Gly Asn 130 135 140Arg Ile Ile Met Gly Lys Asn His Val Phe Arg Phe Asn His Pro Glu145 150 155 160Gln Ala Arg Ala Glu Arg Glu Lys Thr Pro Ser Ala Glu Thr Pro Ser 165 170 175Glu Pro Val Asp Trp Thr Phe Ala Gln Arg Glu Leu Leu Glu Lys Gln 180 185 190Gly Ile Asp Met Lys Gln Glu Met Glu Lys Arg Leu Gln Glu Met Glu 195 200 205Ile Leu Tyr Lys Lys Glu Lys Glu Glu Ala Asp Leu Leu Leu Glu Gln 210 215 220Gln Arg Leu Asp Tyr Glu Ser Lys Leu Gln Ala Leu Gln Lys Gln Val225 230 235 240Glu Thr Arg Ser Leu Ala Ala Glu Thr Thr Glu Glu Glu Glu Glu Glu 245 250 255Glu Glu Val Pro Trp Thr Gln His Glu Phe Glu Leu Ala Gln Trp Ala 260 265 270Phe Arg Lys Trp Lys Ser His Gln Phe Thr Ser Leu Arg Asp Leu Leu 275 280 285Trp Gly Asn Ala Val Tyr Leu Lys Glu Ala Asn Ala Ile Ser Val Glu 290 295 300Leu Lys Lys Lys Val Gln Phe Gln Phe Val Leu Leu Thr Asp Thr Leu305 310 315 320Tyr Ser Pro Leu Pro Pro Glu Leu Leu Pro Thr Glu Met Glu Lys Thr 325 330 335His Glu Asp Arg Pro Phe Pro Arg Thr Val Val Ala Val Glu Val Gln 340 345 350Asp Leu Lys Asn Gly Ala Thr His Tyr Trp Ser Leu Glu Lys Leu Lys 355 360 365Gln Arg Leu Asp Leu Met Arg Glu Met Tyr Asp Arg Ala Gly Glu Met 370 375 380Ala Ser Ser Ala Gln Asp Glu Ser Glu Thr Thr Val Thr Gly Ser Asp385 390 395 400Pro Phe Tyr Asp Arg Phe His Trp Phe Lys Leu Val Gly Ser Ser Pro 405 410 415Ile Phe His Gly Cys Val Asn Glu Arg Leu Ala Asp Arg Thr Pro Ser 420 425 430Pro Thr Phe Ser Thr Ala Asp Ser Asp Ile Thr Glu Leu Ala Asp Glu 435 440 445Gln Gln Asp Glu Met Glu Asp Phe Asp Asp Glu Ala Phe Val Asp Asp 450 455 460Ala Gly Ser Asp Ala Gly Thr Glu Glu Gly Ser Asp Leu Phe Ser Asp465 470 475 480Gly His Asp Pro Phe Tyr Asp Arg Ser Pro Trp Phe Ile Leu Val Gly 485 490 495Arg Ala Phe Val Tyr Leu Ser Asn Leu Leu Tyr Pro Val Pro Leu Ile 500 505 510His Arg Val Ala Ile Val Ser Glu Lys Gly Glu Val Arg Gly Phe Leu 515 520 525Arg Val Ala Val Gln Ala Ile Ala Ala

Asp Glu Glu Ala Pro Asp Tyr 530 535 540Gly Ser Gly Ile Arg Gln Ser Gly Thr Ala Lys Ile Ser Phe Asp Asn545 550 555 560Glu Tyr Phe Asn Gln Ser Asp Phe Ser Ser Val Ala Met Thr Arg Ser 565 570 575Gly Leu Ser Leu Glu Glu Leu Arg Ile Val Glu Gly Gln Gly Gln Ser 580 585 590Ser Glu Val Ile Thr Pro Pro Glu Glu Ile Ser Arg Ile Asn Asp Leu 595 600 605Asp Leu Lys Ser Ser Thr Leu Leu Asp Gly Lys Met Val Met Glu Gly 610 615 620Phe Ser Glu Glu Ile Gly Asn His Leu Lys Leu Gly Ser Ala Phe Thr625 630 635 640Phe Arg Val Thr Val Leu Gln Ala Ser Gly Ile Leu Pro Glu Tyr Ala 645 650 655Asp Ile Phe Cys Gln Phe Asn Phe Leu His Arg His Asp Glu Ala Phe 660 665 670Ser Thr Glu Pro Leu Lys Asn Asn Gly Arg Gly Ser Pro Leu Ala Phe 675 680 685Tyr His Val Gln Asn Ile Ala Val Glu Ile Thr Glu Ser Phe Val Asp 690 695 700Tyr Ile Lys Thr Lys Pro Ile Val Phe Glu Val Phe Gly His Tyr Gln705 710 715 720Gln His Pro Leu His Leu Gln Gly Gln Glu Leu Asn Ser Pro Pro Gln 725 730 735Pro Cys Arg Arg Phe Phe Pro Pro Pro Met Pro Leu Ser Lys Pro Val 740 745 750Pro Ala Thr Lys Leu Asn Thr Met Ser Lys Thr Ser Leu Gly Gln Ser 755 760 765Met Ser Lys Tyr Asp Leu Leu Val Trp Phe Glu Ile Ser Glu Leu Glu 770 775 780Pro Thr Gly Glu Tyr Ile Pro Ala Val Val Asp His Thr Ala Gly Leu785 790 795 800Pro Cys Gln Gly Thr Phe Leu Leu His Gln Gly Ile Gln Arg Arg Ile 805 810 815Thr Val Thr Ile Ile His Glu Lys Gly Ser Glu Leu His Trp Lys Asp 820 825 830Val Arg Glu Leu Val Val Gly Arg Ile Arg Asn Lys Pro Glu Val Asp 835 840 845Glu Ala Ala Val Asp Ala Ile Leu Ser Leu Asn Ile Ile Ser Ala Lys 850 855 860Tyr Leu Lys Ser Ser His Asn Ser Ser Arg Thr Phe Tyr Arg Phe Glu865 870 875 880Ala Val Trp Asp Ser Ser Leu His Asn Ser Leu Leu Leu Asn Arg Val 885 890 895Thr Pro Tyr Gly Glu Lys Ile Tyr Met Thr Leu Ser Ala Tyr Leu Glu 900 905 910Leu Asp His Cys Ile Gln Pro Ala Val Ile Thr Lys Asp Val Cys Met 915 920 925Val Phe Tyr Ser Arg Asp Ala Lys Ile Ser Pro Pro Arg Ser Leu Arg 930 935 940Ser Leu Phe Gly Ser Gly Tyr Ser Lys Ser Pro Asp Ser Asn Arg Val945 950 955 960Thr Gly Ile Tyr Glu Leu Ser Leu Cys Lys Met Ser Asp Thr Gly Ser 965 970 975Pro Gly Met Gln Arg Arg Arg Arg Lys Ile Leu Asp Thr Ser Val Ala 980 985 990Tyr Val Arg Gly Glu Glu Asn Leu Ala Gly Trp Arg Pro Arg Gly Asp 995 1000 1005Ser Leu Ile Leu Glu His Gln Trp Glu Leu Glu Lys Leu Glu Leu Leu 1010 1015 1020His Glu Val Glu Lys Thr Arg His Phe Leu Leu Leu Arg Glu Arg Leu1025 1030 1035 1040Gly Asp Ser Ile Pro Lys Ser Leu Ser Asp Ser Leu Ser Pro Ser Leu 1045 1050 1055Ser Ser Gly Thr Leu Ser Thr Ser Thr Ser Ile Ser Ser Gln Ile Ser 1060 1065 1070Thr Thr Thr Phe Glu Ser Ala Ile Thr Pro Ser Glu Ser Ser Gly Tyr 1075 1080 1085Asp Ser Gly Asp Ile Glu Ser Leu Val Asp Arg Glu Lys Glu Leu Ala 1090 1095 1100Thr Lys Cys Leu Gln Leu Leu Thr His Thr Phe Asn Arg Glu Phe Ser1105 1110 1115 1120Gln Val His Gly Ser Val Ser Asp Cys Lys Leu Ser Asp Ile Ser Pro 1125 1130 1135Ile Gly Arg Asp Pro Ser Glu Ser Ser Phe Ser Ser Ala Thr Leu Thr 1140 1145 1150Pro Ser Ser Thr Cys Pro Ser Leu Val Asp Ser Arg Ser Asn Ser Leu 1155 1160 1165Asp Gln Lys Thr Pro Glu Ala Asn Ser Arg Ala Ser Ser Pro Cys Pro 1170 1175 1180Glu Phe Glu Gln Phe Gln Ile Val Pro Ala Val Glu Thr Pro Tyr Leu1185 1190 1195 1200Ala Arg Ala Gly Lys Asn Glu Phe Leu Asn Leu Val Pro Asp Ile Glu 1205 1210 1215Glu Ile Arg Pro Ser Ser Val Val Ser Lys Lys Gly Tyr Leu His Phe 1220 1225 1230Lys Glu Pro Leu Tyr Ser Asn Trp Ala Lys His Phe Val Val Val Arg 1235 1240 1245Arg Pro Tyr Val Phe Ile Tyr Asn Ser Asp Lys Asp Pro Val Glu Arg 1250 1255 1260Gly Ile Ile Asn Leu Ser Thr Ala Gln Val Glu Tyr Ser Glu Asp Gln1265 1270 1275 1280Gln Ala Met Val Lys Thr Pro Asn Thr Phe Ala Val Cys Thr Lys His 1285 1290 1295Arg Gly Val Leu Leu Gln Ala Leu Asn Asp Lys Asp Met Asn Asp Trp 1300 1305 1310Leu Tyr Ala Phe Asn Pro Leu Leu Ala Gly Thr Ile Arg Ser Lys Leu 1315 1320 1325Ser Arg Arg Cys Pro Ser Gln Ser Lys Tyr 1330 1335313094DNAHomo sapiens 31tttgactggc cgtagagtct gcgcagttgg tgaatggcgt tggtggcggg aaagttgagt 60ctctcctgcg ccgagccttc ggggcgatgt gtagtgcctt ccatagggct gagtctggga 120ccgagctcct tgcccgactt gaaggtagaa gttccttgaa agaaatagaa ccaaatctgt 180ttgctgatga agattcacct gtgcatggtg atattcttga atttcatggc ccagaaggaa 240caggaaaaac agaaatgctt tatcacctaa cagcacgatg tatacttccc aaatcagaag 300gtggcctgga agtagaagtc ttatttattg atacagatta ccactttgat atgctccggc 360tagttacaat tcttgagcac agactatccc aaagctctga agaaataatc aaatactgcc 420tgggaagatt ttttttggtg tactgcagta gtagcaccca cttacttctt acactttact 480cactagaaag tatgttttgt agtcacccat ctctctgcct tttgattttg gatagcctgt 540cagcttttta ctggatagac cgcgtcaatg gaggagaaag tgtgaactta caggagtcta 600ctctgaggaa atgttctcag tgcttagaga agcttgtaaa tgactatcgc ctggttcttt 660ttgcaacgac acaaactata atgcagaaag cctcgagctc atcagaagaa ccttctcatg 720cctctcgacg actgtgtgat gtggacatag actacagacc ttatctctgt aaggcatggc 780agcaactggt gaagcacagg atgtttttct ccaaacaaga tgattctcaa agcagcaacc 840aattttcatt agtttcacgt tgtttaaaaa gtaacagttt aaaaaaacat ttttttatta 900ttggagaaag tggggttgaa ttttgttgat atacatcata aaatagtctt ttgcagggta 960ctacgcaagc cttaaaattt ttcttaagac agagtcttgc tctgtctccc aggctggagt 1020gcagtggcac aatcatggct cactgcagcc ttgaactcct ggcctcaagg gatcctccta 1080tgtgtgcctc ctagagtgca gggattacag gcgtgagcca ctgctcgtgg ccaaaagttt 1140tctttttttt tttttttctt tttgaaacag tcttactctg tctcccaggc tgctggagtg 1200cagtggcaca atctcggccc gctgcagcct ctgcctcttg ggttcaagtg attcttccac 1260ctcagcctcc caggtagctg ggattacagg cacccaccac cacgcctggc taatttttgt 1320atttttaata gagacggggt ttcaccatgt tggccaggct ggtctcgaac tcctgacctc 1380aagtgatcca cccacctcgg cctcccaaag tgctaggatt acaggcccgt gcccagccct 1440aaagttttaa actctagggg aattaacagt atttctttac agaatggatt tgttaaacta 1500gcacagtaaa agtaaagact attctgtttc taggctgttg aatcaaagtg attttagcaa 1560ttaaactttg tattaattta ccaccaatat ttcttcacaa aggaactttt aaaagattat 1620ctcagaaagt aaatctgaga ggtaagaagt aataatgagt aaatggtaag tacttgagta 1680aatctaaaga aatattgata gtaaggcaat cctaagcaaa aagaacaaag ctggaggcat 1740cacgctaccc agcttcaaac tatactacaa ggctacagta accaaaacag catagtactg 1800gcacaaaaac acacgtagac tgatggaaca gaatagagaa tttagaaatg agaccacaca 1860cctataattt ttttgatctt cgatgaacct gacaaaaaca agcaatgggc aatggattct 1920ctattcaata aatcgtgctg ggataactgg ccagccatat ggaaaagatt gaaaatggac 1980gccttcctta tgccatatac aaaaattaac tcaagatgga ttaaagactt aatgtaaaac 2040ccaaaacagt aaaaatcctg gaagacaacc caggcagtac cattcaggac ataggcacag 2100gcaaagattt catgacgaag acgccaaaaa caattgcaac agaagcaaaa attcacaaat 2160gggatctaat taaactaaag agctgcacag caaaagaaac tatcaagaga gtaaacagac 2220agcttacaga atgggagaaa attgttgcaa actatgcatc tgagaaaggt ctgaaatcca 2280gcatctatac gtaatttaaa caaatttaga agaaaaaacc accccattaa aaagtgggca 2340aaggacatga acagacactt ttcaaaagaa gacatctgtg gccaacaatc ctatggaaaa 2400aagcccagca tcactgatca ttagagaaat gcaaatcgaa acaacaacga gataccatct 2460cacaccagtc caaatggcta ttataaaaat gtcagaaaat aacagatgct ggtgaggttg 2520tggagaaaaa gatatgctta tacactgttg gtggaaatgt aaattaaatt agttcagcca 2580ttgtggaaga cagtgtgggg ataaagacag agataccatt caacccagca atctcattac 2640tgggtatata cccaaaggaa tagaaatcat tgttataaag acacatgcac gcgtatgttc 2700gttgcagcac tgcccatcag tgacagactg gattaaaaaa atgtggtaca tacacaccag 2760ggaatactat acagccataa aaaggaacaa gactgactgg gcgtggtggc tcatgcctgt 2820gatcctagca ctttgcgagg ccgaggtggg tggattgccc gcgctcagga ggtcaagacc 2880agcctgggca acacggtgaa accccatctc tattaaaata caaaaaatta gctgggcatg 2940gtggtgcgtg cctgtagtgc cagctactca ggaggccgag gcaggagaat tgctggaacc 3000caggaggtgg aggttgcagt gagctgagat cgcgccattg cactcccgcc tgggcgactc 3060catctctaaa aaaaaaaaaa aaaaaaaaaa aaaa 309432280PRTHomo sapiens 32Met Cys Ser Ala Phe His Arg Ala Glu Ser Gly Thr Glu Leu Leu Ala 1 5 10 15Arg Leu Glu Gly Arg Ser Ser Leu Lys Glu Ile Glu Pro Asn Leu Phe 20 25 30Ala Asp Glu Asp Ser Pro Val His Gly Asp Ile Leu Glu Phe His Gly 35 40 45Pro Glu Gly Thr Gly Lys Thr Glu Met Leu Tyr His Leu Thr Ala Arg 50 55 60Cys Ile Leu Pro Lys Ser Glu Gly Gly Leu Glu Val Glu Val Leu Phe65 70 75 80Ile Asp Thr Asp Tyr His Phe Asp Met Leu Arg Leu Val Thr Ile Leu 85 90 95Glu His Arg Leu Ser Gln Ser Ser Glu Glu Ile Ile Lys Tyr Cys Leu 100 105 110Gly Arg Phe Phe Leu Val Tyr Cys Ser Ser Ser Thr His Leu Leu Leu 115 120 125Thr Leu Tyr Ser Leu Glu Ser Met Phe Cys Ser His Pro Ser Leu Cys 130 135 140Leu Leu Ile Leu Asp Ser Leu Ser Ala Phe Tyr Trp Ile Asp Arg Val145 150 155 160Asn Gly Gly Glu Ser Val Asn Leu Gln Glu Ser Thr Leu Arg Lys Cys 165 170 175Ser Gln Cys Leu Glu Lys Leu Val Asn Asp Tyr Arg Leu Val Leu Phe 180 185 190Ala Thr Thr Gln Thr Ile Met Gln Lys Ala Ser Ser Ser Ser Glu Glu 195 200 205Pro Ser His Ala Ser Arg Arg Leu Cys Asp Val Asp Ile Asp Tyr Arg 210 215 220Pro Tyr Leu Cys Lys Ala Trp Gln Gln Leu Val Lys His Arg Met Phe225 230 235 240Phe Ser Lys Gln Asp Asp Ser Gln Ser Ser Asn Gln Phe Ser Leu Val 245 250 255Ser Arg Cys Leu Lys Ser Asn Ser Leu Lys Lys His Phe Phe Ile Ile 260 265 270Gly Glu Ser Gly Val Glu Phe Cys 275 28033691DNAHomo sapiens 33gtcctcctcg ccctccaggc cgcccgcgcc gcgccggagt ccgctgtccg ccagctaccc 60gcttcctgcc gcccgccgct gccatgctgc ccgccgcgct gctccgccgc ccgggacttg 120gccgcctcgt ccgccacgcc cgtgcctatg ccgaggccgc cgccgccccg gctgccgcct 180ctggccccaa ccagatgtcc ttcaccttcg cctctcccac gcaggtgttc ttcaacggtg 240ccaacgtccg gcaggtggac gtgcccacgc tgaccggagc cttcggcatc ctggcggccc 300acgtgcccac gctgcaggtc ctgcggccgg ggctggtcgt ggtgcatgca gaggacggca 360ccacctccaa atactttgtg agcagcggtt ccatcgcagt gaacgccgac tcttcggtgc 420agttgttggc cgaagaggcc gtgacgctgg acatgttgga cctgggggca gccaaggcaa 480acttggagaa ggcccaggcg gagctggtgg ggacagctga cgaggccacg cgggcagaga 540tccagatccg aatcgaggcc aacgaggccc tggtgaaggc cctggagtag gcgagccagc 600cgccaaggtt gacctcagct tcggagccac ctctggatga actgccccca gcccccgccc 660cattaaagac ccggaagcct gaaaaaaaaa a 69134168PRTHomo sapiens 34Met Leu Pro Ala Ala Leu Leu Arg Arg Pro Gly Leu Gly Arg Leu Val 1 5 10 15Arg His Ala Arg Ala Tyr Ala Glu Ala Ala Ala Ala Pro Ala Ala Ala 20 25 30Ser Gly Pro Asn Gln Met Ser Phe Thr Phe Ala Ser Pro Thr Gln Val 35 40 45Phe Phe Asn Gly Ala Asn Val Arg Gln Val Asp Val Pro Thr Leu Thr 50 55 60Gly Ala Phe Gly Ile Leu Ala Ala His Val Pro Thr Leu Gln Val Leu65 70 75 80Arg Pro Gly Leu Val Val Val His Ala Glu Asp Gly Thr Thr Ser Lys 85 90 95Tyr Phe Val Ser Ser Gly Ser Ile Ala Val Asn Ala Asp Ser Ser Val 100 105 110Gln Leu Leu Ala Glu Glu Ala Val Thr Leu Asp Met Leu Asp Leu Gly 115 120 125Ala Ala Lys Ala Asn Leu Glu Lys Ala Gln Ala Glu Leu Val Gly Thr 130 135 140Ala Asp Glu Ala Thr Arg Ala Glu Ile Gln Ile Arg Ile Glu Ala Asn145 150 155 160Glu Ala Leu Val Lys Ala Leu Glu 165351378DNAHomo sapiens 35gcgcggcccg ctgcaatccg tggaggaacg cgccgccgag ccaccatcat gcctgggcac 60ttacaggaag gcttcggctg cgtggtcacc aaccgattcg accagttatt tgacgacgaa 120tcggacccct tcgaggtgct gaaggcagca gagaacaaga aaaaagaagc cggcgggggc 180ggcgttgggg gccctggggc caagagcgca gctcaggccg cggcccagac caactccaac 240gcggcaggca aacagctgcg caaggagtcc cagaaagacc gcaagaaccc gctgcccccc 300agcgttggcg tggttgacaa gaaagaggag acgcagccgc ccgtggcgct taagaaagaa 360ggaataagac gagttggaag aagacctgat caacaacttc agggtgaagg gaaaataatt 420gatagaagac cagaaaggcg accacctcgt gaacgaagat tcgaaaagcc acttgaagaa 480aagggtgaag gaggcgaatt ttcagttgat agaccgatta ttgaccgacc tattcgaggt 540cgtggtggtc ttggaagagg tcgagggggc cgtggacgtg gaatgggccg aggagatgga 600tttgattctc gtggcaaacg tgaatttgat aggcatagtg gaagtgatag atcttctttt 660tcacattaca gtggcctgaa gcacgaggac aaacgtggag gtagcggatc tcacaactgg 720ggaactgtca aagacgaatt aacagagtcc cccaaataca ttcagaaaca aatatcttat 780aattacagtg acttggatca atcaaatgtg actgaggaaa cacctgaagg tgaagaacat 840catccagtgg cagacactga aaataaggag aatgaagttg aagaggtaaa agaggagggt 900ccaaaagaga tgactttgga tgagtggaag gctattcaaa ataaggaccg ggcaaaagta 960gaatttaata tccgaaaacc aaatgaaggt gctgatgggc agtggaagaa gggatttgtt 1020cttcataaat caaagagtga agaggctcat gctgaagatt cggttatgga ccatcatttc 1080cggaagccag caaatgatat aacgtctcag ctggagatca attttggaga ccttggccgc 1140ccaggacgtg gcggcagggg aggacgaggt ggacgtgggc gtggtgggcg cccaaaccgt 1200ggcagcagga ccgacaagtc aagtgcttct gctcctgatg tggatgaccc agaggcattc 1260ccagctctgg cttaactgga tgccataaga caaccctggt tcctttgtga acccttctgt 1320tcaaagcttt tgcatgctta aggattccaa acgactaaga aaaaaaaaaa aaaaaaaa 1378362896DNAHomo sapiens 36gggcgcgcca gctcgtagca ggggagcgcc cgcggcgtcg ggtttgggct ggaggtcgcc 60atggggcgag gcagcggcac cttcgagcgt ctcctagaca aggcgaccag ccagctcctg 120ttggagacag attgggagtc cattttgcag atctgcgacc tgatccgcca aggggacaca 180caagcaaaat atgctgtgaa ttccatcaag aagaaagtca acgacaagaa cccacacgtc 240gccttgtatg ccctggaggt catggaatct gtggtaaaga actgtggcca gacagttcat 300gatgaggtgg ccaacaagca gaccatggag gagctgaagg acctgctgaa gagacaagtg 360gaggtaaacg tccgtaacaa gatcctgtac ctgatccagg cctgggcgca tgccttccgg 420aacgagccca agtacaaggt ggtccaggac acctaccaga tcatgaaggt ggaggggcac 480gtctttccag aattcaaaga gagcgatgcc atgtttgctg ccgagagagc cccagactgg 540gtggacgctg aggaatgcca ccgctgcagg gtgcagttcg gggtgatgac ccgtaagcac 600cactgccggg cgtgtgggca gatattctgt ggaaagtgtt cttccaagta ctccaccatc 660cccaagtttg gcatcgagaa ggaggtgcgc gtgtgtgagc cctgctacga gcagctgaac 720aggaaagcgg agggaaaggc cacttccacc actgagctgc cccccgagta cctgaccagc 780cccctgtctc agcagtccca gctgcccccc aagagggacg agacggccct gcaggaggag 840gaggagctgc agctggccct ggcgctgtca cagtcagagg cggaggagaa ggagaggctg 900agacagaagt ccacgtacac ttcgtacccc aaggcggagc ccatgccctc ggcctcctca 960gcgccccccg ccagcagcct gtactcttca cctgtgaact cgtcggcgcc tctggctgag 1020gacatcgacc ctgagctcgc acggtatctc aaccggaact actgggagaa gaagcaggag 1080gaggctcgca agagccccac gccatctgcg cccgtgcccc tgacggagcc ggctgcacag 1140cctggggaag ggcacgcagc ccccaccaac gtggtggaga accccctccc ggagacagac 1200tctcagccca ttcctccctc tggtggcccc tttagtgagc cacagttcca caatggcgag 1260tctgaggaga gccacgagca gttcctgaag gcgctgcaga acgccgtcac caccttcgtg 1320aaccgcatga agagtaacca catgcggggc cgcagcatca ccaatgactc ggccgtgctc 1380tcactcttcc agtccatcaa cggcatgcac ccgcagctgc tggagctgct caaccagctg 1440gacgagcgca ggctgtacta tgaggggctg caggacaagc tggcacagat ccgcgatgcc 1500cggggggcgc tgagtgccct gcgcgaagag caccgggaga agcttcgccg ggcagccgag 1560gaggcagagc gccagcgcca gatccagctg gcccagaagc tggagataat gcggcagaag 1620aagcaggagt acctggaggt gcagaggcag ctggccatcc agcgcctgca ggagcaggag 1680aaggagcggc agatgcggct ggagcagcag aagcagacgg tccagatgcg cgcgcagatg 1740cccgccttcc ccctgcccta cgcccagctc caggccatgc ccgcagccgg aggtgtgctc 1800taccagccct cgggaccagc cagcttcccc agcaccttca gccctgccgg ctcggtggag 1860ggctccccaa tgcacggcgt gtacatgagc cagccggccc ctgccgctgg cccctacccc 1920agcatgccca gcactgcggc tgatcccagc atggtgagtg cctacatgta cccagcaggg 1980gccactgggg cgcaggcggc cccccaggcc caggccggac ccaccgccag ccccgcttac 2040tcatcctacc agcctactcc cacagcgggc taccagaacg

