EGG ALLERGY ANTIGEN

Abstract

The present invention provides a novel antigen for an egg allergy, a method for diagnosing an egg allergy and a kit for diagnosing an egg allergy, a pharmaceutical composition comprising the antigen, an egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which the antigen is eliminated or reduced, a method for producing a processed product of an egg in which the antigen is eliminated or reduced, and a tester for determining the presence or absence of an egg antigen in an object of interest.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a U.S. national stage filing, under 35 U.S.C. .sctn. 371(c), of International Application No. PCT/JP2017/020654, filed on Jun. 2, 2017, which claims priority to Japanese Patent Application No. 2016-111308, filed on Jun. 2, 2016. The entire contents of each of the aforementioned applications are incorporated herein by reference.

TECHNICAL FIELD

[0002] The present invention relates to a novel antigen of an egg allergy. The present invention also relates to a kit, a composition, and a method for diagnosing an egg allergy. The present invention also relates to a pharmaceutical composition comprising the antigen and an egg or a processed product of an egg in which the antigen is eliminated or reduced, or a bird which lays or has hatched from the egg. The present invention also relates to a method for producing a processed product of an egg in which the antigen is eliminated or reduced. The present invention also relates to a tester for determining the presence or absence of an egg antigen in an object of interest.

BACKGROUND ART

[0003] In serum and tissues of allergic patients, IgE antibodies specific to particular antigens (hereinafter, also referred to as "allergens") are produced. Physiological consequences caused by interaction between such IgE antibodies and such particular antigens elicit allergic reactions. The term "antigen" refers in its broad sense to a food or a food material which causes an allergic symptom and in its narrow sense to a protein contained in a food or a food material to which a specific IgE antibody binds (also referred to as the following, an allergenic component).

[0004] In the process of production of conventional allergy testing agents, antigen reagents are commonly prepared simply by grinding a candidate allergenic food, food material or the like (Patent Literature 1). For this reason, the only case where conventional allergy tests have permitted detection of a positive allergic reaction is when the allergen component contained in a conventional antigen reagent is present in an amount exceeding a threshold that allows determination of a positive reaction for binding to an IgE antibody and the diagnostic efficiency has been too low to be considered to be sufficient.

[0005] The allergens set forth in Table 1 below are currently known as egg allergens (Non Patent Literature 1).

TABLE-US-00001 TABLE 1 Species Allergen Biochemical name MW(SDS-PAGE) Food Allergen Entry Date Modified Date Gallus Gal d 1 Ovomucoid 28 Yes 2016 Apr. 4 2010 Apr. 29 domesticus Gal d 2 Ovalbumin 44 Yes 2016 Apr. 4 2010 Apr. 29 (chicken) Gal d 3 Ovotransferrin 78 Yes 2016 Apr. 4 2010 Apr. 29 Gal d 4 Lysozyme C 14 Yes 2016 Apr. 4 2010 Apr. 29 Gal d 5 Serum albumin 69 Yes 2016 Apr. 4 2015 Dec. 19 Gal d 6 YGP42 35 kDa Yes 2016 Apr. 4 2011 Aug. 4 Gal d 7 Myosin light chain 1f 22 kDa Yes 2016 Apr. 4 2015 Aug. 17 Gal d 8 alpha-parvalbumin 11.8 kDa Yes 2016 Apr. 4 2016 Feb. 22 Gal d 9 Enolase 50 kDa Yes 2016 Apr. 4 2016 Feb. 22 Gal d 10 Aldolase Yes 2016 Apr. 4 2016 Feb. 22

[0006] Some allergen components are suggested to exist in foods and food materials which are allergen candidates, and test kits for such allergen components have been commercialized. However, while it is necessary to exhaustively identify allergen components in order to enhance the reliability of allergy tests, the patient detection rate by the measurement of such allergen components is far insufficient. Identification of novel allergens in eggs is very important not only for increasing the precision of diagnostic agent, but also for determining targets of low allergenic foods, low allergenic food materials, and therapeutic agents.