tggcctccca ggccccacag 2100agcctcccgg ccatctctca gcctccgcag tccagcacca tgggctacat ggggagccag 2160tcagtctcca tgggctacca gccttacaac atgcagaatc tcatgaccac cctcccaagc 2220caggatgcgt ctctgccacc ccagcagccc tacatcgcgg ggcagcagcc catgtaccag 2280cagatggcac cctctggcgg tcccccccag cagcagcccc ccgtggccca gcaaccgcag 2340gcacaggggc cgccggcaca gggcagcgag gcccagctca tttcattcga ctgacccagg 2400ccatgctcac gtccggagta acactacata cagttcacct gaaacgcctc gtctctaact 2460gccgtcgtcc tgcctccctg tcctctactg ccggtagtgt cccttctctg cgagtgaggg 2520ggggccttca ccccaagccc acctcccttg tcctcagcct actgcagtcc ctgagttagt 2580ctctgctttc tttccccagg gctgggccat ggggagggaa ggactttctc ccaggggaag 2640cccccagccc tgtgggtcat ggtctgtgag aggtggcagg aatggggacc ctcacccccc 2700aagcagcctg tgccctctgg ccgcactgtg agctggctgt ggtgtctggg tgtggcctgg 2760ggctccctct gcaggggcct ctctcggcag ccacagccaa gggtggaggc ttcaggtctc 2820cagcttctct gcttctcagc tgccatctcc agtgccccag aatggtacag cgataataaa 2880atgtatttca gaaagg 289637777PRTHomo sapiens 37Met Gly Arg Gly Ser Gly Thr Phe Glu Arg Leu Leu Asp Lys Ala Thr 1 5 10 15Ser Gln Leu Leu Leu Glu Thr Asp Trp Glu Ser Ile Leu Gln Ile Cys 20 25 30Asp Leu Ile Arg Gln Gly Asp Thr Gln Ala Lys Tyr Ala Val Asn Ser 35 40 45Ile Lys Lys Lys Val Asn Asp Lys Asn Pro His Val Ala Leu Tyr Ala 50 55 60Leu Glu Val Met Glu Ser Val Val Lys Asn Cys Gly Gln Thr Val His65 70 75 80Asp Glu Val Ala Asn Lys Gln Thr Met Glu Glu Leu Lys Asp Leu Leu 85 90 95Lys Arg Gln Val Glu Val Asn Val Arg Asn Lys Ile Leu Tyr Leu Ile 100 105 110Gln Ala Trp Ala His Ala Phe Arg Asn Glu Pro Lys Tyr Lys Val Val 115 120 125Gln Asp Thr Tyr Gln Ile Met Lys Val Glu Gly His Val Phe Pro Glu 130 135 140Phe Lys Glu Ser Asp Ala Met Phe Ala Ala Glu Arg Ala Pro Asp Trp145 150 155 160Val Asp Ala Glu Glu Cys His Arg Cys Arg Val Gln Phe Gly Val Met 165 170 175Thr Arg Lys His His Cys Arg Ala Cys Gly Gln Ile Phe Cys Gly Lys 180 185 190Cys Ser Ser Lys Tyr Ser Thr Ile Pro Lys Phe Gly Ile Glu Lys Glu 195 200 205Val Arg Val Cys Glu Pro Cys Tyr Glu Gln Leu Asn Arg Lys Ala Glu 210 215 220Gly Lys Ala Thr Ser Thr Thr Glu Leu Pro Pro Glu Tyr Leu Thr Ser225 230 235 240Pro Leu Ser Gln Gln Ser Gln Leu Pro Pro Lys Arg Asp Glu Thr Ala 245 250 255Leu Gln Glu Glu Glu Glu Leu Gln Leu Ala Leu Ala Leu Ser Gln Ser 260 265 270Glu Ala Glu Glu Lys Glu Arg Leu Arg Gln Lys Ser Thr Tyr Thr Ser 275 280 285Tyr Pro Lys Ala Glu Pro Met Pro Ser Ala Ser Ser Ala Pro Pro Ala 290 295 300Ser Ser Leu Tyr Ser Ser Pro Val Asn Ser Ser Ala Pro Leu Ala Glu305 310 315 320Asp Ile Asp Pro Glu Leu Ala Arg Tyr Leu Asn Arg Asn Tyr Trp Glu 325 330 335Lys Lys Gln Glu Glu Ala Arg Lys Ser Pro Thr Pro Ser Ala Pro Val 340 345 350Pro Leu Thr Glu Pro Ala Ala Gln Pro Gly Glu Gly His Ala Ala Pro 355 360 365Thr Asn Val Val Glu Asn Pro Leu Pro Glu Thr Asp Ser Gln Pro Ile 370 375 380Pro Pro Ser Gly Gly Pro Phe Ser Glu Pro Gln Phe His Asn Gly Glu385 390 395 400Ser Glu Glu Ser His Glu Gln Phe Leu Lys Ala Leu Gln Asn Ala Val 405 410 415Thr Thr Phe Val Asn Arg Met Lys Ser Asn His Met Arg Gly Arg Ser 420 425 430Ile Thr Asn Asp Ser Ala Val Leu Ser Leu Phe Gln Ser Ile Asn Gly 435 440 445Met His Pro Gln Leu Leu Glu Leu Leu Asn Gln Leu Asp Glu Arg Arg 450 455 460Leu Tyr Tyr Glu Gly Leu Gln Asp Lys Leu Ala Gln Ile Arg Asp Ala465 470 475 480Arg Gly Ala Leu Ser Ala Leu Arg Glu Glu His Arg Glu Lys Leu Arg 485 490 495Arg Ala Ala Glu Glu Ala Glu Arg Gln Arg Gln Ile Gln Leu Ala Gln 500 505 510Lys Leu Glu Ile Met Arg Gln Lys Lys Gln Glu Tyr Leu Glu Val Gln 515 520 525Arg Gln Leu Ala Ile Gln Arg Leu Gln Glu Gln Glu Lys Glu Arg Gln 530 535 540Met Arg Leu Glu Gln Gln Lys Gln Thr Val Gln Met Arg Ala Gln Met545 550 555 560Pro Ala Phe Pro Leu Pro Tyr Ala Gln Leu Gln Ala Met Pro Ala Ala 565 570 575Gly Gly Val Leu Tyr Gln Pro Ser Gly Pro Ala Ser Phe Pro Ser Thr 580 585 590Phe Ser Pro Ala Gly Ser Val Glu Gly Ser Pro Met His Gly Val Tyr 595 600 605Met Ser Gln Pro Ala Pro Ala Ala Gly Pro Tyr Pro Ser Met Pro Ser 610 615 620Thr Ala Ala Asp Pro Ser Met Val Ser Ala Tyr Met Tyr Pro Ala Gly625 630 635 640Ala Thr Gly Ala Gln Ala Ala Pro Gln Ala Gln Ala Gly Pro Thr Ala 645 650 655Ser Pro Ala Tyr Ser Ser Tyr Gln Pro Thr Pro Thr Ala Gly Tyr Gln 660 665 670Asn Val Ala Ser Gln Ala Pro Gln Ser Leu Pro Ala Ile Ser Gln Pro 675 680 685Pro Gln Ser Ser Thr Met Gly Tyr Met Gly Ser Gln Ser Val Ser Met 690 695 700Gly Tyr Gln Pro Tyr Asn Met Gln Asn Leu Met Thr Thr Leu Pro Ser705 710 715 720Gln Asp Ala Ser Leu Pro Pro Gln Gln Pro Tyr Ile Ala Gly Gln Gln 725 730 735Pro Met Tyr Gln Gln Met Ala Pro Ser Gly Gly Pro Pro Gln Gln Gln 740 745 750Pro Pro Val Ala Gln Gln Pro Gln Ala Gln Gly Pro Pro Ala Gln Gly 755 760 765Ser Glu Ala Gln Leu Ile Ser Phe Asp 770 775382569DNAHomo sapiens 38tccctcgtct ctctcgggca acatggcggg cgtggaggag gtagcggcct ccgggagcca 60cctgaatggc gacctggatc cagacgacag ggaagaagga gctgcctcta cggctgagga 120agcagccaag aaaaaaagac gaaagaagaa gaagagcaaa gggccttctg cagcagggga 180acaggaacct gataaagaat caggagcctc agtggatgaa gtagcaagac agttggaaag 240atcagcattg gaagataaag aaagagatga agatgatgaa gatggagatg gcgatggaga 300tggagcaact ggaaagaaga agaaaaagaa gaagaagaag agaggaccaa aagttcaaac 360agaccctccc tcagttccaa tatgtgacct gtatcctaat ggtgtatttc ccaaaggaca 420agaatgcgaa tacccaccca cacaagatgg gcgaacagct gcttggagaa ctacaagtga 480agaaaagaaa gcattagatc aggcaagtga agagatttgg aatgattttc gagaagctgc 540agaagcacat cgacaagtta gaaaatacgt aatgagctgg atcaagcctg ggatgacaat 600gatagaaatc tgtgaaaagt tggaagactg ttcacgcaag ttaataaaag agaatggatt 660aaatgcaggc ctggcatttc ctactggatg ttctctcaat aattgtgctg cccattatac 720tcccaatgcc ggtgacacaa cagtattaca gtatgatgac atctgtaaaa tagactttgg 780aacacatata agtggtagga ttattgactg tgcttttact gtcactttta atcccaaata 840tgatacgtta ttaaaagctg taaaagatgc tactaacact ggaataaagt gtgctggaat 900tgatgttcgt ctgtgtgatg ttggtgaggc catccaagaa gttatggagt cctatgaagt 960tgaaatagat gggaagacat atcaagtgaa accaatccgt aatctaaatg gacattcaat 1020tgggcaatat agaatacatg ctggaaaaac agtgccgatt gtgaaaggag gggaggcaac 1080aagaatggag gaaggagaag tatatgcaat tgaaaccttt ggtagtacag gaaaaggtgt 1140tgttcatgat gatatggaat gttcacatta catgaaaaat tttgatgttg gacatgtgcc 1200aataaggctt ccaagaacaa aacacttgtt aaatgtcatc aatgaaaact ttggaaccct 1260tgccttctgc cgcagatggc tggatcgctt gggagaaagt aaatacttga tggctctgaa 1320gaatctgtgt gacttgggca ttgtagatcc atatccacca ttatgtgaca ttaaaggatc 1380atatacagcg caatttgaac ataccatcct gttgcgtcca acatgtaaag aagttgtcag 1440cagaggagat gactattaaa cttagtccaa agccacctca acacctttat tttctgagct 1500ttgttggaaa acatgatacc agaattaatt tgccacatgt tgtctgtttt aacagtggac 1560ccatgtaata cttttatcca tgtttaaaaa agaaggaatt tggacaaagg caaaccgtct 1620aatgtaatta accaacgaaa aagctttccg gacttttaaa tgctaactgt ttttcccctt 1680cctgtctagg aaaatgctat aaagctcaaa ttagttagga atgacttata cgttttgttt 1740tgaataccta agagatactt tttggatatt tatattgcca tattcttact tgaatgcttt 1800gaatgactac atccagttct gcacctatac cctctggtgt tgctttttaa ccttcctgga 1860atccattttc taaaaaataa agacacattc ttctcagcac cacacaacac ctattccaaa 1920atcgaccaca tatttggaag taaagctctc ctcagcaaat gtaaaagaac agaaattata 1980acaaactgtc tctcagacca cagtataacc aaactagaac tcaggattaa gaaactcact 2040caaaaccaca caactacatg gaaactgaac aacctgctcc tgaatgacta ctggatacat 2100aacaaaatga aggcagaaat aaagatgttc tttaaaacca atgagaacaa agacacaaca 2160taccagaatc tctgggacac attcaaagca gtgtgtagag ggaaatttat agcactaaat 2220gcccacaaga gaaagcagga aatatctaaa attgacaccc taacatcaca attaaaagaa 2280ctagagaagc aagagcaaac acattgaaaa gctaagagaa ggcaagaaat aactaagatc 2340agagcagaac tgaaggaaat agagacacaa aaaactcttc aaaaaatcaa tgaatccagg 2400agctggtttt ttgaaacgat caacaaaatt gatagacact agcaagacta ataaagaaga 2460aaggagagaa gaatcaaata gaagcaataa aaaatgataa aggggatatc accaccaatc 2520ccacagaaat aaaccaccat cagagaatac tacaaacacc tctacgcaa 256939478PRTHomo sapiens 39Met Ala Gly Val Glu Glu Val Ala Ala Ser Gly Ser His Leu Asn Gly 1 5 10 15Asp Leu Asp Pro Asp Asp Arg Glu Glu Gly Ala Ala Ser Thr Ala Glu 20 25 30Glu Ala Ala Lys Lys Lys Arg Arg Lys Lys Lys Lys Ser Lys Gly Pro 35 40 45Ser Ala Ala Gly Glu Gln Glu Pro Asp Lys Glu Ser Gly Ala Ser Val 50 55 60Asp Glu Val Ala Arg Gln Leu Glu Arg Ser Ala Leu Glu Asp Lys Glu65 70 75 80Arg Asp Glu Asp Asp Glu Asp Gly Asp Gly Asp Gly Asp Gly Ala Thr 85 90 95Gly Lys Lys Lys Lys Lys Lys Lys Lys Lys Arg Gly Pro Lys Val Gln 100 105 110Thr Asp Pro Pro Ser Val Pro Ile Cys Asp Leu Tyr Pro Asn Gly Val 115 120 125Phe Pro Lys Gly Gln Glu Cys Glu Tyr Pro Pro Thr Gln Asp Gly Arg 130 135 140Thr Ala Ala Trp Arg Thr Thr Ser Glu Glu Lys Lys Ala Leu Asp Gln145 150 155 160Ala Ser Glu Glu Ile Trp Asn Asp Phe Arg Glu Ala Ala Glu Ala His 165 170 175Arg Gln Val Arg Lys Tyr Val Met Ser Trp Ile Lys Pro Gly Met Thr 180 185 190Met Ile Glu Ile Cys Glu Lys Leu Glu Asp Cys Ser Arg Lys Leu Ile 195 200 205Lys Glu Asn Gly Leu Asn Ala Gly Leu Ala Phe Pro Thr Gly Cys Ser 210 215 220Leu Asn Asn Cys Ala Ala His Tyr Thr Pro Asn Ala Gly Asp Thr Thr225 230 235 240Val Leu Gln Tyr Asp Asp Ile Cys Lys Ile Asp Phe Gly Thr His Ile 245 250 255Ser Gly Arg Ile Ile Asp Cys Ala Phe Thr Val Thr Phe Asn Pro Lys 260 265 270Tyr Asp Thr Leu Leu Lys Ala Val Lys Asp Ala Thr Asn Thr Gly Ile 275 280 285Lys Cys Ala Gly Ile Asp Val Arg Leu Cys Asp Val Gly Glu Ala Ile 290 295 300Gln Glu Val Met Glu Ser Tyr Glu Val Glu Ile Asp Gly Lys Thr Tyr305 310 315 320Gln Val Lys Pro Ile Arg Asn Leu Asn Gly His Ser Ile Gly Gln Tyr 325 330 335Arg Ile His Ala Gly Lys Thr Val Pro Ile Val Lys Gly Gly Glu Ala 340 345 350Thr Arg Met Glu Glu Gly Glu Val Tyr Ala Ile Glu Thr Phe Gly Ser 355 360 365Thr Gly Lys Gly Val Val His Asp Asp Met Glu Cys Ser His Tyr Met 370 375 380Lys Asn Phe Asp Val Gly His Val Pro Ile Arg Leu Pro Arg Thr Lys385 390 395 400His Leu Leu Asn Val Ile Asn Glu Asn Phe Gly Thr Leu Ala Phe Cys 405 410 415Arg Arg Trp Leu Asp Arg Leu Gly Glu Ser Lys Tyr Leu Met Ala Leu 420 425 430Lys Asn Leu Cys Asp Leu Gly Ile Val Asp Pro Tyr Pro Pro Leu Cys 435 440 445Asp Ile Lys Gly Ser Tyr Thr Ala Gln Phe Glu His Thr Ile Leu Leu 450 455 460Arg Pro Thr Cys Lys Glu Val Val Ser Arg Gly Asp Asp Tyr465 470 475401183DNAHomo sapiensmisc_feature(0)...(0)n = a, t, c or g 40cgcccaagaa gaaaatggcc ataagtggag tccctgtgct aggatttttc atcatagctg 60tgctgatgag cgctcaggaa tcatgggcta tcaaagaaga acatgtgatc atccaggccg 120agttctatct gaatcctgac caatcaggcg agtttatgtt tgactttgat ggtgatgaga 180ttttccatgt ggatatggca aagaaggaga cggtctggcg gcttgaagaa tttggacgat 240ttgccagctt tgaggctcaa ggtgcattgg ccaacatagc tgtggacaaa gccaacttgg 300aaatcatgac aaagcgctcc aactatactc cgatcaccaa tgtacctcca gaggtaactg 360tgctcacgaa cagccctgtg gaactgagag agcccaacgt cctcatctgt ttcatcgaca 420agttcacccc accagtggtc aatgtcacgt ggcttcgaaa tggaaaacct gtcaccacag 480gagtgtcaga gacagtcttc ctgcccaggg aagaccacct tttccgcaag ttccactatc 540tccccttcct gccctcaact gaggacgttt acgactgcag ggtggagcac tggggcttgg 600atgagcctct tctcaagcac tgggagtttg atgctccaag ccctctccca gagactacag 660agaacgtggt gtgtgccctg ggcctgactg tgggtctggt gggcatcatt attgggacca 720tcttcatcat caagggagtg cgcaaaagca atgcagcaga acgcaggggg cctctgtaag 780gcacatggag gtgatgatgt ttcttagaga gaagatcact gaagaaactt ctgctttaat 840gactttacaa agctggcaat attacaatcc ttgacctcag tgaaagcagt catcttcagc 900gttttccagc cctatagcca ccccaagtgt ggttatgcct cctcgattgc tccgtactct 960aacatctagc tggcttccct gtctattgcc ttttcctgta tctattttcc tctatttcct 1020atcattttat tatcaccatg caatgcctct ggaataaaac atacaggagt ctgtctctgc 1080tatggaatgc cccatggggc atctcttgtg tacttattgt ttaaggtttc ctcaaactgn 1140gattcttctg aacacaataa actattttga tgatcttggg tgg 118341254PRTHomo sapiens 41Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val 1 5 10 15Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile 20 25 30Ile Gln Ala Glu Phe Tyr Leu Asn Pro Asp Gln Ser Gly Glu Phe Met 35 40 45Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp Met Ala Lys Lys 50 55 60Glu Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Phe Ala Ser Phe Glu65 70 75 80Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp Lys Ala Asn Leu Glu 85 90 95Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro Ile Thr Asn Val Pro Pro 100 105 110Glu Val Thr Val Leu Thr Asn Ser Pro Val Glu Leu Arg Glu Pro Asn 115 120 125Val Leu Ile Cys Phe Ile Asp Lys Phe Thr Pro Pro Val Val Asn Val 130 135 140Thr Trp Leu Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr145 150 155 160Val Phe Leu Pro Arg Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu 165 170 175Pro Phe Leu Pro Ser Thr Glu Asp Val Tyr Asp Cys Arg Val Glu His 180 185 190Trp Gly Leu Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro 195 200 205Ser Pro Leu Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu Gly Leu 210 215 220Thr Val Gly Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys225 230 235 240Gly Val Arg Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro Leu 245 25042266DNAHomo sapiens 42atgcccaagt gtcccaagtg caacaaggag gtgtacttcg ccgagagggt gacctctctg 60ggcaaggact ggcatcggcc ctgcctgaag tgcgagaaat gtgggaagac gctgacctct 120gggggccacg ctgagcacga aggcaaaccc tactgcaacc acccctgcta cgcagccatg 180tttgggccta aaggctttgg gcggggcgga gccgagagcc acactttcaa gtaaaccagg 240tggtggagac ccatccttgg ctgctt 2664377PRTHomo sapiens 43Met Pro Lys Cys Pro Lys Cys Asn Lys Glu Val Tyr Phe Ala Glu Arg 1 5 10 15Val Thr Ser Leu Gly Lys Asp Trp His Arg Pro Cys Leu Lys Cys Glu 20 25 30Lys Cys Gly Lys Thr Leu Thr Ser Gly Gly His Ala Glu His Glu Gly 35 40 45Lys Pro Tyr Cys Asn His Pro Cys Tyr Ala Ala Met Phe Gly Pro Lys 50 55 60Gly Phe Gly Arg Gly Gly Ala Glu Ser His Thr Phe Lys65 70 75441665DNAHomo sapiens 44gaaggaactg gttctgctca cacttgctgg cttgcgcatc aggactggct ttatctcctg 60actcacggtg caaaggtgca ctctgcgaac gttaagtccg tccccagcgc ttggaatcct 120acggccccca cagccggatc ccctcagcct tccaggtcct caactcccgt ggacgctgaa 180caatggcctc catggggcta caggtaatgg gcatcgcgct ggccgtcctg ggctggctgg 240ccgtcatgct gtgctgcgcg ctgcccatgt ggcgcgtgac ggccttcatc

ggcagcaaca 300ttgtcacctc gcagaccatc tgggagggcc tatggatgaa ctgcgtggtg cagagcaccg 360gccagatgca gtgcaaggtg tacgactcgc tgctggcact gccgcaggac ctgcaggcgg 420cccgcgccct cgtcatcatc agcatcatcg tggctgctct gggcgtgctg ctgtccgtgg 480tggggggcaa gtgtaccaac tgcctggagg atgaaagcgc caaggccaag accatgatcg 540tggcgggcgt ggtgttcctg ttggccggcc ttatggtgat agtgccggtg tcctggacgg 600cccacaacat catccaagac ttctacaatc cgctggtggc ctccgggcag aagcgggaga 660tgggtgcctc gctctacgtc ggctgggccg cctccggcct gctgctcctt ggcggggggc 720tgctttgctg caactgtcca ccccgcacag acaagcctta ctccgccaag tattctgctg 780cccgctctgc tgctgccagc aactacgtgt aaggtgccac ggctccactc tgttcctctc 840tgctttgttc ttccctggac tgagctcagc gcaggctgtg accccaggag ggccctgcca 900cgggccactg gctgctgggg actggggact gggcagagac tgagccaggc aggaaggcag 960cagccttcag cctctctggc ccactcggac aacttcccaa ggccgcctcc tgctagcaag 1020aacagagtcc accctcctct ggatattggg gagggacgga agtgacaggg tgtggtggtg 1080gagtggggag ctggcttctg ctggccagga tagcttaacc ctgactttgg gatctgcctg 1140catcggcgtt ggccactgtc cccatttaca ttttccccac tctgtctgcc tgcatctcct 1200ctgttccggg taggccttga tatcacctct gggactgtgc cttgctcacc gaaacccgcg 1260cccaggagta tggctgaggc cttgcccacc cacctgcctg ggaagtgcag agtggatgga 1320cgggtttaga ggggaggggc gaaggtgctg taaacaggtt tgggcagtgg tgggggaggg 1380ggccagagag gcggctcagg ttgcccagct ctgtggcctc aggactctct gcctcacccg 1440cttcagccca gggcccctgg agactgatcc cctctgagtc ctctgcccct tccaaggaca 1500ctaatgagcc tgggagggtg gcagggagga ggggacagct tcacccttgg aagtcctggg 1560gtttttcctc ttccttcttt gtggtttctg ttttgtaatt taagaagagc tattcatcac 1620tgtaattatt attattttct acaataaatg ggacctgtgc acagg 166545209PRTHomo sapiens 45Met Ala Ser Met Gly Leu Gln Val Met Gly Ile Ala Leu Ala Val Leu 1 5 10 15Gly Trp Leu Ala Val Met Leu Cys Cys Ala Leu Pro Met Trp Arg Val 20 25 30Thr Ala Phe Ile Gly Ser Asn Ile Val Thr Ser Gln Thr Ile Trp Glu 35 40 45Gly Leu Trp Met Asn Cys Val Val Gln Ser Thr Gly Gln Met Gln Cys 50 55 60Lys Val Tyr Asp Ser Leu Leu Ala Leu Pro Gln Asp Leu Gln Ala Ala65 70 75 80Arg Ala Leu Val Ile Ile Ser Ile Ile Val Ala Ala Leu Gly Val Leu 85 90 95Leu Ser Val Val Gly Gly Lys Cys Thr Asn Cys Leu Glu Asp Glu Ser 100 105 110Ala Lys Ala Lys Thr Met Ile Val Ala Gly Val Val Phe Leu Leu Ala 115 120 125Gly Leu Met Val Ile Val Pro Val Ser Trp Thr Ala His Asn Ile Ile 130 135 140Gln Asp Phe Tyr Asn Pro Leu Val Ala Ser Gly Gln Lys Arg Glu Met145 150 155 160Gly Ala Ser Leu Tyr Val Gly Trp Ala Ala Ser Gly Leu Leu Leu Leu 165 170 175Gly Gly Gly Leu Leu Cys Cys Asn Cys Pro Pro Arg Thr Asp Lys Pro 180 185 190Tyr Ser Ala Lys Tyr Ser Ala Ala Arg Ser Ala Ala Ala Ser Asn Tyr 195 200 205Val461009DNAHomo sapiens 46ggcagtagct tgctgatgct cccagctgaa taaagccctt ccttctacaa tttggtgtct 60gaggggtttt gtctgcggct cgtcctgcta catttcttgg ttccctgacc aggaaacgag 120gtaactgatg gacagccgag gcagcccctt aggcggctta ggcctcccct gtggagcatc 180cctgaggcgg actccggcca gcccgagtga tgcgatccaa agagcactcc cgggtaggaa 240attgccccgg tggaatgcct caccagagca gcgtgtagca gttccctgtg gaggattaac 300acagtggctg aacaccggga aggaactggc acttggagtc cggacatctg aaacttggta 360agactagtct ttggaacttg ccccactcca tctaggtgga agtgtggcct gatcacccac 420gacatgcctg cattggcact tctgttctgg ttttgacttg acttagattg tgtgatactt 480tggttttggt tttggtttga cctggcttgg attctagata ctctgatttg gttttgattt 540tggtttggtg taaactgcaa gagtgtgtat gcccttttta cctgtttttt tgtttgtggc 600atgtgtgtgg tgtgggtgtg gtgttttgtc tcgaagaagc atgggtcagg tacaaataag 660cccaccccac taggaactat gttaaaaaaa aattcaagaa agaatttaag ggagattaca 720gtgttactgt gacaccagga aaacttagaa ctttgtgtga aatagactgg ccagcattag 780aggtgggttg gccatcagaa ggaagcctgg acaggtccct tgtttcaaag gtatgacaca 840aggtaacacc aattctaagt taatttgaag tttgcttaaa gttaacagtg taacatgtat 900tatggtaact tctaatcttg tggccttaga cagtctagtc caaaggcata aagaaagttt 960gctttaaaaa aaaaaaaaag gaatggttat cttcaaaaaa aaaaaaaaa 1009471250DNAHomo sapiens 47aattcggcac gagggcaggt gcaggcgcac gcggcgagag cgtatggagc cgagccgtta 60gcgcgcgccg tcggtgagtc agtccgtccg tccgtccgtc cgtcggggcg ccgcagctcc 120cgccaggccc agcggccccg gcccctcgtc tccccgcacc cggagccacc cggtggagcg 180ggccttgccg cggcagccat gtccatgggc ctggagatca cgggcaccgc gctggccgtg 240ctgggctggc tgggcaccat cgtgtgctgc gcgttgccca tgtggcgcgt gtcggccttc 300atcggcagca acatcatcac gtcgcagaac atctgggagg gcctgtggat gaactgcgtg 360gtgcagagca ccggccagat gcagtgcaag gtgtacgact cgctgctggc actgccacag 420gaccttcagg cggcccgcgc cctcatcgtg gtggccatcc tgctggccgc cttcgggctg 480ctagtggcgc tggtgggcgc ccagtgcacc aactgcgtgc aggacgacac ggccaaggcc 540aagatcacca tcgtggcagg cgtgctgttc cttctcgccg ccctgctcac cctcgtgccg 600gtgtcctggt cggccaacac cattatccgg gacttctaca accccgtggt gcccgaggcg 660cagaagcgcg agatgggcgc gggcctgtac gtgggctggg cggccgcggc gctgcagctg 720ctggggggcg cgctgctctg ctgctcgtgt cccccacgcg agaagaagta cacggccacc 780aaggtcgtct actccgcgcc gcgctccacc ggcccgggag ccagcctggg cacaggctac 840gaccgcaagg actacgtcta agggacagac gcagggagac cccaccacca ccaccaccac 900caacaccacc accaccaccg cgagctggag cgcgcaccag gccatccagc gtgcagcctt 960gcctcggagg ccagcccacc cccagaagcc aggaagcccc cgcgctggac tggggcagct 1020tccccagcag ccacggcttt gcgggccggg cagtcgactt cggggcccag ggaccaacct 1080gcatggactg tgaaacctca cccttctgga gcacggggcc tgggtgaccg ccaatacttg 1140accaccccgt cgagccccat cgggccgctg cccccatgtc gcgctgggca gggaccggca 1200gccctggaag gggcacttga tatttttcaa taaaagcctc tcgttttagc 125048220PRTHomo sapiens 48Met Ser Met Gly Leu Glu Ile Thr Gly Thr Ala Leu Ala Val Leu Gly 1 5 10 15Trp Leu Gly Thr Ile Val Cys Cys Ala Leu Pro Met Trp Arg Val Ser 20 25 30Ala Phe Ile Gly Ser Asn Ile Ile Thr Ser Gln Asn Ile Trp Glu Gly 35 40 45Leu Trp Met Asn Cys Val Val Gln Ser Thr Gly Gln Met Gln Cys Lys 50 55 60Val Tyr Asp Ser Leu Leu Ala Leu Pro Gln Asp Leu Gln Ala Ala Arg65 70 75 80Ala Leu Ile Val Val Ala Ile Leu Leu Ala Ala Phe Gly Leu Leu Val 85 90 95Ala Leu Val Gly Ala Gln Cys Thr Asn Cys Val Gln Asp Asp Thr Ala 100 105 110Lys Ala Lys Ile Thr Ile Val Ala Gly Val Leu Phe Leu Leu Ala Ala 115 120 125Leu Leu Thr Leu Val Pro Val Ser Trp Ser Ala Asn Thr Ile Ile Arg 130 135 140Asp Phe Tyr Asn Pro Val Val Pro Glu Ala Gln Lys Arg Glu Met Gly145 150 155 160Ala Gly Leu Tyr Val Gly Trp Ala Ala Ala Ala Leu Gln Leu Leu Gly 165 170 175Gly Ala Leu Leu Cys Cys Ser Cys Pro Pro Arg Glu Lys Lys Tyr Thr 180 185 190Ala Thr Lys Val Val Tyr Ser Ala Pro Arg Ser Thr Gly Pro Gly Ala 195 200 205Ser Leu Gly Thr Gly Tyr Asp Arg Lys Asp Tyr Val 210 215 220493321DNAHomo sapiens 49atgaagattt tgatacttgg tatttttctg tttttatgta gtaccccagc ctgggcgaaa 60gaaaagcatt attacattgg aattattgaa acgacttggg attatgcctc tgaccatggg 120gaaaagaaac ttatttctgt tgacacggaa cattccaata tctatcttca aaatggccca 180gatagaattg ggagactata taagaaggcc ctttatcttc agtacacaga tgaaaccttt 240aggacaacta tagaaaaacc ggtctggctt gggtttttag gccctattat caaagctgaa 300actggagata aagtttatgt acacttaaaa aaccttgcct ctaggcccta cacctttcat 360tcacatggaa taacttacta taaggaacat gagggggcca tctaccctga taacaccaca 420gattttcaaa gagcagatga caaagtatat ccaggagagc agtatacata catgttgctt 480gccactgaag aacaaagtcc tggggaagga gatggcaatt gtgtgactag gatttaccat 540tcccacattg atgctccaaa agatattgcc tcaggactca tcggaccttt aataatctgt 600aaaaaagatt ctctagataa agaaaaagaa aaacatattg accgagaatt tgtggtgatg 660ttttctgtgg tggatgaaaa tttcagctgg tacctagaag acaacattaa aacctactgc 720tcagaaccag agaaagttga caaagacaac gaagacttcc aggagagtaa cagaatgtat 780tctgtgaatg gatacacttt tggaagtctc ccaggactct ccatgtgtgc tgaagacaga 840gtaaaatggt acctttttgg tatgggtaat gaagttgatg tgcacgcagc tttctttcac 900gggcaagcac tgactaacaa gaactaccgt attgacacaa tcaacctctt tcctgctacc 960ctgtttgatg cttatatggt ggcccagaac cctggagaat ggatgctcag ctgtcagaat 1020ctaaaccatc tgaaagccgg tttgcaagcc tttttccagg tccaggagtg taacaagtct 1080tcatcaaagg ataatatccg tgggaagcat gttagacact actacattgc cgctgaggaa 1140atcatctgga actatgctcc ctctggtata gacatcttca ctaaagaaaa cttaacagca 1200cctggaagtg actcagcggt gttttttgaa caaggtacca caagaattgg aggctcttat 1260aaaaagctgg tttatcgtga gtacacagat gcctccttca caaatcgaaa ggagagaggc 1320cctgaagaag agcatcttgg catcctgggt cctgtcattt gggcagaggt gggagacacc 1380atcagagtaa ccttccataa caaaggagca tatcccctca gtattgagcc gattggggtg 1440agattcaata agaacaacga gggcacatac tattccccaa attacaaccc ccagagcaga 1500agtgtgcctc cttcagcctc ccatgtggca cccacagaaa cattcaccta tgaatggact 1560gtccccaaag aagtaggacc cactaatgca gatcctgtgt gtctagctaa gatgtattat 1620tctgctgtgg atcccactaa agatatattc actgggctta ttgggccaat gaaaatatgc 1680aagaaaggaa gtttacatgc aaatgggaga cagaaagatg tagacaagga attctatttg 1740tttcctacag tatttgatga gaatgagagt ttactcctgg aagataatat tagaatgttt 1800acaactgcac ctgatcaggt ggataaggaa gatgaagact ttcaggaatc taataaaatg 1860cactccatga atggattcat gtatgggaat cagccgggtc tcactatgtg caaaggagat 1920tcggtcgtgt ggtacttatt cagcgccgga aatgaggccg atgtacatgg aatatacttt 1980tcaggaaaca catatctgtg gagaggagaa cggagagaca cagcaaacct cttccctcaa 2040acaagtctta cgctccacat gtggcctgac acagagggga cttttaatgt tgaatgcctt 2100acaactgatc attacacagg cggcatgaag caaaaatata ctgtgaacca atgcaggcgg 2160cagtctgagg attccacctt ctacctggga gagaggacat actatatcgc agcagtggag 2220gtggaatggg attattcccc acaaagggag tgggaaaagg agctgcatca tttacaagag 2280cagaatgttt caaatgcatt tttagataag ggagagtttt acataggctc aaagtacaag 2340aaagttgtgt atcggcagta tactgatagc acattccgtg ttccagtgga gagaaaagct 2400gaagaagaac atctgggaat tctaggtcca caacttcatg cagatgttgg agacaaagtc 2460aaaattatct ttaaaaacat ggccacaagg ccctactcaa tacatgccca tggggtacaa 2520acagagagtt ctacagttac tccaacatta ccaggtgaaa ctctcactta cgtatggaaa 2580atcccagaaa gatctggagc tggaacagag gattctgctt gtattccatg ggcttattat 2640tcaactgtgg atcaagttaa ggacctctac agtggattaa ttggccccct gattgtttgt 2700cgaagacctt acttgaaagt attcaatccc agaaggaagc tggaatttgc ccttctgttt 2760ctagtttttg atgagaatga atcttggtac ttagatgaca acatcaaaac atactctgat 2820caccccgaga aagtaaacaa agatgatgag gaattcatag aaagcaataa aatgcatgct 2880attaatggaa gaatgtttgg aaacctacaa ggcctcacaa tgcacgtggg agatgaagtc 2940aactggtatc tgatgggaat gggcaatgaa atagacttac acactgtaca ttttcacggc 3000catagcttcc aatacaagca caggggagtt tatagttctg atgtctttga cattttccct 3060ggaacatacc aaaccctaga aatgtttcca agaacacctg gaatttggtt actccactgc 3120catgtgaccg accacattca tgctggaatg gaaaccactt acaccgttct acaaaatgaa 3180gacaccaaat ctggctgaat gaaataaatt ggtgataagt ggaaaaaaga gaaaaaccaa 3240tgattcataa caatgtatgt gaaagtgtaa aatagaatgt tactttggaa tgactataaa 3300cattaaaaga gactggagca t 3321501065PRTHomo sapiens 50Met Lys Ile Leu Ile Leu Gly Ile Phe Leu Phe Leu Cys Ser Thr Pro 1 5 10 15Ala Trp Ala Lys Glu Lys His Tyr Tyr Ile Gly Ile Ile Glu Thr Thr 20 25 30Trp Asp Tyr Ala Ser Asp His Gly Glu Lys Lys Leu Ile Ser Val Asp 35 40 45Thr Glu His Ser Asn Ile Tyr Leu Gln Asn Gly Pro Asp Arg Ile Gly 50 55 60Arg Leu Tyr Lys Lys Ala Leu Tyr Leu Gln Tyr Thr Asp Glu Thr Phe65 70 75 80Arg Thr Thr Ile Glu Lys Pro Val Trp Leu Gly Phe Leu Gly Pro Ile 85 90 95Ile Lys Ala Glu Thr Gly Asp Lys Val Tyr Val His Leu Lys Asn Leu 100 105 110Ala Ser Arg Pro Tyr Thr Phe His Ser His Gly Ile Thr Tyr Tyr Lys 115 120 125Glu His Glu Gly Ala Ile Tyr Pro Asp Asn Thr Thr Asp Phe Gln Arg 130 135 140Ala Asp Asp Lys Val Tyr Pro Gly Glu Gln Tyr Thr Tyr Met Leu Leu145 150 155 160Ala Thr Glu Glu Gln Ser Pro Gly Glu Gly Asp Gly Asn Cys Val Thr 165 170 175Arg Ile Tyr His Ser His Ile Asp Ala Pro Lys Asp Ile Ala Ser Gly 180 185 190Leu Ile Gly Pro Leu Ile Ile Cys Lys Lys Asp Ser Leu Asp Lys Glu 195 200 205Lys Glu Lys His Ile Asp Arg Glu Phe Val Val Met Phe Ser Val Val 210 215 220Asp Glu Asn Phe Ser Trp Tyr Leu Glu Asp Asn Ile Lys Thr Tyr Cys225 230 235 240Ser Glu Pro Glu Lys Val Asp Lys Asp Asn Glu Asp Phe Gln Glu Ser 245 250 255Asn Arg Met Tyr Ser Val Asn Gly Tyr Thr Phe Gly Ser Leu Pro Gly 260 265 270Leu Ser Met Cys Ala Glu Asp Arg Val Lys Trp Tyr Leu Phe Gly Met 275 280 285Gly Asn Glu Val Asp Val His Ala Ala Phe Phe His Gly Gln Ala Leu 290 295 300Thr Asn Lys Asn Tyr Arg Ile Asp Thr Ile Asn Leu Phe Pro Ala Thr305 310 315 320Leu Phe Asp Ala Tyr Met Val Ala Gln Asn Pro Gly Glu Trp Met Leu 325 330 335Ser Cys Gln Asn Leu Asn His Leu Lys Ala Gly Leu Gln Ala Phe Phe 340 345 350Gln Val Gln Glu Cys Asn Lys Ser Ser Ser Lys Asp Asn Ile Arg Gly 355 360 365Lys His Val Arg His Tyr Tyr Ile Ala Ala Glu Glu Ile Ile Trp Asn 370 375 380Tyr Ala Pro Ser Gly Ile Asp Ile Phe Thr Lys Glu Asn Leu Thr Ala385 390 395 400Pro Gly Ser Asp Ser Ala Val Phe Phe Glu Gln Gly Thr Thr Arg Ile 405 410 415Gly Gly Ser Tyr Lys Lys Leu Val Tyr Arg Glu Tyr Thr Asp Ala Ser 420 425 430Phe Thr Asn Arg Lys Glu Arg Gly Pro Glu Glu Glu His Leu Gly Ile 435 440 445Leu Gly Pro Val Ile Trp Ala Glu Val Gly Asp Thr Ile Arg Val Thr 450 455 460Phe His Asn Lys Gly Ala Tyr Pro Leu Ser Ile Glu Pro Ile Gly Val465 470 475 480Arg Phe Asn Lys Asn Asn Glu Gly Thr Tyr Tyr Ser Pro Asn Tyr Asn 485 490 495Pro Gln Ser Arg Ser Val Pro Pro Ser Ala Ser His Val Ala Pro Thr 500 505 510Glu Thr Phe Thr Tyr Glu Trp Thr Val Pro Lys Glu Val Gly Pro Thr 515 520 525Asn Ala Asp Pro Val Cys Leu Ala Lys Met Tyr Tyr Ser Ala Val Asp 530 535 540Pro Thr Lys Asp Ile Phe Thr Gly Leu Ile Gly Pro Met Lys Ile Cys545 550 555 560Lys Lys Gly Ser Leu His Ala Asn Gly Arg Gln Lys Asp Val Asp Lys 565 570 575Glu Phe Tyr Leu Phe Pro Thr Val Phe Asp Glu Asn Glu Ser Leu Leu 580 585 590Leu Glu Asp Asn Ile Arg Met Phe Thr Thr Ala Pro Asp Gln Val Asp 595 600 605Lys Glu Asp Glu Asp Phe Gln Glu Ser Asn Lys Met His Ser Met Asn 610 615 620Gly Phe Met Tyr Gly Asn Gln Pro Gly Leu Thr Met Cys Lys Gly Asp625 630 635 640Ser Val Val Trp Tyr Leu Phe Ser Ala Gly Asn Glu Ala Asp Val His 645 650 655Gly Ile Tyr Phe Ser Gly Asn Thr Tyr Leu Trp Arg Gly Glu Arg Arg 660 665 670Asp Thr Ala Asn Leu Phe Pro Gln Thr Ser Leu Thr Leu His Met Trp 675 680 685Pro Asp Thr Glu Gly Thr Phe Asn Val Glu Cys Leu Thr Thr Asp His 690 695 700Tyr Thr Gly Gly Met Lys Gln Lys Tyr Thr Val Asn Gln Cys Arg Arg705 710 715 720Gln Ser Glu Asp Ser Thr Phe Tyr Leu Gly Glu Arg Thr Tyr Tyr Ile 725 730 735Ala Ala Val Glu Val Glu Trp Asp Tyr Ser Pro Gln Arg Glu Trp Glu 740 745 750Lys Glu Leu His His Leu Gln Glu Gln Asn Val Ser Asn Ala Phe Leu 755 760 765Asp Lys Gly Glu Phe Tyr Ile Gly Ser Lys Tyr Lys Lys Val Val Tyr 770 775 780Arg Gln Tyr Thr Asp Ser Thr Phe Arg Val Pro Val Glu Arg Lys Ala785 790 795 800Glu Glu Glu His Leu Gly Ile Leu Gly Pro Gln Leu His Ala Asp Val 805 810 815Gly Asp Lys Val Lys Ile Ile Phe Lys Asn Met Ala Thr Arg Pro Tyr 820 825 830Ser Ile His Ala His Gly Val Gln Thr Glu Ser Ser Thr Val Thr Pro 835 840 845Thr Leu Pro Gly Glu Thr Leu Thr Tyr Val Trp Lys Ile Pro Glu Arg 850 855 860Ser Gly Ala Gly Thr Glu Asp Ser Ala Cys Ile Pro

Trp Ala Tyr Tyr865 870 875 880Ser Thr Val Asp Gln Val Lys Asp Leu Tyr Ser Gly Leu Ile Gly Pro 885 890 895Leu Ile Val Cys Arg Arg Pro Tyr Leu Lys Val Phe Asn Pro Arg Arg 900 905 910Lys Leu Glu Phe Ala Leu Leu Phe Leu Val Phe Asp Glu Asn Glu Ser 915 920 925Trp Tyr Leu Asp Asp Asn Ile Lys Thr Tyr Ser Asp His Pro Glu Lys 930 935 940Val Asn Lys Asp Asp Glu Glu Phe Ile Glu Ser Asn Lys Met His Ala945 950 955 960Ile Asn Gly Arg Met Phe Gly Asn Leu Gln Gly Leu Thr Met His Val 965 970 975Gly Asp Glu Val Asn Trp Tyr Leu Met Gly Met Gly Asn Glu Ile Asp 980 985 990Leu His Thr Val His Phe His Gly His Ser Phe Gln Tyr Lys His Arg 995 1000 1005Gly Val Tyr Ser Ser Asp Val Phe Asp Ile Phe Pro Gly Thr Tyr Gln 1010 1015 1020Thr Leu Glu Met Phe Pro Arg Thr Pro Gly Ile Trp Leu Leu His Cys1025 1030 1035 1040His Val Thr Asp His Ile His Ala Gly Met Glu Thr Thr Tyr Thr Val 1045 1050 1055Leu Gln Asn Glu Asp Thr Lys Ser Gly 1060 1065511603DNAHomo sapiens 51ggccagggat caggcagcgg ctcaggcgac cctgagtgtg cccccacccc gccatggccc 60ggctgctgca ggcgtcctgc ctgctttccc tgctcctggc cggcttcgtc tcgcagagcc 120ggggacaaga gaagtcgaag atggactgcc atggtggcat aagtggcacc atttacgagt 180acggagccct caccattgat ggggaggagt acatcccctt caagcagtat gctggcaaat 240acgtcctctt tgtcaacgtg gccagctact gaggcctgac gggccagtac attgaactga 300atgcactaca ggaagagctt gcaccattcg gtctggtcat tctgggcttt ccctgcaacc 360aatttggaaa acaggaacca ggagagaact cagagatcct tcctaccctc aagtatgtcc 420gaccaggtgg aggctttgtc cctaatttcc agctctttga gaaaggggat gtcaatggag 480agaaagagca gaaattctac actttcctaa agaactcctg tcctcccacc tcggagctcc 540tgggtacatc tgaccgcctc ttctgggaac ccatgaaggt tcacgacatc cgctggaact 600ttgagaagtt cctggtgggg ccagatggta tacccatcat gcgctggcac caccggacca 660cggtcagcaa cgtcaagatg gacatcctgt cctacatgag gcggcaggca gccctggggg 720tcaagaggaa gtaactgaag gccgtctcat cccatgtcca ccatgtaggg gagggacttt 780gttcaggaag aaatccgtgt ctccaaccac actatctacc catcacagac ccctttccta 840tcactcaagg ccccagcctg gcacaaatgg atgcatacag ttctgtgtac tgccaggcat 900gtgggtgtgg gtgcatgtgg gtgtttacac acatgcctac aggtatgcgt gattgtgtgt 960gtgtgcatgg gtgtacagcc acgtgtccta cctatgtgtc tttctgggaa tgtgtaccat 1020ctgtgtgcct gcagctgtgt agtgctggac agtgacaacc ctttctctcc agttctccac 1080tccaatgata atagttcact tacacctaaa cccaaaggaa aaaccagctc taggtccaat 1140tgttctgctc taactgatac ctcaaccttg gggccagcat ctcccactgc ctccaaatat 1200tagtaactat gactgacgtc cccagaagtt tctgggtcta ccacactccc caacccccca 1260ctcctacttc ctgaagggcc ctcccaaggc tacatcccca ccccacagtt ctccctgaga 1320gagatcaacc tccctagatc aaccaaggca gatgtgacaa gcaagggcca cggaccccat 1380aggcaggggt ggcgtcttca tgagggaggg gcccaaagcc cttgtgggcg gacctcccct 1440gagcctgtct gaggggccag cccttagtgc attcaggcta aggcccctgg gcagggatgc 1500caccctgctc cttcggagga cgtgccctca cccctcactg gtccactggc ttgagactca 1560ccccgtctgc ccagtaaaag cctttctgca gcaaaaaacc ccc 160352226PRTHomo sapiensVARIANT0-00Xaa = any amino acid 52Met Ala Arg Leu Leu Gln Ala Ser Cys Leu Leu Ser Leu Leu Leu Ala 1 5 10 15Gly Phe Val Ser Gln Ser Arg Gly Gln Glu Lys Ser Lys Met Asp Cys 20 25 30His Gly Gly Ile Ser Gly Thr Ile Tyr Glu Tyr Gly Ala Leu Thr Ile 35 40 45Asp Gly Glu Glu Tyr Ile Pro Phe Lys Gln Tyr Ala Gly Lys Tyr Val 50 55 60Leu Phe Val Asn Val Ala Ser Tyr Xaa Gly Leu Thr Gly Gln Tyr Ile65 70 75 80Glu Leu Asn Ala Leu Gln Glu Glu Leu Ala Pro Phe Gly Leu Val Ile 85 90 95Leu Gly Phe Pro Cys Asn Gln Phe Gly Lys Gln Glu Pro Gly Glu Asn 100 105 110Ser Glu Ile Leu Pro Thr Leu Lys Tyr Val Arg Pro Gly Gly Gly Phe 115 120 125Val Pro Asn Phe Gln Leu Phe Glu Lys Gly Asp Val Asn Gly Glu Lys 130 135 140Glu Gln Lys Phe Tyr Thr Phe Leu Lys Asn Ser Cys Pro Pro Thr Ser145 150 155 160Glu Leu Leu Gly Thr Ser Asp Arg Leu Phe Trp Glu Pro Met Lys Val 165 170 175His Asp Ile Arg Trp Asn Phe Glu Lys Phe Leu Val Gly Pro Asp Gly 180 185 190Ile Pro Ile Met Arg Trp His His Arg Thr Thr Val Ser Asn Val Lys 195 200 205Met Asp Ile Leu Ser Tyr Met Arg Arg Gln Ala Ala Leu Gly Val Lys 210 215 220Arg Lys22553399DNAHomo sapiens 53atgaagtcca gcggcctctt ccccttcctg gtgctgcttg ccctgggaac tctggcacct 60tgggctgtgg aaggctctgg aaagtccttc aaagctggag tctgtcctcc taagaaatct 120gcccagtgcc ttagatacaa gaaacctgag tgccagagtg actggcagtg tccagggaag 180aagagatgtt gtcctgacac ttgtggcatc aaatgcctgg atcctgttga caccccaaac 240ccaacaagga ggaagcctgg gaagtgccca gtgacttatg gccaatgttt gatgcttaac 300ccccccaatt tctgtgagat ggatggccag tgcaagcgtg acttgaagtg ttgcatgggc 360atgtgtggga aatcctgcgt ttcccctgtg aaagcttga 39954132PRTHomo sapiens 54Met Lys Ser Ser Gly Leu Phe Pro Phe Leu Val Leu Leu Ala Leu Gly 1 5 10 15Thr Leu Ala Pro Trp Ala Val Glu Gly Ser Gly Lys Ser Phe Lys Ala 20 25 30Gly Val Cys Pro Pro Lys Lys Ser Ala Gln Cys Leu Arg Tyr Lys Lys 35 40 45Pro Glu Cys Gln Ser Asp Trp Gln Cys Pro Gly Lys Lys Arg Cys Cys 50 55 60Pro Asp Thr Cys Gly Ile Lys Cys Leu Asp Pro Val Asp Thr Pro Asn65 70 75 80Pro Thr Arg Arg Lys Pro Gly Lys Cys Pro Val Thr Tyr Gly Gln Cys 85 90 95Leu Met Leu Asn Pro Pro Asn Phe Cys Glu Met Asp Gly Gln Cys Lys 100 105 110Arg Asp Leu Lys Cys Cys Met Gly Met Cys Gly Lys Ser Cys Val Ser 115 120 125Pro Val Lys Ala 130553557DNAHomo sapiens 55gagagggtcc ttcagggtct gcttatgccc ttgttcaaga acaccagtgt cagctctctg 60tactctggtt gcagactgac cttgctcagg cctgagaagg atggggcagc caccagagtg 120gatgctgtct gcacccatcg tcctgacccc aaaagccctg gactggacag agagcggctg 180tactggaagc tgagccagct gacccacggc atcactgagc tgggccccta caccctggac 240aggcacagtc tctatgtcaa tggtttcacc catcagagct ctatgacgac caccagaact 300cctgatacct ccacaatgca cctggcaacc tcgagaactc cagcctccct gtctggacct 360acgaccgcca gccctctcct ggtgctattc acaattaact tcaccatcac taacctgcgg 420tatgaggaga acatgcatca ccctggctct agaaagttta acaccacgga gagagtcctt 480cagggtctgc tcaggcctgt gttcaagaac accagtgttg gccctctgta ctctggctgc 540agactgacct tgctcaggcc caagaaggat ggggcagcca ccaaagtgga tgccatctgc 600acctaccgcc ctgatcccaa aagccctgga ctggacagag agcagctata ctgggagctg 660agccagctaa cccacagcat cactgagctg ggcccctaca ccctggacag ggacagtctc 720tatgtcaatg gtttcacaca gcggagctct gtgcccacca ctagcattcc tgggaccccc 780acagtggacc tgggaacatc tgggactcca gtttctaaac ctggtccctc ggctgccagc 840cctctcctgg tgctattcac tctcaacttc accatcacca acctgcggta tgaggagaac 900atgcagcacc ctggctccag gaagttcaac accacggaga gggtccttca gggcctgctc 960aggtccctgt tcaagagcac cagtgttggc cctctgtact ctggctgcag actgactttg 1020ctcaggcctg aaaaggatgg gacagccact ggagtggatg ccatctgcac ccaccaccct 1080gaccccaaaa gccctaggct ggacagagag cagctgtatt gggagctgag ccagctgacc 1140cacaatatca ctgagctggg ccactatgcc ctggacaacg acagcctctt tgtcaatggt 1200ttcactcatc ggagctctgt gtccaccacc agcactcctg ggacccccac agtgtatctg 1260ggagcatcta agactccagc ctcgatattt ggcccttcag ctgccagcca tctcctgata 1320ctattcaccc tcaacttcac catcactaac ctgcggtatg aggagaacat gtggcctggc 1380tccaggaagt tcaacactac agagagggtc cttcagggcc tgctaaggcc cttgttcaag 1440aacaccagtg ttggccctct gtactctggc tccaggctga ccttgctcag gccagagaaa 1500gatggggaag ccaccggagt ggatgccatc tgcacccacc gccctgaccc cacaggccct 1560gggctggaca gagagcagct gtatttggag ctgagccagc tgacccacag catcactgag 1620ctgggcccct acacactgga cagggacagt ctctatgtca atggtttcac ccatcggagc 1680tctgtaccca ccaccagcac cggggtggtc agcgaggagc cattcacact gaacttcacc 1740atcaacaacc tgcgctacat ggcggacatg ggccaacccg gctccctcaa gttcaacatc 1800acagacaacg tcatgaagca cctgctcagt cctttgttcc agaggagcag cctgggtgca 1860cggtacacag gctgcagggt catcgcacta aggtctgtga agaacggtgc tgagacacgg 1920gtggacctcc tctgcaccta cctgcagccc ctcagcggcc caggtctgcc tatcaagcag 1980gtgttccatg agctgagcca gcagacccat ggcatcaccc ggctgggccc ctactctctg 2040gacaaagaca gcctctacct taacggttac aatgaacctg gtctagatga gcctcctaca 2100actcccaagc cagccaccac attcctgcct cctctgtcag aagccacaac agccatgggg 2160taccacctga agaccctcac actcaacttc accatctcca atctccagta ttcaccagat 2220atgggcaagg gctcagctac attcaactcc accgaggggg tccttcagca cctgctcaga 2280cccttgttcc agaagagcag catgggcccc ttctacttgg gttgccaact gatctccctc 2340aggcctgaga aggatggggc agccactggt gtggacacca cctgcaccta ccaccctgac 2400cctgtgggcc ccgggctgga catacagcag ctttactggg agctgagtca gctgacccat 2460ggtgtcaccc aactgggctt ctatgtcctg gacagggata gcctcttcat caatggctat 2520gcaccccaga atttatcaat ccggggcgag taccagataa atttccacat tgtcaactgg 2580aacctcagta atccagaccc cacatcctca gagtacatca ccctgctgag ggacatccag 2640gacaaggtca ccacactcta caaaggcagt caactacatg acacattccg cttctgcctg 2700gtcaccaact tgacgatgga ctccgtgttg gtcactgtca aggcattgtt ctcctccaat 2760ttggacccca gcctggtgga gcaagtcttt ctagataaga ccctgaatgc ctcattccat 2820tggctgggct ccacctacca gttggtggac atccatgtga cagaaatgga gtcatcagtt 2880tatcaaccaa caagcagctc cagcacccag cacttctacc cgaatttcac catcaccaac 2940ctaccatatt cccaggacaa agcccagcca ggcaccacca attaccagag gaacaaaagg 3000aatattgagg atgcgctcaa ccaactcttc cgaaacagca gcatcaagag ttatttttct 3060gactgtcaag tttcaacatt caggtctgtc cccaacaggc accacaccgg ggtggactcc 3120ctgtgtaact tctcgccact ggctcggaga gtagacagag ttgccatcta tgaggaattt 3180ctgcggatga cccggaatgg tacccagctg cagaacttca ccctggacag gagcagtgtc 3240cttgtggatg ggtattctcc caacagaaat gagcccttaa ctgggaattc tgaccttccc 3300ttctgggctg tcatcttcat cggcttggca ggactcctgg gactcatcac atgcctgatc 3360tgcggtgtcc tggtgaccac ccgccggcgg aagaaggaag gagaatacaa cgtccagcaa 3420cagtgcccag gctactacca gtcacaccta gacctggagg atctgcaatg actggaactt 3480gccggtgcct ggggtgcctt tcccccagcc agggtccaaa gaagcttggc tggggcagaa 3540ataaaccata ttggtcg 3557561148PRTHomo sapiens 56Met Pro Leu Phe Lys Asn Thr Ser Val Ser Ser Leu Tyr Ser Gly Cys 1 5 10 15Arg Leu Thr Leu Leu Arg Pro Glu Lys Asp Gly Ala Ala Thr Arg Val 20 25 30Asp Ala Val Cys Thr His Arg Pro Asp Pro Lys Ser Pro Gly Leu Asp 35 40 45Arg Glu Arg Leu Tyr Trp Lys Leu Ser Gln Leu Thr His Gly Ile Thr 50 55 60Glu Leu Gly Pro Tyr Thr Leu Asp Arg His Ser Leu Tyr Val Asn Gly65 70 75 80Phe Thr His Gln Ser Ser Met Thr Thr Thr Arg Thr Pro Asp Thr Ser 85 90 95Thr Met His Leu Ala Thr Ser Arg Thr Pro Ala Ser Leu Ser Gly Pro 100 105 110Thr Thr Ala Ser Pro Leu Leu Val Leu Phe Thr Ile Asn Phe Thr Ile 115 120 125Thr Asn Leu Arg Tyr Glu Glu Asn Met His His Pro Gly Ser Arg Lys 130 135 140Phe Asn Thr Thr Glu Arg Val Leu Gln Gly Leu Leu Arg Pro Val Phe145 150 155 160Lys Asn Thr Ser Val Gly Pro Leu Tyr Ser Gly Cys Arg Leu Thr Leu 165 170 175Leu Arg Pro Lys Lys Asp Gly Ala Ala Thr Lys Val Asp Ala Ile Cys 180 185 190Thr Tyr Arg Pro Asp Pro Lys Ser Pro Gly Leu Asp Arg Glu Gln Leu 195 200 205Tyr Trp Glu Leu Ser Gln Leu Thr His Ser Ile Thr Glu Leu Gly Pro 210 215 220Tyr Thr Leu Asp Arg Asp Ser Leu Tyr Val Asn Gly Phe Thr Gln Arg225 230 235 240Ser Ser Val Pro Thr Thr Ser Ile Pro Gly Thr Pro Thr Val Asp Leu 245 250 255Gly Thr Ser Gly Thr Pro Val Ser Lys Pro Gly Pro Ser Ala Ala Ser 260 265 270Pro Leu Leu Val Leu Phe Thr Leu Asn Phe Thr Ile Thr Asn Leu Arg 275 280 285Tyr Glu Glu Asn Met Gln His Pro Gly Ser Arg Lys Phe Asn Thr Thr 290 295 300Glu Arg Val Leu Gln Gly Leu Leu Arg Ser Leu Phe Lys Ser Thr Ser305 310 315 320Val Gly Pro Leu Tyr Ser Gly Cys Arg Leu Thr Leu Leu Arg Pro Glu 325 330 335Lys Asp Gly Thr Ala Thr Gly Val Asp Ala Ile Cys Thr His His Pro 340 345 350Asp Pro Lys Ser Pro Arg Leu Asp Arg Glu Gln Leu Tyr Trp Glu Leu 355 360 365Ser Gln Leu Thr His Asn Ile Thr Glu Leu Gly His Tyr Ala Leu Asp 370 375 380Asn Asp Ser Leu Phe Val Asn Gly Phe Thr His Arg Ser Ser Val Ser385 390 395 400Thr Thr Ser Thr Pro Gly Thr Pro Thr Val Tyr Leu Gly Ala Ser Lys 405 410 415Thr Pro Ala Ser Ile Phe Gly Pro Ser Ala Ala Ser His Leu Leu Ile 420 425 430Leu Phe Thr Leu Asn Phe Thr Ile Thr Asn Leu Arg Tyr Glu Glu Asn 435 440 445Met Trp Pro Gly Ser Arg Lys Phe Asn Thr Thr Glu Arg Val Leu Gln 450 455 460Gly Leu Leu Arg Pro Leu Phe Lys Asn Thr Ser Val Gly Pro Leu Tyr465 470 475 480Ser Gly Ser Arg Leu Thr Leu Leu Arg Pro Glu Lys Asp Gly Glu Ala 485 490 495Thr Gly Val Asp Ala Ile Cys Thr His Arg Pro Asp Pro Thr Gly Pro 500 505 510Gly Leu Asp Arg Glu Gln Leu Tyr Leu Glu Leu Ser Gln Leu Thr His 515 520 525Ser Ile Thr Glu Leu Gly Pro Tyr Thr Leu Asp Arg Asp Ser Leu Tyr 530 535 540Val Asn Gly Phe Thr His Arg Ser Ser Val Pro Thr Thr Ser Thr Gly545 550 555 560Val Val Ser Glu Glu Pro Phe Thr Leu Asn Phe Thr Ile Asn Asn Leu 565 570 575Arg Tyr Met Ala Asp Met Gly Gln Pro Gly Ser Leu Lys Phe Asn Ile 580 585 590Thr Asp Asn Val Met Lys His Leu Leu Ser Pro Leu Phe Gln Arg Ser 595 600 605Ser Leu Gly Ala Arg Tyr Thr Gly Cys Arg Val Ile Ala Leu Arg Ser 610 615 620Val Lys Asn Gly Ala Glu Thr Arg Val Asp Leu Leu Cys Thr Tyr Leu625 630 635 640Gln Pro Leu Ser Gly Pro Gly Leu Pro Ile Lys Gln Val Phe His Glu 645 650 655Leu Ser Gln Gln Thr His Gly Ile Thr Arg Leu Gly Pro Tyr Ser Leu 660 665 670Asp Lys Asp Ser Leu Tyr Leu Asn Gly Tyr Asn Glu Pro Gly Leu Asp 675 680 685Glu Pro Pro Thr Thr Pro Lys Pro Ala Thr Thr Phe Leu Pro Pro Leu 690 695 700Ser Glu Ala Thr Thr Ala Met Gly Tyr His Leu Lys Thr Leu Thr Leu705 710 715 720Asn Phe Thr Ile Ser Asn Leu Gln Tyr Ser Pro Asp Met Gly Lys Gly 725 730 735Ser Ala Thr Phe Asn Ser Thr Glu Gly Val Leu Gln His Leu Leu Arg 740 745 750Pro Leu Phe Gln Lys Ser Ser Met Gly Pro Phe Tyr Leu Gly Cys Gln 755 760 765Leu Ile Ser Leu Arg Pro Glu Lys Asp Gly Ala Ala Thr Gly Val Asp 770 775 780Thr Thr Cys Thr Tyr His Pro Asp Pro Val Gly Pro Gly Leu Asp Ile785 790 795 800Gln Gln Leu Tyr Trp Glu Leu Ser Gln Leu Thr His Gly Val Thr Gln 805 810 815Leu Gly Phe Tyr Val Leu Asp Arg Asp Ser Leu Phe Ile Asn Gly Tyr 820 825 830Ala Pro Gln Asn Leu Ser Ile Arg Gly Glu Tyr Gln Ile Asn Phe His 835 840 845Ile Val Asn Trp Asn Leu Ser Asn Pro Asp Pro Thr Ser Ser Glu Tyr 850 855 860Ile Thr Leu Leu Arg Asp Ile Gln Asp Lys Val Thr Thr Leu Tyr Lys865 870 875 880Gly Ser Gln Leu His Asp Thr Phe Arg Phe Cys Leu Val Thr Asn Leu 885 890 895Thr Met Asp Ser Val Leu Val Thr Val Lys Ala Leu Phe Ser Ser Asn 900 905 910Leu Asp Pro Ser Leu Val Glu Gln Val Phe Leu Asp Lys Thr Leu Asn 915 920 925Ala Ser Phe His Trp Leu Gly Ser Thr Tyr Gln Leu Val Asp Ile His 930 935 940Val Thr Glu Met Glu Ser Ser Val Tyr Gln Pro Thr Ser Ser Ser Ser945 950 955 960Thr Gln His Phe Tyr Pro Asn Phe Thr Ile Thr Asn Leu Pro Tyr Ser