[0007] On the separation and purification of proteins, a method for separating and purifying many different proteins from a small amount of sample has been used in recent years, which is more specifically a two-dimensional electrophoresis consisting of isoelectric focusing in the first dimension, followed by SDS-PAGE (Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis) in the second dimension. The present applicant has conventionally developed some 2D electrophoresis methods with high separation ability (Patent Literature 2-5).

CITATION LIST

Patent Literature

[0008] PTL1: Japanese Patent Application Publication No. JP 2002-286716

[0009] PTL2: Japanese Patent Application Publication No. JP 2011-33544

[0010] PTL3: Japanese Patent Application Publication No. JP 2011-33546

[0011] PTL4: Japanese Patent Application Publication No. JP 2011-33547

[0012] PTL5: Japanese Patent Application Publication No. JP 2011-33548

Non Patent Literature

[0012]

[0013] NPL1: Allergen Nomenclature, WHO/IUIS Allergen Nomenclature Sub-Committee, [search on May 31, 2016], Internet <URL: http://www.allergen.org/search.php?allergenname=&allergensource=gallus+do- mesticus&Tax Source=&TaxOrder=&foodallerg=all&bioname=>

SUMMARY OF INVENTION

Technical Problem

[0014] The present invention provides novel antigens of an allergy to egg. The present invention also provides methods and kits for diagnosing allergy to egg. The present invention also provides a pharmaceutical composition comprising the antigen and an egg or a processed product of an egg in which the antigen is eliminated or reduced, or a bird which lays or has hatched from the egg. The present invention further provides testers for determining the presence or absence of an egg antigen in an object of interest.

Solution to Problem

[0015] In order to solve the aforementioned problems, the present inventors had made intensive studies to identify causative antigens of an allergy to egg. As a result, the inventors succeeded in identifying novel antigens to which an IgE antibody in the serum of an egg-allergic patient specifically binds. The present invention has been completed based on this finding.

[0016] Thus, in one embodiment, the present invention can be as defined below.

[0017] [1] A kit for diagnosing an allergy to an egg, the kit comprising, as an antigen, at least one of proteins defined below in any of the following (1) to (3):

(1) (1A) a protein comprising a C-terminal portion of Vitellogenin-3 or a variant thereof, which is defined below in any of (1A-a) to (1A-e) which is an antigen for the egg allergy:

[0018] (1A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 2;

[0019] (1A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 2;

[0020] (1A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 1;

[0021] (1A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 1; or

[0022] (1A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 1; or

[0023] (1B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 2-11;

(2) (2A) a protein comprising a C-terminal portion of Vitellogenin-3 or a variant thereof, which is defined below in any of (2A-a) to (2A-e) which is an antigen for the egg allergy:

[0024] (2A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 13;

[0025] (2A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 13;

[0026] (2A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 12;

[0027] (2A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 12; or

[0028] (2A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 12; or

[0029] (2B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 9-11, 13, 14, and 16;

(3) (3A) A protein comprising a middle portion of Vitellogenin-1 or a C-terminal portion of lipovitelin-1 or a variant thereof, which is defined below in any of (3A-a) to (3A-e) which is an antigen for the egg allergy:

[0030] (3A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 18;

[0031] (3A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 18;

[0032] (3A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 17;

[0033] (3A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 17; or

[0034] (3A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 17; or

[0035] (3B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 18-45.

[0036] [2] A composition for diagnosing an allergy to an egg, comprising, as an antigen, at least one of proteins as defined above in any of (1) to (3) of [1].

[0037] [3] A method for providing an indicator for diagnosing an allergy to an egg in a subject, the method comprising the steps of:

(i) contacting a sample obtained from the subject with an antigen, wherein the sample is a solution comprising an IgE antibody; (ii) detecting binding between the IgE antibody present in the sample from the subject and the antigen; and (iii) when the binding between the IgE antibody in the subject and the antigen is detected, an indicator of the fact that the subject is allergic to an egg is provided; wherein the antigen is at least one of proteins as defined above in any of (1) to (3) of [1].