965 970 975Gln Asp Lys Ala Gln Pro Gly Thr Thr Asn Tyr Gln Arg Asn Lys Arg 980 985 990Asn Ile Glu Asp Ala Leu Asn Gln Leu Phe Arg Asn Ser Ser Ile Lys 995 1000 1005Ser Tyr Phe Ser Asp Cys Gln Val Ser Thr Phe Arg Ser Val Pro Asn 1010 1015 1020Arg His His Thr Gly Val Asp Ser Leu Cys Asn Phe Ser Pro Leu Ala1025 1030 1035 1040Arg Arg Val Asp Arg Val Ala Ile Tyr Glu Glu Phe Leu Arg Met Thr 1045 1050 1055Arg Asn Gly Thr Gln Leu Gln Asn Phe Thr Leu Asp Arg Ser Ser Val 1060 1065 1070Leu Val Asp Gly Tyr Ser Pro Asn Arg Asn Glu Pro Leu Thr Gly Asn 1075 1080 1085Ser Asp Leu Pro Phe Trp Ala Val Ile Phe Ile Gly Leu Ala Gly Leu 1090 1095 1100Leu Gly Leu Ile Thr Cys Leu Ile Cys Gly Val Leu Val Thr Thr Arg1105 1110 1115 1120Arg Arg Lys Lys Glu Gly Glu Tyr Asn Val Gln Gln Gln Cys Pro Gly 1125 1130 1135Tyr Tyr Gln Ser His Leu Asp Leu Glu Asp Leu Gln 1140 114557853DNAHomo sapiens 57ctagtcctga cttcacttct gatgaggaag cctctctcct tagccttcag cctttcctcc 60caccctgcca taagtaattt gatcctcaag aagttaaacc acacctcatt ggtccctggc 120taattcacca atttacaaac agcaggaaat agaaacttaa gagaaataca cacttctgag 180aaactgaaac gacaggggaa aggaggtctc actgagcacc gtcccagcat ccggacacca 240cagcggccct tcgctccacg cagaaaacca cacttctcaa accttcactc aacacttcct 300tccccaaagc cagaagatgc acaaggagga acatgaggtg gctgtgctgg gggcaccccc 360cagcaccatc cttccaaggt ccaccgtgat caacatccac agcgagacct ccgtgcccga 420ccatgtcgtc tggtccctgt tcaacaccct cttcttgaac tggtgctgtc tgggcttcat 480agcattcgcc tactccgtga agtctaggga caggaagatg gttggcgacg tgaccggggc 540ccaggcctat gcctccaccg ccaagtgcct gaacatctgg gccctgattc tgggcatcct 600catgaccatt ggattcatcc tgtcactggt attcggctct gtgacagtct accatattat 660gttacagata atacaggaaa aacggggtta ctagtagccg cccatagcct gcaacctttg 720cactccactg tgcaatgctg gccctgcacg ctggggctgt tgcccctgcc cccttggtcc 780tgcccctaga tacagcagtt tatacccaca cacctgtcta cagtgtcatt caataaagtg 840cacgtgcttg tga 85358125PRTHomo sapiens 58Met His Lys Glu Glu His Glu Val Ala Val Leu Gly Ala Pro Pro Ser 1 5 10 15Thr Ile Leu Pro Arg Ser Thr Val Ile Asn Ile His Ser Glu Thr Ser 20 25 30Val Pro Asp His Val Val Trp Ser Leu Phe Asn Thr Leu Phe Leu Asn 35 40 45Trp Cys Cys Leu Gly Phe Ile Ala Phe Ala Tyr Ser Val Lys Ser Arg 50 55 60Asp Arg Lys Met Val Gly Asp Val Thr Gly Ala Gln Ala Tyr Ala Ser65 70 75 80Thr Ala Lys Cys Leu Asn Ile Trp Ala Leu Ile Leu Gly Ile Leu Met 85 90 95Thr Ile Gly Phe Ile Leu Ser Leu Val Phe Gly Ser Val Thr Val Tyr 100 105 110His Ile Met Leu Gln Ile Ile Gln Glu Lys Arg Gly Tyr 115 120 125591512DNAHomo sapiens 59ttccggtccc ccaggacatg tccaatcagg gaagtaagta cgtcaataag gaaattcaaa 60atgctgtcaa cggggtgaaa cagataaaga ctctcataga aaaaacaaac gaagagcgca 120agacactgct cagcaaccta gaagaagcca agaagaagaa agaggatgcc ctaaatgaga 180ccagggaatc agagacaaag ctgaaggagc tcccaggagt gtgcaatgag accatgatgg 240ccctctggga agagtgtaag ccctgcctga aacagacctg catgaagttc tacgcacgcg 300tctgcagaag tggctcaggc ctggttggcc gccagcttga ggagttcctg aaccagagct 360cgcccttcta cttctggatg aatggtgacc gcatcgactc cctgctggag aacgaccggc 420agcagacgca catgctggat gtcatgcagg accacttcag ccgcgcgtcc agcatcatag 480acgagctctt ccaggacagg ttcttcaccc gggagcccca ggatacctac cactacctgc 540ccttcagcct gccccaccgg aggcctcact tcttctttcc caagtcccgc atcgtccgca 600gcttgatgcc cttctctccg tacgagcccc tgaacttcca cgccatgttc cagcccttcc 660ttgagatgat acacgaggct cagcaggcca tggacatcca cttccacagc ccggccttcc 720agcacccgcc aacagaattc atacgagaag gcgacgatga ccggactgtg tgccgggaga 780tccgccacaa ctccacgggc tgcctgcgga tgaaggacca gtgtgacaag tgccgggaga 840tcttgtctgt ggactgttcc accaacaacc cctcccaggc taagctgcgg cgggagctcg 900acgaatccct ccaggtcgct gagaggttga ccaggaaata caacgagctg ctaaagtcct 960accagtggaa gatgctcaac acctcctcct tgctggagca gctgaacgag cagtttaact 1020gggtgtcccg gctggcaaac ctcacgcaag gcgaagacca gtactatctg cgggtcacca 1080cggtggcttc ccacacttct gactcggacg ttccttccgg tgtcactgag gtggtcgtga 1140agctctttga ctctgatccc atcactgtga cggtccctgt agaagtctcc aggaagaacc 1200ctaaatttat ggagaccgtg gcggagaaag cgctgcagga ataccgcaaa aagcaccggg 1260aggagtgaga tgtggatgtt gcttttgcac ctacgggggc atctgagtcc agctcccccc 1320aagatgagct gcagcccccc agagagagct ctgcacgtca ccaagtaacc aggccccagc 1380ctccaggccc ccaactccgc ccagcctctc cccgctctgg atcctgcact ctaacactcg 1440actctgctgc tcatgggaag aacagaattg ctcctgcatg caactaattc aataaaactg 1500tcttgtgagc tg 151260416PRTHomo sapiens 60Met Ser Asn Gln Gly Ser Lys Tyr Val Asn Lys Glu Ile Gln Asn Ala 1 5 10 15Val Asn Gly Val Lys Gln Ile Lys Thr Leu Ile Glu Lys Thr Asn Glu 20 25 30Glu Arg Lys Thr Leu Leu Ser Asn Leu Glu Glu Ala Lys Lys Lys Lys 35 40 45Glu Asp Ala Leu Asn Glu Thr Arg Glu Ser Glu Thr Lys Leu Lys Glu 50 55 60Leu Pro Gly Val Cys Asn Glu Thr Met Met Ala Leu Trp Glu Glu Cys65 70 75 80Lys Pro Cys Leu Lys Gln Thr Cys Met Lys Phe Tyr Ala Arg Val Cys 85 90 95Arg Ser Gly Ser Gly Leu Val Gly Arg Gln Leu Glu Glu Phe Leu Asn 100 105 110Gln Ser Ser Pro Phe Tyr Phe Trp Met Asn Gly Asp Arg Ile Asp Ser 115 120 125Leu Leu Glu Asn Asp Arg Gln Gln Thr His Met Leu Asp Val Met Gln 130 135 140Asp His Phe Ser Arg Ala Ser Ser Ile Ile Asp Glu Leu Phe Gln Asp145 150 155 160Arg Phe Phe Thr Arg Glu Pro Gln Asp Thr Tyr His Tyr Leu Pro Phe 165 170 175Ser Leu Pro His Arg Arg Pro His Phe Phe Phe Pro Lys Ser Arg Ile 180 185 190Val Arg Ser Leu Met Pro Phe Ser Pro Tyr Glu Pro Leu Asn Phe His 195 200 205Ala Met Phe Gln Pro Phe Leu Glu Met Ile His Glu Ala Gln Gln Ala 210 215 220Met Asp Ile His Phe His Ser Pro Ala Phe Gln His Pro Pro Thr Glu225 230 235 240Phe Ile Arg Glu Gly Asp Asp Asp Arg Thr Val Cys Arg Glu Ile Arg 245 250 255His Asn Ser Thr Gly Cys Leu Arg Met Lys Asp Gln Cys Asp Lys Cys 260 265 270Arg Glu Ile Leu Ser Val Asp Cys Ser Thr Asn Asn Pro Ser Gln Ala 275 280 285Lys Leu Arg Arg Glu Leu Asp Glu Ser Leu Gln Val Ala Glu Arg Leu 290 295 300Thr Arg Lys Tyr Asn Glu Leu Leu Lys Ser Tyr Gln Trp Lys Met Leu305 310 315 320Asn Thr Ser Ser Leu Leu Glu Gln Leu Asn Glu Gln Phe Asn Trp Val 325 330 335Ser Arg Leu Ala Asn Leu Thr Gln Gly Glu Asp Gln Tyr Tyr Leu Arg 340 345 350Val Thr Thr Val Ala Ser His Thr Ser Asp Ser Asp Val Pro Ser Gly 355 360 365Val Thr Glu Val Val Val Lys Leu Phe Asp Ser Asp Pro Ile Thr Val 370 375 380Thr Val Pro Val Glu Val Ser Arg Lys Asn Pro Lys Phe Met Glu Thr385 390 395 400Val Ala Glu Lys Ala Leu Gln Glu Tyr Arg Lys Lys His Arg Glu Glu 405 410 415611564DNAHomo sapiens 61cggacgcgtg ggcggacgcg tgggcgaggg cgcgagtgag gagcagaccc aggcatcgcg 60cgccgagaag gccggagcgt cggcacctga acgcgaggcg ctccattgcg cgtgcgcgtt 120gaggggcttc ccgcacctga tcgcgagacc ccaacggctg gtggcgtcgc ctgcgcgggc 180gtccccacac tgccggtccg gaaaggcgac ttccgggggc tttggcacct ggcggacgct 240cccggagcgt cggcacctga acgcgaggcg ctccattgcg cgtgcgcgtt gaggggcttc 300ccgcacctga tcgcgagacc ccaacggctg gtggcgtcgc ctgcgcgtct cggctgagct 360ggccatggcg cacctgtgcg ggctgaggcg gagccgggcg tttctcgccc tgctgggatc 420gctgctcctc tctggggtcc tggcggccga ccgagaacgc agcatccacg acttctgcct 480ggtgtcgaag gtggtgggca gatgccgggc ctccatgcct aagtggtggt acaatgtcac 540tgacggatcc tgccagctgt ttgtgtatgg gggctgtgac ggaaacagca ataattacct 600gaccaaggag gagtgcctca agaaatgtgc cactgtcaca gagaatgcca cgggtgacct 660ggccaccagc aggaatgcag cggattcctc tgtcccaagt gctcccagaa ggcaggattc 720tgaagaccac tccagcgata tgttcaacta tgaagaatac tgcaccgcca acgcagtcac 780tgggccttgc cgtgcatcct tcccacgctg gtactttgac gtggagagga actcctgcaa 840taacttcatc tatggaggct gccggggcaa taagaacagc taccgctctg aggaggcctg 900catgctccgc tgcttccgcc agcaggagaa tcctcccctg ccccttggct caaaggtggt 960ggttctggcg gggctgttcg tgatggtgtt gatcctcttc ctgggagcct ccatggtcta 1020cctgatccgg gtggcacgga ggaaccagga gcgtgccctg cgcaccgtct ggagctccgg 1080acatgacaag gagcagctgg tgaagaacac atatgtcctg tgaccgccct gtcgccaaga 1140ggactgggga agggagggga gactatgtgt gagctttttt taaatagcgg gattgactcg 1200gatttgagtg atcattaggg ctgaggtgtg tttctctggg aggtaggacg gctgcttcct 1260ggtctggcag ggatgggttt gctttggaaa tcctctagga ggctcctcct cgcatggcct 1320gcagtctggc agcagccccg agttgtttcc tcgctgatcg atttctttcc tccaggtaga 1380gttttctttg cttatgttga attccattgc ctcttttctc atcacagaag tgatgttgga 1440atcgtttctt ttgtttgtct gatttatggt ttttttaagt ataaacaaaa gttttttatt 1500aacatctgaa agaaggaaag taaaatgtac aagtttaata aaaaggggcc ttccccttta 1560gaat 156462252PRTHomo sapiens 62Met Ala His Leu Cys Gly Leu Arg Arg Ser Arg Ala Phe Leu Ala Leu 1 5 10 15Leu Gly Ser Leu Leu Leu Ser Gly Val Leu Ala Ala Asp Arg Glu Arg 20 25 30Ser Ile His Asp Phe Cys Leu Val Ser Lys Val Val Gly Arg Cys Arg 35 40 45Ala Ser Met Pro Lys Trp Trp Tyr Asn Val Thr Asp Gly Ser Cys Gln 50 55 60Leu Phe Val Tyr Gly Gly Cys Asp Gly Asn Ser Asn Asn Tyr Leu Thr65 70 75 80Lys Glu Glu Cys Leu Lys Lys Cys Ala Thr Val Thr Glu Asn Ala Thr 85 90 95Gly Asp Leu Ala Thr Ser Arg Asn Ala Ala Asp Ser Ser Val Pro Ser 100 105 110Ala Pro Arg Arg Gln Asp Ser Glu Asp His Ser Ser Asp Met Phe Asn 115 120 125Tyr Glu Glu Tyr Cys Thr Ala Asn Ala Val Thr Gly Pro Cys Arg Ala 130 135 140Ser Phe Pro Arg Trp Tyr Phe Asp Val Glu Arg Asn Ser Cys Asn Asn145 150 155 160Phe Ile Tyr Gly Gly Cys Arg Gly Asn Lys Asn Ser Tyr Arg Ser Glu 165 170 175Glu Ala Cys Met Leu Arg Cys Phe Arg Gln Gln Glu Asn Pro Pro Leu 180 185 190Pro Leu Gly Ser Lys Val Val Val Leu Ala Gly Leu Phe Val Met Val 195 200 205Leu Ile Leu Phe Leu Gly Ala Ser Met Val Tyr Leu Ile Arg Val Ala 210 215 220Arg Arg Asn Gln Glu Arg Ala Leu Arg Thr Val Trp Ser Ser Gly His225 230 235 240Asp Lys Glu Gln Leu Val Lys Asn Thr Tyr Val Leu 245 250631147DNAHomo sapiens 63ggacgtcctt ccccaggagc cgactggcca atcacaggca ggaagatgaa ggttctgtgg 60gctgcgttgc tggtcacatt cctggcagga tgccaggcca aggtggagca agcggtggag 120acagagccgg agcccgagct gcgccagcag accgagtggc agagcggcca gcgctgggaa 180ctggcactgg gtcgcttttg ggattacctg cgctgggtgc agacactgtc tgagcaggtg 240caggaggagc tgctcagctc ccaggtcacc caggaactga gggcgctgat ggacgagacc 300atgaaggagt tgaaggccta caaatcggaa ctggaggaac aactgacccc ggtggcggag 360gagacgcggg cacggctgtc caaggagctg caggcggcgc aggcccggct gggcgcggac 420atggaggacg tgtgcggccg cctggtgcag taccgcggcg aggtgcaggc catgctcggc 480cagagcaccg aggagctgcg ggtgcgcctc gcctcccacc tgcgcaagct gcgtaagcgg 540ctcctccgcg atgccgatga cctgcagaag cgcctggcag tgtaccaggc cggggcccgc 600gagggcgccg agcgcggcct cagcgccatc cgcgagcgcc tggggcccct ggtggaacag 660ggccgcgtgc gggccgccac tgtgggctcc ctggccggcc agccgctaca ggagcgggcc 720caggcctggg gcgagcggct gcgcgcgcgg atggaggaga tgggcagccg gacccgcgac 780cgcctggacg aggtgaagga gcaggtggcg gaggtgcgcg ccaagctgga ggagcaggcc 840cagcagatac gcctgcaggc cgaggccttc caggcccgcc tcaagagctg gttcgagccc 900ctggtggaag acatgcagcg ccagtgggcc gggctggtgg agaaggtgca ggctgccgtg 960ggcaccagcg ccgcccctgt gcccagcgac aatcactgaa cgccgaagcc tgcagccatg 1020cgaccccacg ccaccccgtg cctcctgcct ccgcgcagcc tgcagcggga gaccctgtcc 1080ccgccccagc cgtcctcctg gggtggaccc tagtttaata aagattcacc aagtttcacg 1140caaaaaa 114764317PRTHomo sapiens 64Met Lys Val Leu Trp Ala Ala Leu Leu Val Thr Phe Leu Ala Gly Cys 1 5 10 15Gln Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu 20 25 30Arg Gln Gln Thr Glu Trp Gln Ser Gly Gln Arg Trp Glu Leu Ala Leu 35 40 45Gly Arg Phe Trp Asp Tyr Leu Arg Trp Val Gln Thr Leu Ser Glu Gln 50 55 60Val Gln Glu Glu Leu Leu Ser Ser Gln Val Thr Gln Glu Leu Arg Ala65 70 75 80Leu Met Asp Glu Thr Met Lys Glu Leu Lys Ala Tyr Lys Ser Glu Leu 85 90 95Glu Glu Gln Leu Thr Pro Val Ala Glu Glu Thr Arg Ala Arg Leu Ser 100 105 110Lys Glu Leu Gln Ala Ala Gln Ala Arg Leu Gly Ala Asp Met Glu Asp 115 120 125Val Cys Gly Arg Leu Val Gln Tyr Arg Gly Glu Val Gln Ala Met Leu 130 135 140Gly Gln Ser Thr Glu Glu Leu Arg Val Arg Leu Ala Ser His Leu Arg145 150 155 160Lys Leu Arg Lys Arg Leu Leu Arg Asp Ala Asp Asp Leu Gln Lys Arg 165 170 175Leu Ala Val Tyr Gln Ala Gly Ala Arg Glu Gly Ala Glu Arg Gly Leu 180 185 190Ser Ala Ile Arg Glu Arg Leu Gly Pro Leu Val Glu Gln Gly Arg Val 195 200 205Arg Ala Ala Thr Val Gly Ser Leu Ala Gly Gln Pro Leu Gln Glu Arg 210 215 220Ala Gln Ala Trp Gly Glu Arg Leu Arg Ala Arg Met Glu Glu Met Gly225 230 235 240Ser Arg Thr Arg Asp Arg Leu Asp Glu Val Lys Glu Gln Val Ala Glu 245 250 255Val Arg Ala Lys Leu Glu Glu Gln Ala Gln Gln Ile Arg Leu Gln Ala 260 265 270Glu Ala Phe Gln Ala Arg Leu Lys Ser Trp Phe Glu Pro Leu Val Glu 275 280 285Asp Met Gln Arg Gln Trp Ala Gly Leu Val Glu Lys Val Gln Ala Ala 290 295 300Val Gly Thr Ser Ala Ala Pro Val Pro Ser Asp Asn His305 310 315652493DNAHomo sapiens 65ggatcgattt gagtaagagc atagctgtcg ggagagccca ggattcaaca cgggccttga 60gaaatgtggc tcttgtacct cctggtgccg gccctgttct gcagggcagg aggctccatt 120cccatccctc agaagttatt tggggaggtg acttcccctc tgttccccaa gccttacccc 180aacaactttg aaacaaccac tgtgatcaca gtccccacgg gatacagggt gaagctcgtc 240ttccagcagt ttgacctgga gccttctgaa ggctgcttct atgattatgt caagatctct 300gctgataaga aaagcctggg gaggttctgt gggcaactgg gttctccact gggcaacccc 360ccgggaaaga aggaatttat gtcccaaggg aacaagatgc tgctgacctt ccacacagac 420ttctccaacg aggagaatgg gaccatcatg ttctacaagg gcttcctggc ctactaccaa 480gctgtggacc ttgatgaatg tgcttcccgg agcaaatcag gggaggagga tccccagccc 540cagtgccagc acctgtgtca caactacgtt ggaggctact tctgttcctg ccgtccaggc 600tatgagcttc aggaagacag gcattcctgc caggctgagt gcagcagcga gctgtacacg 660gaggcatcag gctacatctc cagcctggag taccctcggt cctacccccc tgacctgcgc 720tgcaactaca gcatccgggt ggagcggggc ctcaccctgc acctcaagtt cctggagcct 780tttgatattg atgaccacca gcaagtacac tgcccctatg accagctaca gatctatgcc 840aacgggaaga acattggcga gttctgtggg aagcaaaggc cccccgacct cgacaccagc 900agcaatgctg tggatctgct gttcttcaca gatgagtcgg gggacagccg gggctggaag 960ctgcgctaca ccaccgagat catcaagtgc ccccagccca agaccctaga cgagttcacc 1020atcatccaga acctgcagcc tcagtaccag ttccgtgact acttcattgc tacctgcaag 1080caaggctacc agctcataga ggggaaccag gtgctgcatt ccttcacagc tgtctgccag 1140gatgatggca cgtggcatcg tgccatgccc agatgcaaga tcaaggactg tgggcagccc 1200cgaaacctgc ctaatggtga cttccgttac accaccacaa tgggagtgaa cacctacaag 1260gcccgtatcc agtactactg ccatgagcca tattacaaga tgcagaccag agctggcagc 1320agggagtctg agcaaggggt gtacacctgc acagcacagg gcatttggaa gaatgaacag 1380aagggagaga agattcctcg gtgcttgcca gtgtgtggga agcccgtgaa ccccgtggaa 1440cagaggcagc gcataatcgg agggcaaaaa gccaagatgg gcaacttccc ctggcaggtg 1500ttcaccaaca tccacgggcg cgggggcggg gccctgctgg gcgaccgctg gatcctcaca 1560gctgcccaca ccctgtatcc caaggaacac gaagcgcaaa gcaacgcctc tttggatgtg 1620ttcctgggcc acacaaatgt ggaagagctc atgaagctag gaaatcaccc catccgcagg 1680gtcagcgtcc acccggacta ccgtcaggat gagtcctaca attttgaggg ggacatcgcc 1740ctgctggagc tggaaaatag

tgtcaccctg ggtcccaacc tcctccccat ctgcctccct 1800gacaacgata ccttctacga cctgggcttg atgggctatg tcagtggctt cggggtcatg 1860gaggagaaga ttgctcatga cctcaggttt gtccgtctgc ccgtagctaa tccacaggcc 1920tgtgagaact ggctccgggg aaagaatagg atggatgtgt tctctcaaaa catgttctgt 1980gctggacacc catctctaaa gcaggacgcc tgccaggggg atagtggggg cgtttttgca 2040gtaagggacc cgaacactga tcgctgggtg gccacgggca tcgtgtcctg gggcatcggg 2100tgcagcaggg gctatggctt ctacaccaaa gtgctcaact acgtggactg gatcaagaaa 2160gagatggagg aggaggactg agcccagaat tcactaggtt cgaatccaga gagcagtgtg 2220gaaaaaaaaa aaacaaaaaa caactgacca gttgttgata accactaaga gtctctatta 2280aaattactga tgcagaaaga ccgtgtgtga aattctcttt cctgtagtcc cattgatgta 2340ctttacctga aacaacccaa aggccccttt ctttcttctg aggattgcag aggatatagt 2400tatcaatctc tagttgtcac tttcctcttc cactttgata ccattgggtc attgaatata 2460actttttcca aataaagttt tatgagaaat gcc 249366705PRTHomo sapiens 66Met Trp Leu Leu Tyr Leu Leu Val Pro Ala Leu Phe Cys Arg Ala Gly 1 5 10 15Gly Ser Ile Pro Ile Pro Gln Lys Leu Phe Gly Glu Val Thr Ser Pro 20 25 30Leu Phe Pro Lys Pro Tyr Pro Asn Asn Phe Glu Thr Thr Thr Val Ile 35 40 45Thr Val Pro Thr Gly Tyr Arg Val Lys Leu Val Phe Gln Gln Phe Asp 50 55 60Leu Glu Pro Ser Glu Gly Cys Phe Tyr Asp Tyr Val Lys Ile Ser Ala65 70 75 80Asp Lys Lys Ser Leu Gly Arg Phe Cys Gly Gln Leu Gly Ser Pro Leu 85 90 95Gly Asn Pro Pro Gly Lys Lys Glu Phe Met Ser Gln Gly Asn Lys Met 100 105 110Leu Leu Thr Phe His Thr Asp Phe Ser Asn Glu Glu Asn Gly Thr Ile 115 120 125Met Phe Tyr Lys Gly Phe Leu Ala Tyr Tyr Gln Ala Val Asp Leu Asp 130 135 140Glu Cys Ala Ser Arg Ser Lys Ser Gly Glu Glu Asp Pro Gln Pro Gln145 150 155 160Cys Gln His Leu Cys His Asn Tyr Val Gly Gly Tyr Phe Cys Ser Cys 165 170 175Arg Pro Gly Tyr Glu Leu Gln Glu Asp Arg His Ser Cys Gln Ala Glu 180 185 190Cys Ser Ser Glu Leu Tyr Thr Glu Ala Ser Gly Tyr Ile Ser Ser Leu 195 200 205Glu Tyr Pro Arg Ser Tyr Pro Pro Asp Leu Arg Cys Asn Tyr Ser Ile 210 215 220Arg Val Glu Arg Gly Leu Thr Leu His Leu Lys Phe Leu Glu Pro Phe225 230 235 240Asp Ile Asp Asp His Gln Gln Val His Cys Pro Tyr Asp Gln Leu Gln 245 250 255Ile Tyr Ala Asn Gly Lys Asn Ile Gly Glu Phe Cys Gly Lys Gln Arg 260 265 270Pro Pro Asp Leu Asp Thr Ser Ser Asn Ala Val Asp Leu Leu Phe Phe 275 280 285Thr Asp Glu Ser Gly Asp Ser Arg Gly Trp Lys Leu Arg Tyr Thr Thr 290 295 300Glu Ile Ile Lys Cys Pro Gln Pro Lys Thr Leu Asp Glu Phe Thr Ile305 310 315 320Ile Gln Asn Leu Gln Pro Gln Tyr Gln Phe Arg Asp Tyr Phe Ile Ala 325 330 335Thr Cys Lys Gln Gly Tyr Gln Leu Ile Glu Gly Asn Gln Val Leu His 340 345 350Ser Phe Thr Ala Val Cys Gln Asp Asp Gly Thr Trp His Arg Ala Met 355 360 365Pro Arg Cys Lys Ile Lys Asp Cys Gly Gln Pro Arg Asn Leu Pro Asn 370 375 380Gly Asp Phe Arg Tyr Thr Thr Thr Met Gly Val Asn Thr Tyr Lys Ala385 390 395 400Arg Ile Gln Tyr Tyr Cys His Glu Pro Tyr Tyr Lys Met Gln Thr Arg 405 410 415Ala Gly Ser Arg Glu Ser Glu Gln Gly Val Tyr Thr Cys Thr Ala Gln 420 425 430Gly Ile Trp Lys Asn Glu Gln Lys Gly Glu Lys Ile Pro Arg Cys Leu 435 440 445Pro Val Cys Gly Lys Pro Val Asn Pro Val Glu Gln Arg Gln Arg Ile 450 455 460Ile Gly Gly Gln Lys Ala Lys Met Gly Asn Phe Pro Trp Gln Val Phe465 470 475 480Thr Asn Ile His Gly Arg Gly Gly Gly Ala Leu Leu Gly Asp Arg Trp 485 490 495Ile Leu Thr Ala Ala His Thr Leu Tyr Pro Lys Glu His Glu Ala Gln 500 505 510Ser Asn Ala Ser Leu Asp Val Phe Leu Gly His Thr Asn Val Glu Glu 515 520 525Leu Met Lys Leu Gly Asn His Pro Ile Arg Arg Val Ser Val His Pro 530 535 540Asp Tyr Arg Gln Asp Glu Ser Tyr Asn Phe Glu Gly Asp Ile Ala Leu545 550 555 560Leu Glu Leu Glu Asn Ser Val Thr Leu Gly Pro Asn Leu Leu Pro Ile 565 570 575Cys Leu Pro Asp Asn Asp Thr Phe Tyr Asp Leu Gly Leu Met Gly Tyr 580 585 590Val Ser Gly Phe Gly Val Met Glu Glu Lys Ile Ala His Asp Leu Arg 595 600 605Phe Val Arg Leu Pro Val Ala Asn Pro Gln Ala Cys Glu Asn Trp Leu 610 615 620Arg Gly Lys Asn Arg Met Asp Val Phe Ser Gln Asn Met Phe Cys Ala625 630 635 640Gly His Pro Ser Leu Lys Gln Asp Ala Cys Gln Gly Asp Ser Gly Gly 645 650 655Val Phe Ala Val Arg Asp Pro Asn Thr Asp Arg Trp Val Ala Thr Gly 660 665 670Ile Val Ser Trp Gly Ile Gly Cys Ser Arg Gly Tyr Gly Phe Tyr Thr 675 680 685Lys Val Leu Asn Tyr Val Asp Trp Ile Lys Lys Glu Met Glu Glu Glu 690 695 700Asp70567777DNAHomo sapiens 67gctccgggct gaagattgct tctcttctct cctccaaggt ctagtgacgg agcccgcgcg 60cgcgccacca tgcggcagaa ggcggtatcc gttttcttgt gctacctgct gctcttcact 120tgcagtgggg tggaggcagg taagaaaaag tgctcggaga gctcggacag cggctccggg 180ttctggaagg ccctgacctt catggccgtc ggaggaggac tcgcagtcgc cgggctgccc 240gcgctgggct tcaccggcgc cggcatcgcg gccaactcgg tggctgcctc gctgatgagc 300tggtctgcga tcctgaatgg gggcggcgtg cccgccgggg ggctagtggc cacgctgcag 360agcctcgggg ctggtggcag cagcgtcgtc ataggtaata ttggtgccct gatgcggtac 420gccacccaca agtatctcga tagtgaggag gatgaggagt agccagcagc tcccagaacc 480tcttcttcct tcttggccta actcttccag ttaggatcta gaactttgcc tttttttttt 540tttttttttt tttgagatgg gttctcacta tattgtccag gctagagtgc agtggctatt 600cacagatgcg aacatagtac actgcagcct ccaactccta gcctcaagtg atcctcctgt 660ctcaacctcc caagtaggat tacaagcatg cgccgacgat gcccagaatc cagaactttg 720tctatcactc tccccaacaa cctagatgtg aaaacagaat aaacttcacc cagaaaa 77768130PRTHomo sapiens 68Met Arg Gln Lys Ala Val Ser Val Phe Leu Cys Tyr Leu Leu Leu Phe 1 5 10 15Thr Cys Ser Gly Val Glu Ala Gly Lys Lys Lys Cys Ser Glu Ser Ser 20 25 30Asp Ser Gly Ser Gly Phe Trp Lys Ala Leu Thr Phe Met Ala Val Gly 35 40 45Gly Gly Leu Ala Val Ala Gly Leu Pro Ala Leu Gly Phe Thr Gly Ala 50 55 60Gly Ile Ala Ala Asn Ser Val Ala Ala Ser Leu Met Ser Trp Ser Ala65 70 75 80Ile Leu Asn Gly Gly Gly Val Pro Ala Gly Gly Leu Val Ala Thr Leu 85 90 95Gln Ser Leu Gly Ala Gly Gly Ser Ser Val Val Ile Gly Asn Ile Gly 100 105 110Ala Leu Met Arg Tyr Ala Thr His Lys Tyr Leu Asp Ser Glu Glu Asp 115 120 125Glu Glu 130692402DNAHomo sapiens 69agtctccgcc gccgccgtga acatggagcc cccggacgca ccggcccagg cgcgcggggc 60cccgcggctg ctgttgctcg cagtcctgct ggcggcgcac ccagatgccc aggcggaggt 120gcgcttgtct gtacccccgc tggtggaggt gatgcgagga aagtctgtca ttctggactg 180cacccctacg ggaacccacg accattatat gctggaatgg ttccttaccg accgctcggg 240agctcgcccc cgcctagcct cggctgagat gcagggctct gagctccagg tcacaatgca 300cgacacccgg ggccgcagtc ccccatacca gctggactcc caggggcgcc tggtgctggc 360tgaggcccag gtgggcgacg agcgagacta cgtgtgcgtg gtgagggcag gggcggcagg 420cactgctgag gccactgcgc ggctcaacgt gtttgcaaag ccagaggcca ctgaggtctc 480ccccaacaaa gggacactgt ctgtgatgga ggactctgcc caggagatcg ccacctgcaa 540cagccggaac gggaacccgg cccccaagat cacgtggtat cgcaacgggc agcgcctgga 600ggtgcccgta gagatgaacc cagagggcta catgaccagc cgcacggtcc gggaggcctc 660gggcctgctc tccctcacca gcaccctcta cctgcggctc cgcaaggatg accgagacgc 720cagcttccac tgcgccgccc actacagcct gcccgagggc cgccacggcc gcctggacag 780ccccaccttc cacctcaccc tgcactatcc cacggagcac gtgcagttct gggtgggcag 840cccgtccacc ccagcaggct gggtacgcga gggtgacact gtccagctgc tctgccgggg 900ggacggcagc cccagcccgg agtatacgct tttccgcctt caggatgagc aggaggaagt 960gctgaatgtg aatctcgagg ggaacttgac cctggaggga gtgacccggg gccagagcgg 1020gacctatggc tgcagagtgg aggattacga cgcggcagat gacgtgcagc tctccaagac 1080gctggagctg cgcgtggcct atctggaccc cctggagctc agcgagggga aggtgctttc 1140cttacctcta aacagcagtg cagtcgtgaa ctgctccgtg cacggcctgc ccacccctgc 1200cctacgctgg accaaggact ccactcccct gggcgatggc cccatgctgt cgctcagttc 1260tatcaccttc gattccaatg gcacctacgt atgtgaggcc tccctgccca cagtcccggt 1320cctcagccgc acccagaact tcacgctgct ggtccaaggc tcgccagagc taaagacagc 1380ggaaatagag cccaaggcag atggcagctg gagggaagga gacgaagtca cactcatctg 1440ctctgcccgc ggccatccag accccaaact cagctggagc caattggggg gcagccccgc 1500agagccaatc cccggacggc agggttgggt gagcagctct ctgaccctga aagtgaccag 1560cgccctgagc cgcgatggca tctcctgtga agcctccaac ccccacggga acaagcgcca 1620tgtcttccac ttcggcgccg tgagccccca gacctcccag gctggagtgg ccgtcatggc 1680cgtggccgtc agcgtgggcc tcctgctcct cgtcgttgct gtcttctact gcgtgagacg 1740caaagggggc ccctgctgcc gccagcggcg ggagaagggg gctccgccgc caggggagcc 1800agggctgagc cactcggggt cggagcaacc agagcagacc ggccttctca tgggaggtgc 1860ctccggagga gccaggggtg gcagcggggg cttcggagac gagtgctgag ccaagaacct 1920cctagaggct gtccctggac ctggagctgc aggcatcaga gaaccagccc tgctcacgcc 1980atgcccgccc ccgccttccc tcttccctct tccctctccc tgcccagccc tcccttcctt 2040cctctgccgg caaggcaggg acccacagtg gctgcctgcc tccgggaggg aaggagaggg 2100agggtgggtg ggtgggaggg ggccttcctc cagggaatgt gactctccca ggccccagaa 2160tagctcctgg acccaagccc aaggcccagc ctgggacaag gctccgaggg tcggctggcc 2220ggagctattt ttacctcccg cctcccctgc tggtcccccc acctgacgtc ttgctgcaga 2280gtctgacact ggattccccc ccctcacccc gcccctggtc ccactcctgc ccccgcccta 2340cctccgcccc accccatcat ctgtggacac tggagtctgg aataaatgct gtttgtcaca 2400tc 240270628PRTHomo sapiens 70Met Glu Pro Pro Asp Ala Pro Ala Gln Ala Arg Gly Ala Pro Arg Leu 1 5 10 15Leu Leu Leu Ala Val Leu Leu Ala Ala His Pro Asp Ala Gln Ala Glu 20 25 30Val Arg Leu Ser Val Pro Pro Leu Val Glu Val Met Arg Gly Lys Ser 35 40 45Val Ile Leu Asp Cys Thr Pro Thr Gly Thr His Asp His Tyr Met Leu 50 55 60Glu Trp Phe Leu Thr Asp Arg Ser Gly Ala Arg Pro Arg Leu Ala Ser65 70 75 80Ala Glu Met Gln Gly Ser Glu Leu Gln Val Thr Met His Asp Thr Arg 85 90 95Gly Arg Ser Pro Pro Tyr Gln Leu Asp Ser Gln Gly Arg Leu Val Leu 100 105 110Ala Glu Ala Gln Val Gly Asp Glu Arg Asp Tyr Val Cys Val Val Arg 115 120 125Ala Gly Ala Ala Gly Thr Ala Glu Ala Thr Ala Arg Leu Asn Val Phe 130 135 140Ala Lys Pro Glu Ala Thr Glu Val Ser Pro Asn Lys Gly Thr Leu Ser145 150 155 160Val Met Glu Asp Ser Ala Gln Glu Ile Ala Thr Cys Asn Ser Arg Asn 165 170 175Gly Asn Pro Ala Pro Lys Ile Thr Trp Tyr Arg Asn Gly Gln Arg Leu 180 185 190Glu Val Pro Val Glu Met Asn Pro Glu Gly Tyr Met Thr Ser Arg Thr 195 200 205Val Arg Glu Ala Ser Gly Leu Leu Ser Leu Thr Ser Thr Leu Tyr Leu 210 215 220Arg Leu Arg Lys Asp Asp Arg Asp Ala Ser Phe His Cys Ala Ala His225 230 235 240Tyr Ser Leu Pro Glu Gly Arg His Gly Arg Leu Asp Ser Pro Thr Phe 245 250 255His Leu Thr Leu His Tyr Pro Thr Glu His Val Gln Phe Trp Val Gly 260 265 270Ser Pro Ser Thr Pro Ala Gly Trp Val Arg Glu Gly Asp Thr Val Gln 275 280 285Leu Leu Cys Arg Gly Asp Gly Ser Pro Ser Pro Glu Tyr Thr Leu Phe 290 295 300Arg Leu Gln Asp Glu Gln Glu Glu Val Leu Asn Val Asn Leu Glu Gly305 310 315 320Asn Leu Thr Leu Glu Gly Val Thr Arg Gly Gln Ser Gly Thr Tyr Gly 325 330 335Cys Arg Val Glu Asp Tyr Asp Ala Ala Asp Asp Val Gln Leu Ser Lys 340 345 350Thr Leu Glu Leu Arg Val Ala Tyr Leu Asp Pro Leu Glu Leu Ser Glu 355 360 365Gly Lys Val Leu Ser Leu Pro Leu Asn Ser Ser Ala Val Val Asn Cys 370 375 380Ser Val His Gly Leu Pro Thr Pro Ala Leu Arg Trp Thr Lys Asp Ser385 390 395 400Thr Pro Leu Gly Asp Gly Pro Met Leu Ser Leu Ser Ser Ile Thr Phe 405 410 415Asp Ser Asn Gly Thr Tyr Val Cys Glu Ala Ser Leu Pro Thr Val Pro 420 425 430Val Leu Ser Arg Thr Gln Asn Phe Thr Leu Leu Val Gln Gly Ser Pro 435 440 445Glu Leu Lys Thr Ala Glu Ile Glu Pro Lys Ala Asp Gly Ser Trp Arg 450 455 460Glu Gly Asp Glu Val Thr Leu Ile Cys Ser Ala Arg Gly His Pro Asp465 470 475 480Pro Lys Leu Ser Trp Ser Gln Leu Gly Gly Ser Pro Ala Glu Pro Ile 485 490 495Pro Gly Arg Gln Gly Trp Val Ser Ser Ser Leu Thr Leu Lys Val Thr 500 505 510Ser Ala Leu Ser Arg Asp Gly Ile Ser Cys Glu Ala Ser Asn Pro His 515 520 525Gly Asn Lys Arg His Val Phe His Phe Gly Ala Val Ser Pro Gln Thr 530 535 540Ser Gln Ala Gly Val Ala Val Met Ala Val Ala Val Ser Val Gly Leu545 550 555 560Leu Leu Leu Val Val Ala Val Phe Tyr Cys Val Arg Arg Lys Gly Gly 565 570 575Pro Cys Cys Arg Gln Arg Arg Glu Lys Gly Ala Pro Pro Pro Gly Glu 580 585 590Pro Gly Leu Ser His Ser Gly Ser Glu Gln Pro Glu Gln Thr Gly Leu 595 600 605Leu Met Gly Gly Ala Ser Gly Gly Ala Arg Gly Gly Ser Gly Gly Phe 610 615 620Gly Asp Glu Cys625715460DNAHomo sapiens 71cgggcccggt gctgaagggc agggaacaac ttgatggtgc tactttgaac tgcttttctt 60ttctcctttt tgcacaaaga gtctcatgtc tgatatttag acatgatgag ctttgtgcaa 120aaggggagct ggctacttct cgctctgctt catcccacta ttattttggc acaacaggaa 180gctgttgaag gaggatgttc ccatcttggt cagtcctatg cggatagaga tgtctggaag 240ccagaaccat gccaaatatg tgtctgtgac tcaggatccg ttctctgcga tgacataata 300tgtgacgatc aagaattaga ctgccccaac ccagaaattc catttggaga atgttgtgca 360gtttgcccac agcctccaac tgctcctact cgccctccta atggtcaagg acctcaaggc 420cccaagggag atccaggccc tcctggtatt cctgggagaa atggtgaccc tggtattcca 480ggacaaccag ggtcccctgg ttctcctggc ccccctggaa tctgtgaatc atgccctact 540ggtcctcaga actattctcc ccagtatgat tcatatgatg tcaagtctgg agtagcagta 600ggaggactcg caggctatcc tggaccagct ggccccccag gccctcccgg tccccctggt 660acatctggtc atcctggttc ccctggatct ccaggatacc aaggaccccc tggtgaacct 720gggcaagctg gtccttcagg ccctccagga cctcctggtg ctataggtcc atctggtcct 780gctggaaaag atggagaatc aggtagaccc ggacgacctg gagagcgagg attgcctgga 840cctccaggta tcaaaggtcc agctgggata cctggattcc ctggtatgaa aggacacaga 900ggcttcgatg gacgaaatgg agaaaagggt gaaacaggtg ctcctggatt aaagggtgaa 960aatggtcttc caggcgaaaa tggagctcct ggacccatgg gtccaagagg ggctcctggt 1020gagcgaggac ggccaggact tcctggggct gcaggtgctc ggggtaatga cggtgctcga 1080ggcagtgatg gtcaaccagg ccctcctggt cctcctggaa ctgccggatt ccctggatcc 1140cctggtgcta agggtgaagt tggacctgca gggtctcctg gttcaaatgg tgcccctgga 1200caaagaggag aacctggacc tcagggacac gctggtgctc aaggtcctcc tggccctcct 1260gggattaatg gtagtcctgg tggtaaaggc gaaatgggtc ccgctggcat tcctggagct 1320cctggactga tgggagcccg gggtcctcca ggaccagccg gtgctaatgg tgctcctgga 1380ctgcgaggtg gtgcaggtga gcctggtaag aatggtgcca aaggagagcc cggaccacgt 1440ggtgaacgcg gtgaggctgg tattccaggt gttccaggag ctaaaggcga agatggcaag 1500gatggatcac ctggagaacc tggtgcaaat gggcttccag gagctgcagg agaaaggggt 1560gcccctgggt tccgaggacc tgctggacca aatggcatcc caggagaaaa gggtcctgct 1620ggagagcgtg gtgctccagg ccctgcaggg cccagaggag ctgctggaga acctggcaga 1680gatggcgtcc ctggaggtcc aggaatgagg ggcatgcccg gaagtccagg aggaccagga 1740agtgatggga aaccagggcc tcccggaagt caaggagaaa gtggtcgacc aggtcctcct 1800gggccatctg gtccccgagg tcagcctggt gtcatgggct tccccggtcc taaaggaaat 1860gatggtgctc ctggtaagaa tggagaacga ggtggccctg gaggacctgg ccctcagggt 1920cctcctggaa agaatggtga aactggacct caaggacccc cagggcctac tgggcctggt 1980ggtgacaaag gagacacagg accccctggt ccacaaggat tacaaggctt gcctggtaca 2040ggtggtcctc caggagaaaa tggaaaacct ggggaaccag