[0038] [4] A pharmaceutical composition comprising at least one of proteins as defined above in any of (1) to (3) of [1].

[0039] [5] The pharmaceutical composition as set forth in [4], wherein the pharmaceutical composition is intended for the treatment of an allergy to an egg.

[0040] [6] An egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which an antigen is eliminated or reduced, wherein the antigen is at least one of the proteins as defined in (1) to (3) of [1].

[0041] [7] A tester for determining the presence or absence of an egg antigen in an object of interest, comprising an antibody that binds to at least one of proteins as defined above in any of (1) to (3) of [1].

[0042] [8] A tester for determining the presence or absence of an antigen for an egg allergy in an object of interest, comprising a primer having a nucleotide sequence complementary to at least one of the nucleotide sequences set forth in SEQ ID NO: 1, 12, or 17.

[0043] [9] A kit for diagnosing an egg allergy, the kit comprising, as an antigen, at least one protein defined in any one of the following (4) to (10):

(4) (4A) a protein comprising Vitellogenin-3 or a variant thereof, which is defined below in any of (4A-a) to (4A-e) which is an antigen for the egg allergy:

[0044] (4A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 47;

[0045] (4A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 47;

[0046] (4A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 46;

[0047] (4A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 46; or

[0048] (4A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 46; or

[0049] (4B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 47-57;

(5) (5A) a protein comprising a Vitellogenin-2 precursor or a variant thereof, which is defined below in any of (5A-a) to (5A-e) which is an antigen for the egg allergy:

[0050] (5A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 59;

[0051] (5A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 59;

[0052] (5A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 58;

[0053] (5A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 58; or

[0054] (5A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 58; or

[0055] (5B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 59-104;

(6) (6A) a Vitellogenin-2 precursor or a variant thereof, which is defined below in any of (6A-a) to (6A-e) which is an antigen for the egg allergy:

[0056] (6A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 106;

[0057] (6A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 106;

[0058] (6A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 105;

[0059] (6A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 105; or

[0060] (6A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 105; or

[0061] (6B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 106-150;

(7) (7A) an Apolipoprotein B precursor or a variant thereof, which is defined below in any of (7A-a) to (7A-e) which is an antigen for the egg allergy:

[0062] (7A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 152;

[0063] (7A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 152;

[0064] (7A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 151;

[0065] (7A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 151; or

[0066] (7A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 151; or

[0067] (7B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 152-235;

(8) (8A) an Apolipoprotein B precursor or a variant thereof, which is defined below in any of (8A-a) to (8A-e) which is an antigen for the egg allergy:

[0068] (8A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 237;

[0069] (8A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 237;

[0070] (8A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 236;

[0071] (8A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 236; or

[0072] (8A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 236; or

[0073] (8B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 237-249;

(9) (9A) an Apolipoprotein B precursor or a variant thereof, which is defined below in any of (9A-a) to (9A-e) which is an antigen for the egg allergy:

[0074] (9A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 251;

[0075] (9A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 251;

[0076] (9A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 250;

[0077] (9A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 250; or

[0078] (9A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 250; or

[0079] (9B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 251-260;

(10) (10A) a Vitellogenin-2 precursor or a variant thereof, which is defined below in any of (10A-a) to (10A-e) which is an antigen for the egg allergy:

[0080] (10A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 262;

[0081] (10A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 262;

[0082] (10A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 261;

[0083] (10A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 261; or

[0084] (10A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 261; or

[0085] (10B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 262-271.

[0086] [10] A composition for diagnosing an allergy to an egg, comprising, as an antigen, at least one of proteins as defined above in any of (4) to (10) of [9].

[0087] [11] A method for providing an indicator for diagnosing an allergy to an egg in a subject, the method comprising the steps of:

(i) contacting a sample obtained from the subject with an antigen, wherein the sample is a solution comprising an IgE antibody; (ii) detecting binding between the IgE antibody present in the sample from the subject and the antigen; and (iii) when the binding between the IgE antibody in the subject and the antigen is detected, an indicator of the fact that the subject is allergic to an egg is provided; wherein the antigen is at least one of proteins as defined above in any of (4) to (10) of [9].