gtccaaaggg tgatgccggt 2100gcacctggag ctccaggagg caagggtgat gctggtgccc ctggtgaacg tggacctcct 2160ggattggcag gggccccagg acttagaggt ggagctggtc cccctggtcc cgaaggagga 2220aagggtgctg ctggtcctcc tgggccacct ggtgctgctg gtactcctgg tctgcaagga 2280atgcctggag aaagaggagg tcttggaagt cctggtccaa agggtgacaa gggtgaacca 2340ggcggcccag gtgctgatgg tgtcccaggg aaagatggcc caaggggtcc tactggtcct 2400attggtcctc ctggcccagc tggccagcct ggagataagg gtgaaggtgg tgcccccgga 2460cttccaggta tagctggacc tcgtggtagc cctggtgaga gaggtgaaac tggccctcca 2520ggacctgctg gtttccctgg tgctcctgga cagaatggtg aacctggtgg taaaggagaa 2580agaggggctc cgggtgagaa aggtgaagga ggccctcctg gagttgcagg accccctgga 2640ggttctggac ctgctggtcc tcctggtccc caaggtgtca aaggtgaacg tggcagtcct 2700ggtggacctg gtgctgctgg cttccctggt gctcgtggtc ttcctggtcc tcctggtagt 2760aatggtaacc caggaccccc aggtcccagc ggttctccag gcaaggatgg gcccccaggt 2820cctgcgggta acactggtgc tcctggcagc cctggagtgt ctggaccaaa aggtgatgct 2880ggccaaccag gagagaaggg atcgcctggt gcccagggcc caccaggagc tccaggccca 2940cttgggattg ctgggatcac tggagcacgg ggtcttgcag gaccaccagg catgccaggt 3000cctaggggaa gccctggccc tcagggtgtc aagggtgaaa gtgggaaacc aggagctaac 3060ggtctcagtg gagaacgtgg tccccctgga ccccagggtc ttcctggtct ggctggtaca 3120gctggtgaac ctggaagaga tggaaaccct ggatcagatg gtcttccagg ccgagatgga 3180tctcctggtg gcaagggtga tcgtggtgaa aatggctctc ctggtgcccc tggcgctcct 3240ggtcatccag gcccacctgg tcctgtcggt ccagctggaa agagtggtga cagaggagaa 3300agtggccctg ctggccctgc tggtgctccc ggtcctgctg gttcccgagg tgctcctggt 3360cctcaaggcc cacgtggtga caaaggtgaa acaggtgaac gtggagctgc tggcatcaaa 3420ggacatcgag gattccctgg taatccaggt gccccaggtt ctccaggccc tgctggtcag 3480cagggtgcaa tcggcagtcc aggacctgca ggccccagag gacctgttgg acccagtgga 3540cctcctggca aagatggaac cagtggacat ccaggtccca ttggaccacc agggcctcga 3600ggtaacagag gtgaaagagg atctgagggc tccccaggcc acccagggca accaggccct 3660cctggacctc ctggtgcccc tggtccttgc tgtggtggtg ttggagccgc tgccattgct 3720gggattggag gtgaaaaagc tggcggtttt gccccgtatt atggagatga accaatggat 3780ttcaaaatca acaccgatga gattatgact tcactcaagt ctgttaatgg acaaatagaa 3840agcctcatta gtcctgatgg ttctcgtaaa aaccccgcta gaaactgcag agacctgaaa 3900ttctgccatc ctgaactcaa gagtggagaa tactgggttg accctaacca aggatgcaaa 3960ttggatgcta tcaaggtatt ctgtaatatg gaaactgggg aaacatgcat aagtgccaat 4020cctttgaatg ttccacggaa acactggtgg acagattcta gtgctgagaa gaaacacgtt 4080tggtttggag agtccatgga tggtggtttt cagtttagct acggcaatcc tgaacttcct 4140gaagatgtcc ttgatgtgca gctggcattc cttcgacttc tctccagccg agcttcccag 4200aacatcacat atcactgcaa aaatagcatt gcatacatgg atcaggccag tggaaatgta 4260aagaaggccc tgaagctgat ggggtcaaat gaaggtgaat tcaaggctga aggaaatagc 4320aaattcacct acacagttct ggaggatggt tgcacgaaac acactgggga atggagcaaa 4380acagtctttg aatatcgaac acgcaaggct gtgagactac ctattgtaga tattgcaccc 4440tatgacattg gtggtcctga tcaagaattt ggtgtggacg ttggccctgt ttgcttttta 4500taaaccaaac tctatctgaa atcccaacaa aaaaaattta actccatatg tgttcctctt 4560gttctaatct tgtcaaccag tgcaagtgac cgacaaaatt ccagttattt atttccaaaa 4620tgtttggaaa cagtataatt tgacaaagaa aaatgatact tctctttttt tgctgttcca 4680ccaaatacaa ttcaaatgct ttttgtttta tttttttacc aattccaatt tcaaaatgtc 4740tcaatggtgc tataataaat aaacttcaac actctttatg ataacaacac tgtgttatat 4800tctttgaatc ctagcccatc tgcagagcaa tgactgtgct caccagtaaa agataacctt 4860tctttctgaa atagtcaaat acgaaattag aaaagccctc cctattttaa ctacctcaac 4920tggtcagaaa cacagattgt attctatgag tcccagaaga tgaaaaaaat tttatacgtt 4980gataaaactt ataaatttca ttgattaatc tcctggaaga ttggtttaaa aagaaaagtg 5040taatgcaaga atttaaagaa atatttttaa agccacaatt attttaatat tggatatcaa 5100ctgcttgtaa aggtgctcct cttttttctt gtcattgctg gtcaagatta ctaatatttg 5160ggaaggcttt aaagacgcat gttatggtgc taatgtactt tcacttttaa actctagatc 5220agaattgttg acttgcattc agaacataaa tgcacaaaat ctgtacatgt ctcccatcag 5280aaagattcat tggcatgcca cagggattct cctccttcat cctgtaaagg tcaacaataa 5340aaaccaaatt atggggctgc ttttgtcaca ctagcataga gaatgtgttg aaatttaact 5400ttgtaagctt gtatgtggtt gttgatcttt tttttcctta cagacaccca taataaaata 5460721466PRTHomo sapiens 72Met Met Ser Phe Val Gln Lys Gly Ser Trp Leu Leu Leu Ala Leu Leu 1 5 10 15His Pro Thr Ile Ile Leu Ala Gln Gln Glu Ala Val Glu Gly Gly Cys 20 25 30Ser His Leu Gly Gln Ser Tyr Ala Asp Arg Asp Val Trp Lys Pro Glu 35 40 45Pro Cys Gln Ile Cys Val Cys Asp Ser Gly Ser Val Leu Cys Asp Asp 50 55 60Ile Ile Cys Asp Asp Gln Glu Leu Asp Cys Pro Asn Pro Glu Ile Pro65 70 75 80Phe Gly Glu Cys Cys Ala Val Cys Pro Gln Pro Pro Thr Ala Pro Thr 85 90 95Arg Pro Pro Asn Gly Gln Gly Pro Gln Gly Pro Lys Gly Asp Pro Gly 100 105 110Pro Pro Gly Ile Pro Gly Arg Asn Gly Asp Pro Gly Ile Pro Gly Gln 115 120 125Pro Gly Ser Pro Gly Ser Pro Gly Pro Pro Gly Ile Cys Glu Ser Cys 130 135 140Pro Thr Gly Pro Gln Asn Tyr Ser Pro Gln Tyr Asp Ser Tyr Asp Val145 150 155 160Lys Ser Gly Val Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala 165 170 175Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro Gly 180 185 190Ser Pro Gly Ser Pro Gly Tyr Gln Gly Pro Pro Gly Glu Pro Gly Gln 195 200 205Ala Gly Pro Ser Gly Pro Pro Gly Pro Pro Gly Ala Ile Gly Pro Ser 210 215 220Gly Pro Ala Gly Lys Asp Gly Glu Ser Gly Arg Pro Gly Arg Pro Gly225 230 235 240Glu Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile 245 250 255Pro Gly Phe Pro Gly Met Lys Gly His Arg Gly Phe Asp Gly Arg Asn 260 265 270Gly Glu Lys Gly Glu Thr Gly Ala Pro Gly Leu Lys Gly Glu Asn Gly 275 280 285Leu Pro Gly Glu Asn Gly Ala Pro Gly Pro Met Gly Pro Arg Gly Ala 290 295 300Pro Gly Glu Arg Gly Arg Pro Gly Leu Pro Gly Ala Ala Gly Ala Arg305 310 315 320Gly Asn Asp Gly Ala Arg Gly Ser Asp Gly Gln Pro Gly Pro Pro Gly 325 330 335Pro Pro Gly Thr Ala Gly Phe Pro Gly Ser Pro Gly Ala Lys Gly Glu 340 345 350Val Gly Pro Ala Gly Ser Pro Gly Ser Asn Gly Ala Pro Gly Gln Arg 355 360 365Gly Glu Pro Gly Pro Gln Gly His Ala Gly Ala Gln Gly Pro Pro Gly 370 375 380Pro Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro385 390 395 400Ala Gly Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro 405 410 415Gly Pro Ala Gly Ala Asn Gly Ala Pro Gly Leu Arg Gly Gly Ala Gly 420 425 430Glu Pro Gly Lys Asn Gly Ala Lys Gly Glu Pro Gly Pro Arg Gly Glu 435 440 445Arg Gly Glu Ala Gly Ile Pro Gly Val Pro Gly Ala Lys Gly Glu Asp 450 455 460Gly Lys Asp Gly Ser Pro Gly Glu Pro Gly Ala Asn Gly Leu Pro Gly465 470 475 480Ala Ala Gly Glu Arg Gly Ala Pro Gly Phe Arg Gly Pro Ala Gly Pro 485 490 495Asn Gly Ile Pro Gly Glu Lys Gly Pro Ala Gly Glu Arg Gly Ala Pro 500 505 510Gly Pro Ala Gly Pro Arg Gly Ala Ala Gly Glu Pro Gly Arg Asp Gly 515 520 525Val Pro Gly Gly Pro Gly Met Arg Gly Met Pro Gly Ser Pro Gly Gly 530 535 540Pro Gly Ser Asp Gly Lys Pro Gly Pro Pro Gly Ser Gln Gly Glu Ser545 550 555 560Gly Arg Pro Gly Pro Pro Gly Pro Ser Gly Pro Arg Gly Gln Pro Gly 565 570 575Val Met Gly Phe Pro Gly Pro Lys Gly Asn Asp Gly Ala Pro Gly Lys 580 585 590Asn Gly Glu Arg Gly Gly Pro Gly Gly Pro Gly Pro Gln Gly Pro Pro 595 600 605Gly Lys Asn Gly Glu Thr Gly Pro Gln Gly Pro Pro Gly Pro Thr Gly 610 615 620Pro Gly Gly Asp Lys Gly Asp Thr Gly Pro Pro Gly Pro Gln Gly Leu625 630 635 640Gln Gly Leu Pro Gly Thr Gly Gly Pro Pro Gly Glu Asn Gly Lys Pro 645 650 655Gly Glu Pro Gly Pro Lys Gly Asp Ala Gly Ala Pro Gly Ala Pro Gly 660 665 670Gly Lys Gly Asp Ala Gly Ala Pro Gly Glu Arg Gly Pro Pro Gly Leu 675 680 685Ala Gly Ala Pro Gly Leu Arg Gly Gly Ala Gly Pro Pro Gly Pro Glu 690 695 700Gly Gly Lys Gly Ala Ala Gly Pro Pro Gly Pro Pro Gly Ala Ala Gly705 710 715 720Thr Pro Gly Leu Gln Gly Met Pro Gly Glu Arg Gly Gly Leu Gly Ser 725 730 735Pro Gly Pro Lys Gly Asp Lys Gly Glu Pro Gly Gly Pro Gly Ala Asp 740 745 750Gly Val Pro Gly Lys Asp Gly Pro Arg Gly Pro Thr Gly Pro Ile Gly 755 760 765Pro Pro Gly Pro Ala Gly Gln Pro Gly Asp Lys Gly Glu Gly Gly Ala 770 775 780Pro Gly Leu Pro Gly Ile Ala Gly Pro Arg Gly Ser Pro Gly Glu Arg785 790 795 800Gly Glu Thr Gly Pro Pro Gly Pro Ala Gly Phe Pro Gly Ala Pro Gly 805 810 815Gln Asn Gly Glu Pro Gly Gly Lys Gly Glu Arg Gly Ala Pro Gly Glu 820 825 830Lys Gly Glu Gly Gly Pro Pro Gly Val Ala Gly Pro Pro Gly Gly Ser 835 840 845Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly Val Lys Gly Glu Arg Gly 850 855 860Ser Pro Gly Gly Pro Gly Ala Ala Gly Phe Pro Gly Ala Arg Gly Leu865 870 875 880Pro Gly Pro Pro Gly Ser Asn Gly Asn Pro Gly Pro Pro Gly Pro Ser 885 890 895Gly Ser Pro Gly Lys Asp Gly Pro Pro Gly Pro Ala Gly Asn Thr Gly 900 905 910Ala Pro Gly Ser Pro Gly Val Ser Gly Pro Lys Gly Asp Ala Gly Gln 915 920 925Pro Gly Glu Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro 930 935 940Gly Pro Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly945 950 955 960Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val 965 970 975Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly Leu Ser Gly Glu Arg 980 985 990Gly Pro Pro Gly Pro Gln Gly Leu Pro Gly Leu Ala Gly Thr Ala Gly 995 1000 1005Glu Pro Gly Arg Asp Gly Asn Pro Gly Ser Asp Gly Leu Pro Gly Arg 1010 1015 1020Asp Gly Ser Pro Gly Gly Lys Gly Asp Arg Gly Glu Asn Gly Ser Pro1025 1030 1035 1040Gly Ala Pro Gly Ala Pro Gly His Pro Gly Pro Pro Gly Pro Val Gly 1045 1050 1055Pro Ala Gly Lys Ser Gly Asp Arg Gly Glu Ser Gly Pro Ala Gly Pro 1060 1065 1070Ala Gly Ala Pro Gly Pro Ala Gly Ser Arg Gly Ala Pro Gly Pro Gln 1075 1080 1085Gly Pro Arg Gly Asp Lys Gly Glu Thr Gly Glu Arg Gly Ala Ala Gly 1090 1095 1100Ile Lys Gly His Arg Gly Phe Pro Gly Asn Pro Gly Ala Pro Gly Ser1105 1110 1115 1120Pro Gly Pro Ala Gly Gln Gln Gly Ala Ile Gly Ser Pro Gly Pro Ala 1125 1130 1135Gly Pro Arg Gly Pro Val Gly Pro Ser Gly Pro Pro Gly Lys Asp Gly 1140 1145 1150Thr Ser Gly His Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Asn 1155 1160 1165Arg Gly Glu Arg Gly Ser Glu Gly Ser Pro Gly His Pro Gly Gln Pro 1170 1175 1180Gly Pro Pro Gly Pro Pro Gly Ala Pro Gly Pro Cys Cys Gly Gly Val1185 1190 1195 1200Gly Ala Ala Ala Ile Ala Gly Ile Gly Gly Glu Lys Ala Gly Gly Phe 1205 1210 1215Ala Pro Tyr Tyr Gly Asp Glu Pro Met Asp Phe Lys Ile Asn Thr Asp 1220 1225 1230Glu Ile Met Thr Ser Leu Lys Ser Val Asn Gly Gln Ile Glu Ser Leu 1235 1240 1245Ile Ser Pro Asp Gly Ser Arg Lys Asn Pro Ala Arg Asn Cys Arg Asp 1250 1255 1260Leu Lys Phe Cys His Pro Glu Leu Lys Ser Gly Glu Tyr Trp Val Asp1265 1270 1275 1280Pro Asn Gln Gly Cys Lys Leu Asp Ala Ile Lys Val Phe Cys Asn Met 1285 1290 1295Glu Thr Gly Glu Thr Cys Ile Ser Ala Asn Pro Leu Asn Val Pro Arg 1300 1305 1310Lys His Trp Trp Thr Asp Ser Ser Ala Glu Lys Lys His Val Trp Phe 1315 1320 1325Gly Glu Ser Met Asp Gly Gly Phe Gln Phe Ser Tyr Gly Asn Pro Glu 1330 1335 1340Leu Pro Glu Asp Val Leu Asp Val Gln Leu Ala Phe Leu Arg Leu Leu1345 1350 1355 1360Ser Ser Arg Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Ile 1365 1370 1375Ala Tyr Met Asp Gln Ala Ser Gly Asn Val Lys Lys Ala Leu Lys Leu 1380 1385 1390Met Gly Ser Asn Glu Gly Glu Phe Lys Ala Glu Gly Asn Ser Lys Phe 1395 1400 1405Thr Tyr Thr Val Leu Glu Asp Gly Cys Thr Lys His Thr Gly Glu Trp 1410 1415 1420Ser Lys Thr Val Phe Glu Tyr Arg Thr Arg Lys Ala Val Arg Leu Pro1425 1430 1435 1440Ile Val Asp Ile Ala Pro Tyr Asp Ile Gly Gly Pro Asp Gln Glu Phe 1445 1450 1455Gly Val Asp Val Gly Pro Val Cys Phe Leu 1460 1465731051DNAHomo sapiens 73cgcggagtct gagcggcgct cgtcccgtcc caaggccgac gccagcacgc cgtcatggcc 60cccgcagcgg cgacgggggg cagcaccctg cccagtggct tctcggtctt caccaccttg 120cccgacttgc tcttcatctt tgagtttatc ttcgggggcc tggtgtggat cctggtggcc 180tcctccctgg tgccctggcc cctggtccag ggctgggtga tgttcgtgtc tgtgttctgc 240ttcgtggcca ccaccacctt gatcatcctg tacataattg gagcccacgg tggagagact 300tcctgggtca ccttggacgc agcctaccac tgcaccgctg ccctctttta cctcagcgcc 360tcagtcctgg aggccctggc caccatcacg atgcaagacg gcttcaccta caggcactac 420catgaaaaca ttgctgccgt ggtgttctcc tacatagcca ctctgctcta cgtggtccat 480gcggtgttct ctttaatcag atggaagtct tcataaagcc gcagtagaac ttgagctgaa 540aacccagatg gtgttaactg gccgccccac tttccggcat aactttttag aaaacagaaa 600tgcccttgat ggtggaaaaa agaaaacaac caccccccca ctgcccaaaa aaaaaagccc 660tgccctgttg ctcgtgggtg ctgtgtttac tctcccgtgt gccttcgcgt ccgggttggg 720agcttgctgt gtctaacctc caactgctgt gctgtctgct agggtcacct cctgtttgtg 780aaaggggacc ttcttgttcg ggggtgggaa gtggcgaccg tgacctgaga aggaaagaaa 840gatcctctgc tgacccctgg agcagctctc gagaactacc tgttggtatt gtccacaagc 900tctcccgagc gccccatctt gtgccatgtt ttaagtcttc atggatgttc tgcatgtcat 960ggggactaaa actcacccaa cagatctttc cagaggtcca tggtggaaga cgataaccct 1020gtgaaatact ttataaaatg tcttaatgtt c 105174153PRTHomo sapiens 74Met Ala Pro Ala Ala Ala Thr Gly Gly Ser Thr Leu Pro Ser Gly Phe 1 5 10 15Ser Val Phe Thr Thr Leu Pro Asp Leu Leu Phe Ile Phe Glu Phe Ile 20 25 30Phe Gly Gly Leu Val Trp Ile Leu Val Ala Ser Ser Leu Val Pro Trp 35 40 45Pro Leu Val Gln Gly Trp Val Met Phe Val Ser Val Phe Cys Phe Val 50 55 60Ala Thr Thr Thr Leu Ile Ile Leu Tyr Ile Ile Gly Ala His Gly Gly65 70 75 80Glu Thr Ser Trp Val Thr Leu Asp Ala Ala Tyr His Cys Thr Ala Ala 85 90 95Leu Phe Tyr Leu Ser Ala Ser Val Leu Glu Ala Leu Ala Thr Ile Thr 100 105 110Met Gln Asp Gly Phe Thr Tyr Arg His Tyr His Glu Asn Ile Ala Ala 115 120 125Val Val Phe Ser Tyr Ile Ala Thr Leu Leu Tyr Val Val His Ala Val 130 135 140Phe Ser Leu Ile Arg Trp Lys Ser Ser145 150755416DNAHomo sapiens 75gtgtcccata gtgtttccaa acttggaaag ggcgggggag ggcgggagga tgcggagggc 60ggaggtatgc agacaacgag tcagagtttc cccttgaaag cctcaaaagt gtccacgtcc 120tcaaaaagaa tggaaccaat ttaagaagcc agccccgtgg ccacgtccct tcccccattc 180gggccctcct ctgcgccccc gcaggctcct cccagctgtg gctgcccggg cccccagccc 240cagccctccc attggtggag gcccttttgg aggcacccta gggccaggga aacttttgcc 300gtataaatag ggcagatccg ggatttgtta ttttagcacc acggcagcag gaggtttcgg 360ctaagttgga ggtactggcc acgactgcat gcccgcgccc gccatgtgat acctccgccg 420gtgacccagg gctctgcgac acaaggagtc gcatgtctaa gtgctagaca tgctcagctt 480tgtggatacg cggactttgt tgctgcttgc agtaacctta tgcctagcaa catgccaatc 540tttacaagag gaaactgtaa gaaagggccc agccggagat agaggaccac gtggagaaag 600gggtccacca ggccccccag gcagagatgg tgaagatggt

cccacaggcc ctcctggtcc 660acctggtcct cctggccccc ctggtctcgg tgggaacttt gctgctcagt atgatggaaa 720aggagttgga cttggccctg gaccaatggg cttaatggga cctagaggcc cacctggtgc 780agctggagcc ccaggccctc aaggtttcca aggacctgct ggtgagcctg gtgaacctgg 840tcaaactggt cctgcaggtg ctcgtggtcc agctggccct cctggcaagg ctggtgaaga 900tggtcaccct ggaaaacccg gacgacctgg tgagagagga gttgttggac cacagggtgc 960tcgtggtttc cctggaactc ctggacttcc tggcttcaaa ggcattaggg gacacaatgg 1020tctggatgga ttgaagggac agcccggtgc tcctggtgtg aagggtgaac ctggtgcccc 1080tggtgaaaat ggaactccag gtcaaacagg agcccgtggt cttcctggtg agagaggacg 1140tgttggtgcc cctggtccag ctggtgcccg tggaagtgat ggaagtgtgg gtcccgtagg 1200tcctgctggt cctaatgggt ctgctggccc tccaggtttc ccaggtgccc ctggtcccaa 1260gggtgaaatt ggagctgttg gtaacgctgg tcctactgga cccgccggtc cccgtggtga 1320agtgggtctt ccaggcctct ccggccccgt tggacctcct ggtaatcctg gagcaaacgg 1380ccttactggt gccaagggtg ctgctggcct tcccggcgtt gctggggctc ccggcctccc 1440tggaccccgc ggtattcctg gccctcctgg tgctgccggt actactggtg ccagaggact 1500tgttggtgag cctggtccag ctggctccaa aggagagagc ggtaacaagg gtgagcccgg 1560ctccgctggt ccccaaggtc ctcctggtcc cagtggtgaa gaaggaaaga gaggccctaa 1620tggggaagct ggatctgccg gccctccagg acctcctggg ctgagaggta gtcctggttc 1680tcgtggtctt cctggagctg atggcagagc tggcgtcatg ggccctcctg gtagtcgtgg 1740tgcaagtggc cctgctggag tccgaggacc taatggagat gctggtcgcc ctggggagcc 1800tggtctcatg ggacccagag gtcttcctgg ttcccctgga aatatcggcc ccgctggaaa 1860agaaggtcct gtcggcctcc ctggcatcga cggcaggcct ggcccaattg gccccgttgg 1920agcaagagga gagcctggca acattggatt ccctggaccc aaaggcccca ctggtgaccc 1980tggcaaaaac ggtgataaag gtcatgctgg tcttgctggt gctcggggtg ctccaggtcc 2040tgatggaaac aatggtgctc agggacctcc tggaccacag ggtgttcaag gtggaaaagg 2100tgaacagggt cccgctggtc ctccaggctt ccagggtctg cctggcccct caggtcccgc 2160tggtgaagtt ggcaaaccag gagaaagggg tctccatggt gagtttggtc tccctggtcc 2220tgctggtcca agaggggaac gcggtccccc aggtgagagt ggtgctgccg gtcctactgg 2280tcctattgga agccgaggtc cttctggacc cccagggcct gatggaaaca agggtgaacc 2340tggtgtggtt ggtgctgtgg gcactgctgg tccatctggt cctagtggac tcccaggaga 2400gaggggtgct gctggcatac ctggaggcaa gggagaaaag ggtgaacctg gtctcagagg 2460tgaaattggt aaccctggca gagatggtgc tcgtggtgct catggtgctg taggtgcccc 2520tggtcctgct ggagccacag gtgaccgggg cgaagctggg gctgctggtc ctgctggtcc 2580tgctggtcct cggggaagcc ctggtgaacg tggcgaggtc ggtcctgctg gccccaacgg 2640atttgctggt ccggctggtg ctgctggtca accgggtgct aaaggagaaa gaggaggcaa 2700agggcctaag ggtgaaaacg gtgttgttgg tcccacaggc cccgttggag ctgctggccc 2760agctggtcca aatggtcccc ccggtcctgc tggaagtcgt ggtgatggag gcccccctgg 2820tatgactggt ttccctggtg ctgctggacg gactggtccc ccaggaccct ctggtatttc 2880tggccctcct ggtccccctg gtcctgctgg gaaagaaggg cttcgtggtc ctcgtggtga 2940ccaaggtcca gttggccgaa ctggagaagt aggtgcagtt ggtccccctg gcttcgctgg 3000tgagaagggt ccctctggag aggctggtac tgctggacct cctggcactc caggtcctca 3060gggtcttctt ggtgctcctg gtattctggg tctccctggc tcgagaggtg aacgtggtct 3120acctggtgtt gctggtgctg tgggtgaacc tggtcctctt ggcattgccg gccctcctgg 3180ggcccgtggt cctcctggtg ctgtgggtag tcctggagtc aacggtgctc ctggtgaagc 3240tggtcgtgat ggcaaccctg ggaacgatgg tcccccaggt cgcgatggtc aacccggaca 3300caagggagag cgcggttacc ctggcaatat tggtcccgtt ggtgctgcag gtgcacctgg 3360tcctcatggc cccgtgggtc ctgctggcaa acatggaaac cgtggtgaaa ctggtccttc 3420tggtcctgtt ggtcctgctg gtgctgttgg cccaagaggt cctagtggcc cacaaggcat 3480tcgtggcgat aagggagagc ccggtgaaaa ggggcccaga ggtcttcctg gcttcaaggg 3540acacaatgga ttgcaaggtc tgcctggtat cgctggtcac catggtgatc aaggtgctcc 3600tggctccgtg ggtcctgctg gtcctagggg ccctgctggt ccttctggcc ctgctggaaa 3660agatggtcgc actggacatc ctggtacggt tggacctgct ggcattcgag gccctcaggg 3720tcaccaaggc cctgctggcc cccctggtcc ccctggccct cctggacctc caggtgtaag 3780cggtggtggt tatgactttg gttacgatgg agacttctac agggctgacc agcctcgctc 3840agcaccttct ctcagaccca aggactatga agttgatgct actctgaagt ctctcaacaa 3900ccagattgag acccttctta ctcctgaagg ctctagaaag aacccagctc gcacatgccg 3960tgacttgaga ctcagccacc cagagtggag cagcggttac tactggattg accccaacca 4020aggatgcact atggaagcca tcaaagtata ctgtgatttc cctaccggcg aaacctgtat 4080ccgggcccaa cctgaaaaca tcccagccaa gaactggtat aggagctcca aggacaagaa 4140acacgtctgg ctaggagaaa ctatcaatgc tggcagccag tttgaatata atgttgaagg 4200agtgacttcc aaggaaatgg ctacccaact tgccttcatg cgcctgctgg ccaactatgc 4260ctctcagaac atcacctacc actgcaagaa cagcattgca tacatggatg aggagactgg 4320caacctgaaa aaggctgtca ttctacaggg ctctaatgat gttgaacttg ttgctgaggg 4380caacagcagg ttcacttaca ctgttcttgt agatggctgc tctaaaaaga caaatgaatg 4440gggaaagaca atcattgaat acaaaacaaa taagccatca cgcctgccct tccttgatat 4500tgcacctttg gacatcggtg gtgctgacca tgaattcttt gtggacattg gcccagtctg 4560tttcaaataa atgaactcaa tctaaattaa aaaagaaaga aatttgaaaa aactttctct 4620ttgccatttc ttcttcttct tttttaactg aaagctgaat ccttccattt cttctgcaca 4680tctacttgct taaattgtgg gcaaaagaga aaaagaagga ttgatcagag cattgtgcaa 4740tacagtttca ttaactcctt cccccgctcc cccaaaaatt tgaatttttt tttcaacact 4800cttacacctg ttatggaaaa tgtcaacctt tgtaagaaaa ccaaaataaa aattgaaaaa 4860taaaaaccat aaacatttgc accacttgtg gcttttgaat atcttccaca gagggaagtt 4920taaaacccaa acttccaaag gtttaaacta cctcaaaaca ctttcccatg agtgtgatcc 4980acattgttag gtgctgacct agacagagat gaactgaggt ccttgttttg ttttgttcat 5040aatacaaagg tgctaattaa tagtatttca gatacttgaa gaatgttgat ggtgctagaa 5100gaatttgaga agaaatactc ctgtattgag ttgtatcgtg tggtgtattt tttaaaaaat 5160ttgatttagc attcatattt tccatcttat tcccaattaa aagtatgcag attatttgcc 5220caaagttgtc ctcttcttca gattcagcat ttgttctttg ccagtctcat tttcatcttc 5280ttccatggtt ccacagaagc tttgtttctt gggcaagcag aaaaattaaa ttgtacctat 5340tttgtatatg tgagatgttt aaataaattg tgaaaaaaat gaaataaagc atgtttggtt 5400ttccaaaaga acatat 5416761366PRTHomo sapiens 76Met Leu Ser Phe Val Asp Thr Arg Thr Leu Leu Leu Leu Ala Val Thr 1 5 10 15Leu Cys Leu Ala Thr Cys Gln Ser Leu Gln Glu Glu Thr Val Arg Lys 20 25 30Gly Pro Ala Gly Asp Arg Gly Pro Arg Gly Glu Arg Gly Pro Pro Gly 35 40 45Pro Pro Gly Arg Asp Gly Glu Asp Gly Pro Thr Gly Pro Pro Gly Pro 50 55 60Pro Gly Pro Pro Gly Pro Pro Gly Leu Gly Gly Asn Phe Ala Ala Gln65 70 75 80Tyr Asp Gly Lys Gly Val Gly Leu Gly Pro Gly Pro Met Gly Leu Met 85 90 95Gly Pro Arg Gly Pro Pro Gly Ala Ala Gly Ala Pro Gly Pro Gln Gly 100 105 110Phe Gln Gly Pro Ala Gly Glu Pro Gly Glu Pro Gly Gln Thr Gly Pro 115 120 125Ala Gly Ala Arg Gly Pro Ala Gly Pro Pro Gly Lys Ala Gly Glu Asp 130 135 140Gly His Pro Gly Lys Pro Gly Arg Pro Gly Glu Arg Gly Val Val Gly145 150 155 160Pro Gln Gly Ala Arg Gly Phe Pro Gly Thr Pro Gly Leu Pro Gly Phe 165 170 175Lys Gly Ile Arg Gly His Asn Gly Leu Asp Gly Leu Lys Gly Gln Pro 180 185 190Gly Ala Pro Gly Val Lys Gly Glu Pro Gly Ala Pro Gly Glu Asn Gly 195 200 205Thr Pro Gly Gln Thr Gly Ala Arg Gly Leu Pro Gly Glu Arg Gly Arg 210 215 220Val Gly Ala Pro Gly Pro Ala Gly Ala Arg Gly Ser Asp Gly Ser Val225 230 235 240Gly Pro Val Gly Pro Ala Gly Pro Asn Gly Ser Ala Gly Pro Pro Gly 245 250 255Phe Pro Gly Ala Pro Gly Pro Lys Gly Glu Ile Gly Ala Val Gly Asn 260 265 270Ala Gly Pro Thr Gly Pro Ala Gly Pro Arg Gly Glu Val Gly Leu Pro 275 280 285Gly Leu Ser Gly Pro Val Gly Pro Pro Gly Asn Pro Gly Ala Asn Gly 290 295 300Leu Thr Gly Ala Lys Gly Ala Ala Gly Leu Pro Gly Val Ala Gly Ala305 310 315 320Pro Gly Leu Pro Gly Pro Arg Gly Ile Pro Gly Pro Pro Gly Ala Ala 325 330 335Gly Thr Thr Gly Ala Arg Gly Leu Val Gly Glu Pro Gly Pro Ala Gly 340 345 350Ser Lys Gly Glu Ser Gly Asn Lys Gly Glu Pro Gly Ser Ala Gly Pro 355 360 365Gln Gly Pro Pro Gly Pro Ser Gly Glu Glu Gly Lys Arg Gly Pro Asn 370 375 380Gly Glu Ala Gly Ser Ala Gly Pro Pro Gly Pro Pro Gly Leu Arg Gly385 390 395 400Ser Pro Gly Ser Arg Gly Leu Pro Gly Ala Asp Gly Arg Ala Gly Val 405 410 415Met Gly Pro Pro Gly Ser Arg Gly Ala Ser Gly Pro Ala Gly Val Arg 420 425 430Gly Pro Asn Gly Asp Ala Gly Arg Pro Gly Glu Pro Gly Leu Met Gly 435 440 445Pro Arg Gly Leu Pro Gly Ser Pro Gly Asn Ile Gly Pro Ala Gly Lys 450 455 460Glu Gly Pro Val Gly Leu Pro Gly Ile Asp Gly Arg Pro Gly Pro Ile465 470 475 480Gly Pro Val Gly Ala Arg Gly Glu Pro Gly Asn Ile Gly Phe Pro Gly 485 490 495Pro Lys Gly Pro Thr Gly Asp Pro Gly Lys Asn Gly Asp Lys Gly His 500 505 510Ala Gly Leu Ala Gly Ala Arg Gly Ala Pro Gly Pro Asp Gly Asn Asn 515 520 525Gly Ala Gln Gly Pro Pro Gly Pro Gln Gly Val Gln Gly Gly Lys Gly 530 535 540Glu Gln Gly Pro Ala Gly Pro Pro Gly Phe Gln Gly Leu Pro Gly Pro545 550 555 560Ser Gly Pro Ala Gly Glu Val Gly Lys Pro Gly Glu Arg Gly Leu His 565 570 575Gly Glu Phe Gly Leu Pro Gly Pro Ala Gly Pro Arg Gly Glu Arg Gly 580 585 590Pro Pro Gly Glu Ser Gly Ala Ala Gly Pro Thr Gly Pro Ile Gly Ser 595 600 605Arg Gly Pro Ser Gly Pro Pro Gly Pro Asp Gly Asn Lys Gly Glu Pro 610 615 620Gly Val Val Gly Ala Val Gly Thr Ala Gly Pro Ser Gly Pro Ser Gly625 630 635 640Leu Pro Gly Glu Arg Gly Ala Ala Gly Ile Pro Gly Gly Lys Gly Glu 645 650 655Lys Gly Glu Pro Gly Leu Arg Gly Glu Ile Gly Asn Pro Gly Arg Asp 660 665 670Gly Ala Arg Gly Ala His Gly Ala Val Gly Ala Pro Gly Pro Ala Gly 675 680 685Ala Thr Gly Asp Arg Gly Glu Ala Gly Ala Ala Gly Pro Ala Gly Pro 690 695 700Ala Gly Pro Arg Gly Ser Pro Gly Glu Arg Gly Glu Val Gly Pro Ala705 710 715 720Gly Pro Asn Gly Phe Ala Gly Pro Ala Gly Ala Ala Gly Gln Pro Gly 725 730 735Ala Lys Gly Glu Arg Gly Gly Lys Gly Pro Lys Gly Glu Asn Gly Val 740 745 750Val Gly Pro Thr Gly Pro Val Gly Ala Ala Gly Pro Ala Gly Pro Asn 755 760 765Gly Pro Pro Gly Pro Ala Gly Ser Arg Gly Asp Gly Gly Pro Pro Gly 770 775 780Met Thr Gly Phe Pro Gly Ala Ala Gly Arg Thr Gly Pro Pro Gly Pro785 790 795 800Ser Gly Ile Ser Gly Pro Pro Gly Pro Pro Gly Pro Ala Gly Lys Glu 805 810 815Gly Leu Arg Gly Pro Arg Gly Asp Gln Gly Pro Val Gly Arg Thr Gly 820 825 830Glu Val Gly Ala Val Gly Pro Pro Gly Phe Ala Gly Glu Lys Gly Pro 835 840 845Ser Gly Glu Ala Gly Thr Ala Gly Pro Pro Gly Thr Pro Gly Pro Gln 850 855 860Gly Leu Leu Gly Ala Pro Gly Ile Leu Gly Leu Pro Gly Ser Arg Gly865 870 875 880Glu Arg Gly Leu Pro Gly Val Ala Gly Ala Val Gly Glu Pro Gly Pro 885 890 895Leu Gly Ile Ala Gly Pro Pro Gly Ala Arg Gly Pro Pro Gly Ala Val 900 905 910Gly Ser Pro Gly Val Asn Gly Ala Pro Gly Glu Ala Gly Arg Asp Gly 915 920 925Asn Pro Gly Asn Asp Gly Pro Pro Gly Arg Asp Gly Gln Pro Gly His 930 935 940Lys Gly Glu Arg Gly Tyr Pro Gly Asn Ile Gly Pro Val Gly Ala Ala945 950 955 960Gly Ala Pro Gly Pro His Gly Pro Val Gly Pro Ala Gly Lys His Gly 965 970 975Asn Arg Gly Glu Thr Gly Pro Ser Gly Pro Val Gly Pro Ala Gly Ala 980 985 990Val Gly Pro Arg Gly Pro Ser Gly Pro Gln Gly Ile Arg Gly Asp Lys 995 1000 1005Gly Glu Pro Gly Glu Lys Gly Pro Arg Gly Leu Pro Gly Phe Lys Gly 1010 1015 1020His Asn Gly Leu Gln Gly Leu Pro Gly Ile Ala Gly His His Gly Asp1025 1030 1035 1040Gln Gly Ala Pro Gly Ser Val Gly Pro Ala Gly Pro Arg Gly Pro Ala 1045 1050 1055Gly Pro Ser Gly Pro Ala Gly Lys Asp Gly Arg Thr Gly His Pro Gly 1060 1065 1070Thr Val Gly Pro Ala Gly Ile Arg Gly Pro Gln Gly His Gln Gly Pro 1075 1080 1085Ala Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Val Ser 1090 1095 1100Gly Gly Gly Tyr Asp Phe Gly Tyr Asp Gly Asp Phe Tyr Arg Ala Asp1105 1110 1115 1120Gln Pro Arg Ser Ala Pro Ser Leu Arg Pro Lys Asp Tyr Glu Val Asp 1125 1130 1135Ala Thr Leu Lys Ser Leu Asn Asn Gln Ile Glu Thr Leu Leu Thr Pro 1140 1145 1150Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Arg Leu 1155 1160 1165Ser His Pro Glu Trp Ser Ser Gly Tyr Tyr Trp Ile Asp Pro Asn Gln 1170 1175 1180Gly Cys Thr Met Glu Ala Ile Lys Val Tyr Cys Asp Phe Pro Thr Gly1185 1190 1195 1200Glu Thr Cys Ile Arg Ala Gln Pro Glu Asn Ile Pro Ala Lys Asn Trp 1205 1210 1215Tyr Arg Ser Ser Lys Asp Lys Lys His Val Trp Leu Gly Glu Thr Ile 1220 1225 1230Asn Ala Gly Ser Gln Phe Glu Tyr Asn Val Glu Gly Val Thr Ser Lys 1235 1240 1245Glu Met Ala Thr Gln Leu Ala Phe Met Arg Leu Leu Ala Asn Tyr Ala 1250 1255 1260Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Ile Ala Tyr Met Asp1265 1270 1275 1280Glu Glu Thr Gly Asn Leu Lys Lys Ala Val Ile Leu Gln Gly Ser Asn 1285 1290 1295Asp Val Glu Leu Val Ala Glu Gly Asn Ser Arg Phe Thr Tyr Thr Val 1300 1305 1310Leu Val Asp Gly Cys Ser Lys Lys Thr Asn Glu Trp Gly Lys Thr Ile 1315 1320 1325Ile Glu Tyr Lys Thr Asn Lys Pro Ser Arg Leu Pro Phe Leu Asp Ile 1330 1335 1340Ala Pro Leu Asp Ile Gly Gly Ala Asp His Glu Phe Phe Val Asp Ile1345 1350 1355 1360Gly Pro Val Cys Phe Lys 1365771082DNAHomo sapiens 77agctcccttt agcgagtcct tcttttcctg actgcagctc ttttcatttt gccatccttt 60tccagcacca tgatggttct gcaggtttct gcggcccccc ggacagtggc tctgacggcg 120ttactgatgg tgctgctcac atctgtggtc cagggcaggg ccactccaga gaattacctt 180ttccagggac ggcaggaatg ctacgcgttt aatgggacac agcgcttcct ggagagatac 240atctacaacc gggaggagtt cgcgcgcttc gacagcgacg tgggggagtt ccgggcggtg 300acggagctgg ggcggcctgc tgcggagtac tggaacagcc agaaggacat cctggaggag 360aagcgggcag tgccggacag gatgtgcaga cacaactacg agctgggcgg gcccatgacc 420ctgcagcgcc gagtccagcc tagggtgaat gtttccccct ccaagaaggg gcccttgcag 480caccacaacc tgcttgtctg ccacgtgacg gatttctacc caggcagcat tcaagtccga 540tggttcctga atggacagga ggaaacagct ggggtcgtgt ccaccaacct gatccgtaat 600ggagactgga ccttccagat cctggtgatg ctggaaatga ccccccagca gggagatgtc 660tacacctgcc aagtggagca caccagcctg gatagtcctg tcaccgtgga gtggaaggca 720cagtctgatt ctgcccggag taagacattg acgggagctg ggggcttcgt gctggggctc 780atcatctgtg gagtgggcat cttcatgcac aggaggagca agaaagttca acgaggatct 840gcataaacag ggttcctgag ctcactgaaa agactattgt gccttaggaa aagcatttgc 900tgtgtttcgt tagcatctgg ctccaggaca gaccttcaac ttccaaattg atactgctgc 960caagaagttg ctctgaagtc agtttctatc attctgctct ttgattcaaa gcactgtttc 1020tctcactggg cctccaacca tgttcccttc ttcttagcac cacaaataat caaaacccaa 1080ca 108278258PRTHomo sapiens 78Met Met Val Leu Gln Val Ser Ala Ala Pro Arg Thr Val Ala Leu Thr 1 5 10 15Ala Leu Leu Met Val Leu Leu Thr Ser Val Val Gln Gly Arg Ala Thr 20 25 30Pro Glu Asn Tyr Leu Phe Gln Gly Arg Gln Glu Cys Tyr Ala Phe Asn 35 40 45Gly Thr Gln Arg Phe Leu Glu Arg Tyr Ile Tyr Asn Arg Glu Glu Phe 50 55 60Ala Arg Phe Asp Ser Asp Val Gly Glu Phe Arg Ala Val Thr Glu Leu65 70 75 80Gly Arg Pro Ala Ala Glu Tyr Trp Asn Ser Gln Lys Asp Ile Leu Glu 85 90 95Glu Lys Arg Ala Val Pro Asp Arg Met Cys Arg His Asn Tyr Glu Leu 100 105 110Gly Gly Pro Met Thr Leu

Gln Arg Arg Val Gln Pro Arg Val Asn Val 115 120 125Ser Pro Ser Lys Lys Gly Pro Leu Gln His His Asn Leu Leu Val Cys 130 135 140His Val Thr Asp Phe Tyr Pro Gly Ser Ile Gln Val Arg Trp Phe Leu145 150 155 160Asn Gly Gln Glu Glu Thr Ala Gly Val Val Ser Thr Asn Leu Ile Arg 165 170 175Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met Leu Glu Met Thr Pro 180 185 190Gln Gln Gly Asp Val Tyr Thr Cys Gln Val Glu His Thr Ser Leu Asp 195 200 205Ser Pro Val Thr Val Glu Trp Lys Ala Gln Ser Asp Ser Ala Arg Ser 210 215 220Lys Thr Leu Thr Gly Ala Gly Gly Phe Val Leu Gly Leu Ile Ile Cys225 230 235 240Gly Val Gly Ile Phe Met His Arg Arg Ser Lys Lys Val Gln Arg Gly 245 250 255Ser Ala79996DNAHomo sapiens 79gtggaattca tggcatctac ttcgtatgac tattgcagag tgcccatgga agacggggat 60aagcgctgta agcttctgct ggggatagga attctggtgc tcctgatcat cgtgattctg 120ggggtgccct tgattatctt caccatcaag gccaacagcg aggcctgccg ggacggcctt 180cgggcagtga tggagtgtcg caatgtcacc catctcctgc aacaagagct gaccgaggcc 240cagaagggct ttcaggatgt ggaggcccag gccgccacct gcaaccacac tgtgatggcc 300ctaatggctt ccctggatgc agagaaggcc caaggacaaa agaaagtgga ggagcttgag 360ggagagatca ctacattaaa ccataagctt caggacgcgt ctgcagaggt ggagcgactg 420agaagagaaa accaggtctt aagcgtgaga atcgcggaca agaagtacta ccccagctcc 480caggactcca gctccgctgc ggcgccccag ctgctgattg tgctgctggg cctcagcgct 540ctgctgcagt gagatcccag gaagctggca catcttggaa ggtccgtcct gctcggcttt 600tcgcttgaac attcccttga tctcatcagt tctgagcggg tcatggggca acacggttag 660cggggagagc acggggtagc cggagaaggg cctctggagc aggtctggag gggccatggg 720gcagtcctgg gtgtggggac acagtcgggt tgacccaggg ctgtctccct ccagagcctc 780cctccggaca atgagtcccc cctcttgtct cccaccctga gattgggcat ggggtgcggt 840gtggggggca tgtgctgcct gttgttatgg gttttttttg cggggggggt tgcttttttc 900tggggtcttt gagctccaaa aaataaacac ttcctttgag ggagagcaaa aaaaaaaaaa 960aaaaaaaaaa aaaaaaaaaa aaagaattcc accaca 99680180PRTHomo sapiens 80Met Ala Ser Thr Ser Tyr Asp Tyr Cys Arg Val Pro Met Glu Asp Gly 1 5 10 15Asp Lys Arg Cys Lys Leu Leu Leu Gly Ile Gly Ile Leu Val Leu Leu 20 25 30Ile Ile Val Ile Leu Gly Val Pro Leu Ile Ile Phe Thr Ile Lys Ala 35 40 45Asn Ser Glu Ala Cys Arg Asp Gly Leu Arg Ala Val Met Glu Cys Arg 50 55 60Asn Val Thr His Leu Leu Gln Gln Glu Leu Thr Glu Ala Gln Lys Gly65 70 75 80Phe Gln Asp Val Glu Ala Gln Ala Ala Thr Cys Asn His Thr Val Met 85 90 95Ala Leu Met Ala Ser Leu Asp Ala Glu Lys Ala Gln Gly Gln Lys Lys 100 105 110Val Glu Glu Leu Glu Gly Glu Ile Thr Thr Leu Asn His Lys Leu Gln 115 120 125Asp Ala Ser Ala Glu Val Glu Arg Leu Arg Arg Glu Asn Gln Val Leu 130 135 140Ser Val Arg Ile Ala Asp Lys Lys Tyr Tyr Pro Ser Ser Gln Asp Ser145 150 155 160Ser Ser Ala Ala Ala Pro Gln Leu Leu Ile Val Leu Leu Gly Leu Ser 165 170 175Ala Leu Leu Gln 180814316DNAHomo sapiens 81ctgcagctaa taaaaaaaaa aaaagaaaga aagaaactgg tctctgtcct atttcatatg 60ctcaggtaca acttttccag agaagaagag gaggggggcg gggaggagca ggaggaggag 120gaaagaagga ggagaaggag aaggagaaga agaggaagag gaagaggaag aagaagaaga 180agaagaagag gaagaggaag aggaagaaga agaagaagaa gaagaagaag aagaagaaga 240agaagaagaa gaagaagaag aagaagaaga ggaagaagag gaagaagaag aaactgtctc 300tagaccttca ttctcaggac aagttcattg tctggcacca agctccttgg ggtgaatttt 360cttccaaaag agtccgggga gtccaggtat ggaatgggag gcagaaagtt caatcaaggg 420actgggattt cggaatgaat aatgaaggga gatggactgg gtccatgccg aaggtttctc 480cctggtttct cagcccccgg gcgaagactc agggagacat tgagacacac cctgcacagg 540agggggaggg ggagggggag ggcaaagtcc cagggcccca ggagtggctc tcaagggctc 600aggccccgag gcggtgtctg gggttggaag gctcagtatt gagaattccc catctcccca 660gagtttctct ttctctccca acccgtgtca ggtccttcat cctggatact cataacgcgg 720ccccatttct cactcccatt gggcgtcgcg tttctagaga agccaatcag tgtcgccgca 780gttcccaggt tctaaagtcc cacgcacccc gcgggactca tatttttccc agacgcggag 840gttggggtca tggcgccccg aagcctcctc ctgctgctct caggggccct ggccctgacc 900gatacttggg cgggtgagtg cggggtccag agagaaacgg cctctgtggg gaggagtgag 960gggcccgccc ggtgggggcg caggactcag ggagccgcgc ccggaggagg gtctggcggg 1020tctcaccccc tcctcgcccc caggctccca ctccttgagg tatttcagca ccgctgtgtc 1080gcggcccggc cgcggggagc cccgctacat cgccgtggag tacgtagacg acacgcaatt 1140cctgcggttc gacagcgacg ccgcgattcc gaggatggag ccgcgggagc cgtgggtgga 1200gcaagagggg ccgcagtatt gggagtggac cacagggtac gccaaggcca acgcacagac 1260tgaccgagtg gccctgagga acctgctccg ccgctacaac cagagcgagg ctggtgagtg 1320aacccggccg ggggcgcagg tcacgaccac cccccatccg ccacggaccg cccgggtccc 1380cccgagtctc cggatccgaa atctaccccg aggcagcgga cccgcccaga ccctccaccc 1440gggagagtcc caggcgcctt taccgaggtt cattttcagt ttaggccaaa atccccgcgg 1500gttgggcggg gagggggcgg ggctagctgg gcggggctga ctgcggggac cggctagggt 1560ctcacaccct ccagggaatg aatggctgcg acatggggcc cgacggacgc ctcctccgcg 1620ggtatcacca gcacgcgtac gacggcaagg attacatctc cctgaacgag gacctgcgct 1680cctggaccgc ggcggacacc gtggctcaga tcacccagcg cttctatgag gcagaggaat 1740atgcagagga gttcaggacc tacctggagg gcgagtgcct ggagttgctc cgcagatact 1800tggagaatgg gaaggagacg ctacagcgcg caggtaccag gggccatggg cgccttccct 1860atctcctgta gatctcttgg gatggcctcg cacaaggttg ggaggaaagt gggcccaatg 1920ctaggatatc gccctccctc tagtcctgag taggaagaat cttcctggct ttcgagatcc 1980ggtaccagag agtgactgtg agagtccgcc ctgctctctg ggacaattaa gggatgaaat 2040ctctgaggga atggagggaa gacagtccct ggaataccga tccgcggtcc cctttgagcc 2100ctccaacagc cttgggcccc gtgacttttc tctcaagttt tgttctctgc ctcacactca 2160atgtgtttgg ggctctgatt ccagtccctc ggcctccact taggtcaggg ccagaagtcc 2220ctgctcccca ctcagagact cgaactttcc aaggaatagg agattttccc aggtgtctgt 2280gtccaggctg gtgtctgggt tctgtgctcc cttccccacc ccaggtgtcc tgtccattct 2340caggttggtc acatgggtgc tgctggggtt tcccatgagg agtgcaaagt gcctgaattt 2400tctgactctt ctcagatcct ccaaaggcac acgttgccca ccaccccatc tctgaccatg 2460aggccaccct gaggtgctgg gccctgggct tctaccctgc ggagatcacg ctgacctggc 2520agcgggatgg ggaggaacag acccaggaca cagagcttgt ggagaccagg cctgcagggg 2580atggaacctt ccagaagtgg gccgctgtgg tggtgccttc tggagaggaa cagagataca 2640catgccatgt gcagcacgag gggctgcccc agcccctcat cctgagatgg ggtaaggagg 2700gagatgggta aagaggggaa cgaggggtca tgtcttttct cagggaaagc aggagccctt 2760ctggagctct tcagcagggt cagggctgag gcctggagat cagggcccct caccttccct 2820tcctttccca gagcagtctc cccagcccac catccccatc gtgggcatcg ttgctggcct 2880tgttgtcctt ggagctgtgg tcactggagc tgtggtcgct gctgtgatgt ggaggaagaa 2940gagctcaggt aggaaggggt gaggagtgga gtctgagttt tcttgtccca ctgggggttg 3000caagccccaa gtagaagtgt gccctgcctc attactggga agcaccatcc acactcatgg 3060gtctacccag cctgggccct gtgtgccagc acctactcat ttgtaaagct cctgtgaaaa 3120tgaaggacag attcttcact tcgatgatta tggtggtgat gggacctgat cccagcagtc 3180acaaatcaca ggggaaggtc cctgctgatg acagacctca ggagggcagt tggtccagga 3240cccacatctg ctttcttcat atttcttgat cctgccctgg atctacagtt acacttttct 3300ggaaacttct ctgggatcaa agactagggg tttgctctag gaccttatgg ccctgcctcc 3360tttctggcct ctcacaggac attttcttcc catagataga aacagaggga gctactctca 3420ggctgcaggt aagatgaagg aggctgatcc ctgagattgt tgggatattg tggtcaggag 3480cctatgaggg agctcaccca ccccacagtt cctctagcca catctgtggg ctctgaccag 3540gtcctgtttt tgttctaccc caatcactga cagtgcccag ggctctgggg tgtctctcac 3600agctaataaa ggtgacactc cagggcaggg gccctgatgt gagtggggtg ttggggggga 3660acagagggga ctcagctgtg ctattgggtt tctttgactt ggatgtcttg agcatgaaat 3720gggctattta gagtgttacc tctcactgtg actgatacga atttgttcat gaatattttc 3780tctatagtgt gagacagctt ccttgtgtgg gactgagaag caagatatca atgtagcaga 3840attgcacttg tgcctcacga acatacataa attttaaaaa taaagaataa aaatatatct 3900ttttatagat acaggtagat atgtttttat agcatgcacg taaatgtgtg tgtgtgtgtg 3960tgtgtgtgaa gagaaagagt gaatagagag attaagattc ttttaatggt gaaaagatat 4020acatatattt ggaattagcc agcttgactc agtttaggtg atcccaattt tggtggcaac 4080aaccaaagca tcgtagtcag gagccagtcg aacatatgcc ttcctctctc catcagactg 4140aatcagagtg ttgactttgg ccacatcaat gtcacaaact tcttcacagc ctgtttgatc 4200tggtgcttgt tggctttaac atccacagtg aacacaagta ggctgttgtt ttctatcttc 4260ttcacagcct actcagtggt cagcggaaac ttgatgataa catggtggtc aagctt 431682362PRTHomo sapiens 82Met Ala Pro Arg Ser Leu Leu Leu Leu Leu Ser Gly Ala Leu Ala Leu 1 5 10 15Thr Asp Thr Trp Ala Gly Ser His Ser Leu Arg Tyr Phe Ser Thr Ala 20 25 30Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Tyr Ile Ala Val Glu Tyr 35 40 45Val Asp Asp Thr Gln Phe Leu Arg Phe Asp Ser Asp Ala Ala Ile Pro 50 55 60Arg Met Glu Pro Arg Glu Pro Trp Val Glu Gln Glu Gly Pro Gln Tyr65 70 75 80Trp Glu Trp Thr Thr Gly Tyr Ala Lys Ala Asn Ala Gln Thr Asp Arg 85 90 95Val Ala Leu Arg Asn Leu Leu Arg Arg Tyr Asn Gln Ser Glu Ala Gly 100 105 110Ser His Thr Leu Gln Gly Met Asn Gly Cys Asp Met Gly Pro Asp Gly 115 120 125Arg Leu Leu Arg Gly Tyr His Gln His Ala Tyr Asp Gly Lys Asp Tyr 130 135 140Ile Ser Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Val145 150 155 160Ala Gln Ile Thr Gln Arg Phe Tyr Glu Ala Glu Glu Tyr Ala Glu Glu 165 170 175Phe Arg Thr Tyr Leu Glu Gly Glu Cys Leu Glu Leu Leu Arg Arg Tyr 180 185 190Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Ala 195 200 205His Val Ala His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys 210 215 220Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg225 230 235 240Asp Gly Glu Glu Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro 245 250 255Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser 260 265 270Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro 275 280 285Gln Pro Leu Ile Leu Arg Trp Glu Gln Ser Pro Gln Pro Thr Ile Pro 290 295 300Ile Val Gly Ile Val Ala Gly Leu Val Val Leu Gly Ala Val Val Thr305 310 315 320Gly Ala Val Val Ala Ala Val Met Trp Arg Lys Lys Ser Ser Asp Arg 325 330 335Asn Arg Gly Ser Tyr Ser Gln Ala Ala Val Thr Asp Ser Ala Gln Gly 340 345 350Ser Gly Val Ser Leu Thr Ala Asn Lys Val 355 3608310DNAHomo sapiens 83tcagacgcag 108410DNAHomo sapiens 84ttatgggatc 108510DNAHomo sapiens 85cccgcccccg 108610DNAHomo sapiens 86gaggaagaag 108710DNAHomo sapiens 87gaagctttgc 108810DNAHomo sapiens 88taccagtgta 108910DNAHomo sapiens 89tcttctccct 109010DNAHomo sapiens 90ttggcttttc 109110DNAHomo sapiens 91ggaagggagg 109210DNAHomo sapiens 92aagccagccc 109310DNAHomo sapiens 93tttcagattg 109410DNAHomo sapiens 94gcataggctg 109510DNAHomo sapiens 95tttgttaatt 109610DNAHomo sapiens 96gagactcctg 109710DNAHomo sapiens 97cctgtaattc 109810DNAHomo sapiens 98gtggtgcgtg 109910DNAHomo sapiens 99ttggacctgg 1010010DNAHomo sapiens 100cttaaggatt 1010110DNAHomo sapiens 101gtctgtgaga 1010210DNAHomo sapiens 102gaaactgaac 1010310DNAHomo sapiens 103gggcatctct 1010410DNAHomo sapiens 104tttgggccta 1010510DNAHomo sapiens 105atcgtggcgg 1010610DNAHomo sapiens 106tattatggta 1010710DNAHomo sapiens 107gcctacccga 1010810DNAHomo sapiens 108ctcgcgctgg 1010910DNAHomo sapiens 109ttgcttgcca 1011010DNAHomo sapiens 110cctgcttgtc 1011110DNAHomo sapiens 111agggaggggc 1011210DNAHomo sapiens 112tgtgggaaat 1011310DNAHomo sapiens 113cctgatctgc 1011410DNAHomo sapiens 114accattggat 1011510DNAHomo sapiens 115agtttgttag 1011610DNAHomo sapiens 116cctgggaagt 1011710DNAHomo sapiens 117caactaattc 1011810DNAHomo sapiens 118gcctgcagtc 1011910DNAHomo sapiens 119cgaccccacg 1012010DNAHomo sapiens 120ttctgtgctg 1012110DNAHomo sapiens 121cgccgacgat 1012210DNAHomo sapiens 122cccgcccccg 1012310DNAHomo sapiens 123gatcaggcca 1012410DNAHomo sapiens 124gtggaagacg 1012510DNAHomo sapiens 125gatgaggaga 1012610DNAHomo sapiens 126ttcccttctt 1012710DNAHomo sapiens 127ccccctgcag 1012810DNAHomo sapiens 128tgctgcctgt 1012910DNAHomo sapiens 129tgcagcacga 1013010DNAHomo sapiens 130ggttattttg 1013110DNAHomo sapiens 131tgtcatcaca 1013210DNAHomo sapiens 132aaaataaaca 1013310DNAHomo sapiens 133taaaaatgtt 1013410DNAHomo sapiens 134gagcttttga 1013510DNAHomo sapiens 135ggctgatgtg 1013610DNAHomo sapiens 136cgacgaggag 1013710DNAHomo sapiens 137gcccccaata 1013810DNAHomo sapiens 138gcaacttgga 10139408PRTHomo sapiens 139Met Pro Gly His Leu Gln Glu Gly Phe Gly Cys Val Val Thr Asn Arg 1 5 10 15Phe Asp Gln Leu Phe Asp Asp Glu Ser Asp Pro Phe Glu Val Leu Lys 20 25 30Ala Ala Glu Asn Lys Lys Lys Glu Ala Gly Gly Gly Gly Val Gly Gly 35 40 45Pro Gly Ala Lys Ser Ala Ala Gln Ala Ala Ala Gln Thr Asn Ser Asn 50 55 60Ala Ala Gly Lys Gln Leu Arg Lys Glu Ser Gln Lys Asp Arg Lys Asn65 70 75 80Pro Leu Pro Pro Ser Val Gly Val Val Asp Lys Lys Glu Glu Thr Gln 85 90 95Pro Pro Val Ala Leu Lys Lys Glu Gly Ile Arg Arg Val Gly Arg Arg 100 105 110Pro Asp Gln Gln Leu Gln Gly Glu Gly Lys Ile Ile Asp Arg Arg Pro 115 120 125Glu Arg Arg Pro Pro Arg Glu Arg Arg Phe Glu Lys Pro Leu Glu Glu 130 135 140Lys Gly Glu Gly Gly Glu Phe Ser Val Asp Arg Pro Ile Ile Asp Arg145 150 155

160Pro Ile Arg Gly Arg Gly Gly Leu Gly Arg Gly Arg Gly Gly Arg Gly 165 170 175Arg Gly Met Gly Arg Gly Asp Gly Phe Asp Ser Arg Gly Lys Arg Glu 180 185 190Phe Asp Arg His Ser Gly Ser Asp Arg Ser Ser Phe Ser His Tyr Ser 195 200 205Gly Leu Lys His Glu Asp Lys Arg Gly Gly Ser Gly Ser His Asn Trp 210 215 220Gly Thr Val Lys Asp Glu Leu Thr Glu Ser Pro Lys Tyr Ile Gln Lys225 230 235 240Gln Ile Ser Tyr Asn Tyr Ser Asp Leu Asp Gln Ser Asn Val Thr Glu 245 250 255Glu Thr Pro Glu Gly Glu Glu His His Pro Val Ala Asp Thr Glu Asn 260 265 270Lys Glu Asn Glu Val Glu Glu Val Lys Glu Glu Gly Pro Lys Glu Met 275 280 285Thr Leu Asp Glu Trp Lys Ala Ile Gln Asn Lys Asp Arg Ala Lys Val 290 295 300Glu Phe Asn Ile Arg Lys Pro Asn Glu Gly Ala Asp Gly Gln Trp Lys305 310 315 320Lys Gly Phe Val Leu His Lys Ser Lys Ser Glu Glu Ala His Ala Glu 325 330 335Asp Ser Val Met Asp His His Phe Arg Lys Pro Ala Asn Asp Ile Thr 340 345 350Ser Gln Leu Glu Ile Asn Phe Gly Asp Leu Gly Arg Pro Gly Arg Gly 355 360 365Gly Arg Gly Gly Arg Gly Gly Arg Gly Arg Gly Gly Arg Pro Asn Arg 370 375 380Gly Ser Arg Thr Asp Lys Ser Ser Ala Ser Ala Pro Asp Val Asp Asp385 390 395 400Pro Glu Ala Phe Pro Ala Leu Ala 40514010DNAHomo sapiens 140atgataatgg 101411024DNAHomo sapiens 141ccccacccga aacacactca gcccttgcac tgacctgcct tctgattgga ggctggttgc 60ttcggataat gacctccagg accccactgt tggttacagc ctgtttgtat tattcttact 120gcaactcaag acacctgcag cagggcgtga gaaaaagtaa aagaccagta ttttcacatt 180gccaggtacc agaaacacag aagactgaca cccgccactt aagtggggcc agggctggtg 240tctgcccatg ttgccatcct gatgggctgc ttgccacaat gagggatctt cttcaataca 300tcgcttgctt ctttgccttt ttctctgctg ggtttttgat tgtggccacc tggactgact 360gttggatggt gaatgctgat gactctctgg aggtgagcac aaaatgccga ggcctctggt 420gggaatgcgt cacaaatgct tttgatggga ttcgcacctg tgatgagtac gattccatac 480ttgcggagca tcccttgaag ctggtggtaa ctcgagcgtt gatgattact gcagatattc 540tagctgggtt tggatttctc accctgctcc ttggtcttga ctgcgtgaaa ttcctccctg 600atgagccgta cattaaagtc cgcatctgct ttgttgctgg agccacgtta ctaatagcag 660gtaccccagg aatcattggc tctgtgtggt atgctgttga tgtgtatgtg gaacgttcta 720ctttggtttt gcacaatata tttcttggta tccaatataa atttggttgg tcctgttggc 780tcggaatggc tgggtctctg ggttgctttt tggctggagc tgttctcacc tgctgcttat 840atctttttaa agatgtggga cctgagaaaa ctagccttat cccttgagga aagcctattc 900agccgcgagg tgtttccatg gccaagtcat actcagcccc tcgcacagag acggccaaaa 960tgtatgctgt agacacaagg gtgtaaaatg cacgtttcag ggtgtgtttg catatgattt 1020aatc 1024142294PRTHomo sapiens 142Pro Pro Glu Thr His Ser Ala Leu Ala Leu Thr Cys Leu Leu Ile Gly 1 5 10 15Gly Trp Leu Leu Arg Ile Met Thr Ser Arg Thr Pro Leu Leu Val Thr 20 25 30Ala Cys Leu Tyr Tyr Ser Tyr Cys Asn Ser Arg His Leu Gln Gln Gly 35 40 45Val Arg Lys Ser Lys Arg Pro Val Phe Ser His Cys Gln Val Pro Glu 50 55 60Thr Gln Lys Thr Asp Thr Arg His Leu Ser Gly Ala Arg Ala Gly Val65 70 75 80Cys Pro Cys Cys His Pro Asp Gly Leu Leu Ala Thr Met Arg Asp Leu 85 90 95Leu Gln Tyr Ile Ala Cys Phe Phe Ala Phe Phe Ser Ala Gly Phe Leu 100 105 110Ile Val Ala Thr Trp Thr Asp Cys Trp Met Val Asn Ala Asp Asp Ser 115 120 125Leu Glu Val Ser Thr Lys Cys Arg Gly Leu Trp Trp Glu Cys Val Thr 130 135 140Asn Ala Phe Asp Gly Ile Arg Thr Cys Asp Glu Tyr Asp Ser Ile Leu145 150 155 160Ala Glu His Pro Leu Lys Leu Val Val Thr Arg Ala Leu Met Ile Thr 165 170 175Ala Asp Ile Leu Ala Gly Phe Gly Phe Leu Thr Leu Leu Leu Gly Leu 180 185 190Asp Cys Val Lys Phe Leu Pro Asp Glu Pro Tyr Ile Lys Val Arg Ile 195 200 205Cys Phe Val Ala Gly Ala Thr Leu Leu Ile Ala Gly Thr Pro Gly Ile 210 215 220Ile Gly Ser Val Trp Tyr Ala Val Asp Val Tyr Val Glu Arg Ser Thr225 230 235 240Leu Val Leu His Asn Ile Phe Leu Gly Ile Gln Tyr Lys Phe Gly Trp 245 250 255Ser Cys Trp Leu Gly Met Ala Gly Ser Leu Gly Cys Phe Leu Ala Gly 260 265 270Ala Val Leu Thr Cys Cys Leu Tyr Leu Phe Lys Asp Val Gly Pro Glu 275 280 285Lys Thr Ser Leu Ile Pro 29014310DNAHomo sapiens 143gtgggcacag 101441851DNAHomo sapiens 144ggatatcgtc gacccagcgt ccggaccggg acagctcgcg gccccccgag agctctagcc 60gtcgaggagc tgcctgggga cgtttccctg ggccccagcc tggcccgggt caccctggca 120tgaggagatg ggcctgttgc tcctggtccc gttgctcctg ctgcccggct cctacggact 180gcccttctac aacggcttct actactccaa cagcgccaac gaccagaacc taggcaacgg 240tcatggcaaa gacctcctta atggagtgaa gctggtggtg gagacacccg aggagaccct 300gttcacctac caaggggcca gtgtgatcct gccctgcgta ccgctacgag ccggccctgg 360tctccccgcg gcgtgtgcgt gtcaaatggt ggaagctgtc ggagaacggg gccccagaga 420aggacgtgct ggtggccatc gggctgaggc accgctcctt tgggactacc aaggccgcgt 480gcactgcggc aggacaaaga gcatgagctc tcgctggaga tccagatctc gctggaggac 540tatggggctt accgctgtga ggtcattgac gggctggagg atgaaagcgg tctggtggag 600ctggagctgc ggggtgtggt ctttccttac cagtccccaa cgggcgctac cagttcaact 660tccacgaggg ccagcaggtc tgtgcagagc aggctgcggt ggtggcctcc tttgagcagc 720tcttccgggc ctgggaggag ggcctggact ggtgcaacgc gggctggctg caggatgcca 780cggtgcagta ccccatcatg ttgccccggc agccctgcgg tggcccgggc ctggcacctg 840gcgtgcgaag ctacggcccc cgccaccgcc gcctgcaccg ctatgatgta ttctcgttcg 900ctactgccct caaggggcgg gtgtactacc tggagcaccc tgagaacgtg acgctgacag 960aggcaaggga ggcctgccag gaagatgatg ccacgattgc caaggtggac agctctttgc 1020cgcctggaag ttccatggcc tggaccgctg cgacgctggc tggctggcag atggcagcgt 1080ccgctaccct gtggttcacc cgcatcctaa ctgtgggccc ccagagcctg gggtccgaag 1140ctttggcttc cccgacccgc agagccgctt gtacggtgtt tactgtaccg ccagcactag 1200gacctggggc cctcccctgc cgcattccct cactggctgt gtatttattg agtggttcgt 1260tttcccttgt gggttggagc cattttaact gtttttatac ttctcaattt aaattttctt 1320taaacatttt tttactattt tttgtaaagc aaacagaacc caatgcctcc ctttgctcct 1380ggatgcccca ctccaggaat catgcttgct ccccgggctt ctggagggtt ccccgccatc 1440caggctggtc tccctccctt aaggaggttg gtgcccagag tgggcggtgg cctgtctaga 1500atgccgccgg gagtccgggc atggtgggca cagttctccc tgcccctcag cctgggggaa 1560gaagagggcc tcgggggctc cggagctggg ctttgggcct ctcctgccca cctctacttc 1620tctgtgaagc cgctgacccc agtctgccca ctgaggggct agggctggaa gccagttcta 1680ggcttccagg cgaaagctga gggaaggaag aaactccctc cccgttcccc ttcccctctc 1740ggttccaaag aatctgtttg ttgtcatttg tttctcctgt ttccctgtgt ggggaggggc 1800cctcaggtgt gtgtactttg gacaataaat ggtgctatga ctgccttccg c 185114510DNAHomo sapiens 145cctgccccgc 101464111DNAHomo sapiens 146ctcacagccc agcacctgcg gagggagcgc tgaccatggc tccctggcct gaattgggag 60atgcccagcc caaccccgat aagtacctcg aaggggccgc aggtcagcag cccactgccc 120ctgataaaag caaagagacc aacaaaaata acactgaggc acctgtaacc aagattgaac 180ttctgccgtc ctactccacg gctacactga tagatgagcc cactgaggtg gatgacccct 240ggaacctacc cactcttcag gactcgggga tcaagtggtc agagagagac accaaaggga 300agattctctg tttcttccaa gggattggga gattgatttt acttctcgga tttctctact 360ttttcgtgtg ctccctggat attcttagta gcgccttcca gctggttgga ggaaaaatgg 420caggacagtt cttcagcaac agctctatta tgtccaaccc tttgttgggg ctggtgatcg 480gggtgctggt gaccgtcttg gtgcagagct ccagcacctc aacgtccatc gttgtcagca 540tggtgtcctc ttcattgctc actgttcggg ctgccatccc cattatcatg ggggccaaca 600ttggaacgtc aatcaccaac actattgttg cgctcatgca ggtgggagat cggagtgagt 660tcagaagagc ttttgcagga gccactgtcc atgacttctt caactggctg tccctgttgg 720tgctcttgcc cgtggaggtg gccacccatt acctcgagat cataacccag cttatagtgg 780agagcttcca cttcaagaat ggagaagatg ccccagatct tctgaaagtc atcactaagc 840ccttcacaaa gctcattgtc cagctggata aaaaagttat cagccaaatt gcaatgaacg 900atgaaaaagc gaaaaacaag agtcttgtca agatttggtg caaaactttt accaacaaga 960cccagattaa cgtcactgtt ccctcgactg ctaactgcac ctccccttcc ctctgttgga 1020cggatggcat ccaaaactgg accatgaaga atgtgaccta caaggagaac atcgccaaat 1080gccagcatat ctttgtgaat ttccacctcc cggatcttgc tgtgggcacc atcttgctca 1140tactctccct gctggtcctc tgtggttgcc tgatcatgat tgtcaagatc ctgggctctg 1200tgctcaaggg gcaggtcgcc actgtcatca agaagaccat caacactgat ttcccctttc 1260cctttgcatg gttgactggc tacctggcca tcctcgtcgg ggcaggcatg accttcatcg 1320tacagagcag ctctgtgttc acgtcggcct tgacccccct gattggaatc ggcgtgataa 1380ccattgagag ggcttatcca ctcacgctgg gctccaacat cggcaccacc accaccgcca 1440tcctggccgc cttagccagc cctggcaatg cattgaggag ttcactccag atcgccctgt 1500gccacttttt cttcaacatc tccggcatct tgctgtggta cccgatcccg ttcactcgcc 1560tgcccatccg catggccaag gggctgggca acatctctgc caagtatcgc tggttcgccg 1620tcttctacct gatcatcttc ttcttcctga tcccgctgac ggtgtttggc ctctcgctgg 1680ccggctggcg ggtgctggtt ggtgtcgggg ttcccgtcgt cttcatcatc atcctggtac 1740tgtgcctccg actcctgcag tctcgctgcc cacgcgtcct gccgaagaaa ctccagaact 1800ggaacttcct gccgctgtgg atgcgctcgc tgaagccctg ggatgccgtc gtctccaagt 1860tcaccggctg cttccagatg cgctgctgct gctgctgccg cgtgtgctgc cgcgcgtgct 1920gcttgctgtg tggctgcccc aagtgctgcc gctgcagcaa gtgctgcgag gacttggagg 1980aggcgcagga ggggcaggat gtccctgtca aggctcctga gacctttgat aacataacca 2040ttagcagaga ggctcagggt gaggtccctg cctcggactc aaagaccgaa tgcacggcct 2100tgtaggggac gccccagatt gtcagggatg gggggatggt ccttgagttt tgcatgctct 2160cctccctccc acttctgcac cctttcacca cctcgaggag atttgctccc cattagcgaa 2220tgaaattgat gcagtcctac ctaactcgat tccctttggc ttggtgggta ggcctgcagg 2280gcacttttat tccaacccct ggtcactcag taatctttta ctccaggaag gcacaggatg 2340gtacctaaag agaattagag aatgaacctg gcgggacgga tgtctaatcc tgcacctagc 2400tgggttggtc agtagaacct attttcagac tcaaaaacca tcttcagaaa gaaaaggccc 2460agggaaggaa tgtatgagag gctctcccag atgaggaagt gtactctcta tgactatcaa 2520gctcaggcct ctcccttttt ttaaaccaaa gtctggcaac caagagcagc agctccatgg 2580cctccttgcc ccagatcagc ctgggtcagg ggacatagtg tcattgtttg gaaactgcag 2640accacaaggt gtgggtctat cccacttcct agtgctcccc acattcccca tcagggcttc 2700ctcacgtgga caggtgtgct agtccaggca gttcacttgc agtttccttg tcctcatgct 2760tcggggatgg gagccacgcc tgaactagag ttcaggctgg atacatgtgc tcacctgctg 2820ctcttgtctt cctaagagac agagagtggg gcagatggag gagaagaaag tgaggaatga 2880gtagcatagc attctgccaa aagggcccca gattcttaat ttagcaaact aagaagccca 2940attcaaaagc attgtggcta aagtctaacg ctcctctctt ggtcagataa caaaagccct 3000ccctgttgga tcttttgaaa taaaacgtgc aagttatcca ggctcgtagc ctgcatgctg 3060ccaccttgaa tcccagggag tatctgcacc tggaatagct ctccacccct ctctgcctcc 3120ttactttctg tgcaagatga tttcctgggt taacttcctt ctttccatcc acccacccac 3180tggaatctct ttccaaacat ttttccattt tcccacagat gggctttgat tagctgtcct 3240ctctccatgc ctgcaaagct ccagattttt ggggaaagct gtacccaact ggactgccca 3300gtgaactggg atcattgagt acagtcgagc acacgtgtgt gcatgggtca aaggggtgtg 3360ttccttctca tcctagatgc cttctctgtg ccttccacag cctcctgcct gattacacca 3420ctgcccccgc cccaccctca gccatcccaa ttcttcctgg ccagtgcgct ccagccttat 3480ctaggaaagg aggagtgggt gtagccgtgc agcaagattg gggcctcccc catcccagct 3540tctccaccat cccagcaagt caggatatca gacagtcctc ccctgaccct cccccttgta 3600gatatcaatt cccaaacaga gccaaatact ctatatctat agtcacagcc ctgtacagca 3660tttttcataa gttatatagt aaatggtctg catgatttgt gcttctagtg ctctcatttg 3720gaaatgaggc aggcttcttc tatgaaatgt aaagaaagaa accactttgt atattttgta 3780ataccacctc tgtggccatg cctgccccgc ccactctgta tatatgtaag ttaaacccgg 3840gcaggggctg tggccgtctt tgtactctgg tgatttttaa aaattgaatc tttgtacttg 3900cattgattgt ataataattt tgagaccagg tctcgctgtg ttgctcaggc tggtctcaaa 3960ctcctgagat caagcaatcc gcccacctca gcctcccaaa gtgctgagat cacaggcgtg 4020agccaccacc aggcctgatt gtaatttttt tttttttttt tactggttat gggaagggag 4080aaataaaatc atcaaacccc aaaaaaaaaa a 4111147689PRTHomo sapiens 147Met Ala Pro Trp Pro Glu Leu Gly Asp Ala Gln Pro Asn Pro Asp Lys 1 5 10 15Tyr Leu Glu Gly Ala Ala Gly Gln Gln Pro Thr Ala Pro Asp Lys Ser 20 25 30Lys Glu Thr Asn Lys Asn Asn Thr Glu Ala Pro Val Thr Lys Ile Glu 35 40 45Leu Leu Pro Ser Tyr Ser Thr Ala Thr Leu Ile Asp Glu Pro Thr Glu 50 55 60Val Asp Asp Pro Trp Asn Leu Pro Thr Leu Gln Asp Ser Gly Ile Lys65 70 75 80Trp Ser Glu Arg Asp Thr Lys Gly Lys Ile Leu Cys Phe Phe Gln Gly 85 90 95Ile Gly Arg Leu Ile Leu Leu Leu Gly Phe Leu Tyr Phe Phe Val Cys 100 105 110Ser Leu Asp Ile Leu Ser Ser Ala Phe Gln Leu Val Gly Gly Lys Met 115 120 125Ala Gly Gln Phe Phe Ser Asn Ser Ser Ile Met Ser Asn Pro Leu Leu 130 135 140Gly Leu Val Ile Gly Val Leu Val Thr Val Leu Val Gln Ser Ser Ser145 150 155 160Thr Ser Thr Ser Ile Val Val Ser Met Val Ser Ser Ser Leu Leu Thr 165 170 175Val Arg Ala Ala Ile Pro Ile Ile Met Gly Ala Asn Ile Gly Thr Ser 180 185 190Ile Thr Asn Thr Ile Val Ala Leu Met Gln Val Gly Asp Arg Ser Glu 195 200 205Phe Arg Arg Ala Phe Ala Gly Ala Thr Val His Asp Phe Phe Asn Trp 210 215 220Leu Ser Leu Leu Val Leu Leu Pro Val Glu Val Ala Thr His Tyr Leu225 230 235 240Glu Ile Ile Thr Gln Leu Ile Val Glu Ser Phe His Phe Lys Asn Gly 245 250 255Glu Asp Ala Pro Asp Leu Leu Lys Val Ile Thr Lys Pro Phe Thr Lys 260 265 270Leu Ile Val Gln Leu Asp Lys Lys Val Ile Ser Gln Ile Ala Met Asn 275 280 285Asp Glu Lys Ala Lys Asn Lys Ser Leu Val Lys Ile Trp Cys Lys Thr 290 295 300Phe Thr Asn Lys Thr Gln Ile Asn Val Thr Val Pro Ser Thr Ala Asn305 310 315 320Cys Thr Ser Pro Ser Leu Cys Trp Thr Asp Gly Ile Gln Asn Trp Thr 325 330 335Met Lys Asn Val Thr Tyr Lys Glu Asn Ile Ala Lys Cys Gln His Ile 340 345 350Phe Val Asn Phe His Leu Pro Asp Leu Ala Val Gly Thr Ile Leu Leu 355 360 365Ile Leu Ser Leu Leu Val Leu Cys Gly Cys Leu Ile Met Ile Val Lys 370 375 380Ile Leu Gly Ser Val Leu Lys Gly Gln Val Ala Thr Val Ile Lys Lys385 390 395 400Thr Ile Asn Thr Asp Phe Pro Phe Pro Phe Ala Trp Leu Thr Gly Tyr 405 410 415Leu Ala Ile Leu Val Gly Ala Gly Met Thr Phe Ile Val Gln Ser Ser 420 425 430Ser Val Phe Thr Ser Ala Leu Thr Pro Leu Ile Gly Ile Gly Val Ile 435 440 445Thr Ile Glu Arg Ala Tyr Pro Leu Thr Leu Gly Ser Asn Ile Gly Thr 450 455 460Thr Thr Thr Ala Ile Leu Ala Ala Leu Ala Ser Pro Gly Asn Ala Leu465 470 475 480Arg Ser Ser Leu Gln Ile Ala Leu Cys His Phe Phe Phe Asn Ile Ser 485 490 495Gly Ile Leu Leu Trp Tyr Pro Ile Pro Phe Thr Arg Leu Pro Ile Arg 500 505 510Met Ala Lys Gly Leu Gly Asn Ile Ser Ala Lys Tyr Arg Trp Phe Ala 515 520 525Val Phe Tyr Leu Ile Ile Phe Phe Phe Leu Ile Pro Leu Thr Val Phe 530 535 540Gly Leu Ser Leu Ala Gly Trp Arg Val Leu Val Gly Val Gly Val Pro545 550 555 560Val Val Phe Ile Ile Ile Leu Val Leu Cys Leu Arg Leu Leu Gln Ser 565 570 575Arg Cys Pro Arg Val Leu Pro Lys Lys Leu Gln Asn Trp Asn Phe Leu 580 585 590Pro Leu Trp Met Arg Ser Leu Lys Pro Trp Asp Ala Val Val Ser Lys 595 600 605Phe Thr Gly Cys Phe Gln Met Arg Cys Cys Cys Cys Cys Arg Val Cys 610 615 620Cys Arg Ala Cys Cys Leu Leu Cys Gly Cys Pro Lys Cys Cys Arg Cys625 630 635 640Ser Lys Cys Cys Glu Asp Leu Glu Glu Ala Gln Glu Gly Gln Asp Val 645 650 655Pro Val Lys Ala Pro Glu Thr Phe Asp Asn Ile Thr Ile Ser Arg Glu 660 665 670Ala Gln Gly Glu Val Pro Ala Ser Asp Ser Lys Thr Glu Cys Thr Ala 675 680 685Leu

Claims

1. A method of detecting an ovarian tumor in a subject, said method comprising measuring the expression level of an ovarian tumor marker gene in said subject, wherein an increase in said expression level of said ovarian tumor marker gene in said subject, relative to the expression level of said ovarian tumor marker gene in a reference subject not having an ovarian tumor, detects an ovarian tumor in said subject.

2. A method of identifying a subject at increased risk for developing ovarian cancer, said method comprising measuring the expression level of an ovarian tumor marker gene in said subject, wherein an increase in said expression level of said ovarian tumor marker gene in said subject, relative to the expression level of said ovarian tumor marker gene in a reference subject not at increased risk for developing ovarian cancer, identifies an individual at increased risk for developing ovarian cancer.

3. The method of claim 1 or 2, wherein said expression level of said ovarian tumor marker gene is determined in said subject by measuring the expression level of said tumor marker gene in a sample from said subject.

4. The method of claim 3, wherein said sample from said subject is selected from the group consisting of a tissue biopsy, ovarian epithelial cell scrapings, peritoneal fluid, blood, urine, and serum.

5. The method of claim 1 or 2, wherein said expression level of said tumor marker gene is measured in vivo in said subject.

6. The method of claim 1 or 2, wherein said expression level of said tumor marker gene is determined by measuring the level of ovarian tumor marker mRNA.

7. The method of claim 6, wherein said level of ovarian tumor marker mRNA is measured using RT-PCR, Northern hybridization, dot-blotting, or in situ hybridization.

8. The method of claim 1 or 2, wherein said expression level of said ovarian tumor marker gene is determined by measuring the level of ovarian tumor marker polypeptide encoded by said ovarian tumor marker gene.

9. The method of claim 8, wherein said level of ovarian tumor marker polypeptide is measured by ELISA, immunoblotting, or immunohistochemistry.

10. The method of claim 1 or 2, wherein said expression level of said tumor marker gene is compared to the expression level of said tumor marker gene in a reference subject diagnosed with ovarian cancer.

11. The method of claim 2, wherein said expression level of said ovarian tumor marker gene in said subject is compared to the expression level of said tumor marker gene in a reference subject that is identified as having an increased risk for developing ovarian cancer.

12. A method of identifying a tumor as an ovarian tumor, said method comprising measuring the expression level of an ovarian tumor marker gene in a tumor cell from said tumor, wherein an increase in said expression level of said ovarian tumor marker gene in said tumor cell, relative to the expression level of said ovarian tumor marker gene in a noncancerous ovarian cell, identifies the tumor as an ovarian tumor.

13. A method of treating or preventing an ovarian tumor in a subject, said method comprising modulating production or activity of a polypeptide encoded by an ovarian tumor marker gene in an ovarian epithelial cell in said subject.

14. A method of inhibiting the growth or metastasis of an ovarian tumor in a subject, said method comprising contacting an ovarian tumor cell with an antibody that specifically binds an ovarian tumor marker polypeptide encoded by an ovarian tumor marker gene, wherein the binding of said antibody to said ovarian tumor marker polypeptide inhibits the growth or metastasis of said ovarian tumor in said subject.

15. The method of claim 14, wherein said ovarian tumor marker polypeptide is on the surface of said ovarian tumor cell.

16. The method of claim 14, wherein said antibody is coupled to a radioisotope or a toxic compound.

17. A method of diagnosing ovarian cancer in a subject, said method comprising measuring the amount of an ovarian tumor marker polypeptide in said subject, wherein an amount of ovarian tumor marker polypeptide that is greater than the amount of ovarian tumor marker polypeptide measured in a subject not having ovarian cancer diagnoses an ovarian cancer in the subject.

18. The method of claim 17, wherein said ovarian tumor marker polypeptide is present at the surface of a cell.

19. The method of claim 17, wherein said ovarian tumor marker polypeptide is in soluble form.

20. The method of claim 1, 2, 12, 13, 14, or 17, wherein said ovarian tumor marker gene is selected from the group consisting of HLA-DR alpha chain; cysteine-rich protein 1; claudin 4; claudin 3; ceruloplastnin (ferroxidase); gluthathione perroxidase 3; secretory leukocyte protease inhibitor; HOST-1 (FLJ14303 fis); interferon-induced transmembrane protein 1; apolipoprotein J/clusterin; serine protease inhibitor, Kunitz type 2; apoplipoprotein E; complement component 1, r subcomponent; G1P3/IFI-6-16; Lutheran blood group (BCAM); collagen type III, alpha-1; Mal (T cell differentiation protein); collagen type I, alpha-2; HLA-DPB1; bone marrow stroma antigen 2 (BST-2); or HLA-Cw.

21. The method of claim 1, 2, 12, 13, 14, or 17, wherein said ovarian tumor is an epithelial ovarian tumor.

22. The method of claim 21, wherein said epithelial ovarian tumor is selected from the group consisting of a serous cystadenoma, a borderline serous tumor, a serous cystadenocarcinoma, a mucinous cystadenoma, a borderline mucinous tumor, a mucinous cystadenocarcinoma, an endometrioid carcinoma, an undifferentiated carcinoma, a clear cell adenocarcinoma, a cystadenofibroma, an adenofibroma, and a Brenner tumor.

23. A kit comprising an antibody for measuring the expression level of an ovarian tumor marker gene in a subject.

24. A kit comprising a nucleic acid for measuring the expression level of an ovarian tumor marker gene in a subject.

25. The kit of claim 23 or 24, wherein said ovarian tumor marker gene is selected from the group consisting of HLA-DR alpha chain; cysteine-rich protein 1; claudin 4; claudin 3; ceruloplasmin (ferroxidase); glutathione perroxidase 3; secretory leukocyte protease inhibitor; HOST-1 (FLJ14303 fis); interferon-induced transmembrane protein 1; apolipoprotein J/clusterin; serine protease inhibitor, Kunitz type 2; apoplipoprotein E; complement component 1, r subcomponent; G1P3/IFI-6-16; Lutheran blood group (BCAM); collagen type III, alpha-1; Mal (T cell differentiation protein); collagen type I, alpha-2; HLA-DPB1; bone marrow stroma antigen 2 (BST-2); or HLA-Cw.

Images