[0088] [12] A pharmaceutical composition comprising at least one of proteins as defined above in any of (4) to (10) of [9].

[0089] [13] The pharmaceutical composition as set forth in [12], wherein the pharmaceutical composition is intended for the treatment of an allergy to an egg.

[0090] [14] An egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which an antigen is eliminated or reduced, wherein the antigen is at least one of the proteins as defined in (4) to (10) of [9].

[0091] [15] A tester for determining the presence or absence of an egg antigen in an object of interest, comprising an antibody that binds to at least one of proteins as defined above in any of (4) to (10) of [9].

[0092] [16] A tester for determining the presence or absence of an antigen for an egg allergy in an object of interest, comprising a primer having a nucleotide sequence complementary to at least one of the nucleotide sequences set forth in SEQ ID NO: 46, 58, 105, 151, 236, 250, or 261.

[0093] [17] A method for producing a processed product of an egg in which an antigen is eliminated or reduced, comprising the step of confirming that the antigen is eliminated or reduced in the process of producing the processed product, wherein the antigen is at least one of the proteins as defined in any of (1) to (3) of [1] or at least one of the proteins as defined in any of (4) to (10) of [9].

[0094] [18] An antigen derived from an egg, wherein the antigen is at least one of the proteins as defined in any of (1) to (3) of [1] or at least one of the proteins as defined in any of (4) to (10) of [9] and causative of an egg allergy.

Advantageous Effects of Invention

[0095] The present invention can provide novel antigens of an allergy to egg. Since the novel antigens (allergen components) that trigger an egg allergy were identified in the present invention, it is possible to provide highly sensitive methods and kits for diagnosing an egg allergy, pharmaceutical compositions comprising such an antigen, eggs or processed products of eggs in which such an antigen is eliminated or reduced, or birds that lay or have hatched from the eggs, methods for producing a processed product of an egg in which the antigen is eliminated or reduced, and testers for determining the presence or absence of an egg antigen in an object of interest.

BRIEF DESCRIPTION OF DRAWINGS

[0096] FIG. 1 is a photograph of a gel showing a protein electrophoretic pattern in two-dimensional electrophoresis of proteins contained in egg yolk of a chicken egg (raw egg). The bands at the left of the photograph are bands of molecular weight markers. The numbers on the left side of the photograph are molecular weights of respective molecular weight markers (KDa). The numbers on the upper side of the photograph indicate isoelectric points.

[0097] FIG. 2 is a photograph of an immunoblot of a two-dimensional electrophoretic pattern of proteins contained in egg yolk of a chicken egg (raw egg) stained using serum of Egg-allergic patient 1.

[0098] FIG. 3 is a photograph of a gel of a two-dimensional electrophoretic pattern of proteins contained in egg yolk of a chicken egg (raw egg). Spots 1, 2, and 3 that have specifically reacted with the serum of Egg-allergic patient 1 are indicated with respective surrounding boxes.

[0099] FIG. 4 is a photograph of an immunoblot of a two-dimensional electrophoretic pattern of proteins contained in egg yolk of a chicken egg (raw egg) stained using serum of Egg-allergic patient 2. Spots 4 to 8 that have specifically reacted with the serum of Egg-allergic patient 2 are indicated with respective surrounding boxes.

[0100] FIG. 5 is a photograph of an immunoblot of a two-dimensional electrophoretic pattern of proteins contained in egg yolk of a chicken egg (raw egg) stained using serum of Egg-allergic patient 3. Spots 9 and 10 that have specifically reacted with the serum of Egg-allergic patient 3 are indicated with respective surrounding boxes.

[0101] FIG. 6 is a photograph of an immunoblot of a two-dimensional electrophoretic pattern of proteins contained in egg yolk of a chicken egg (raw egg) stained using serum of Egg-allergic patient 4. Spot 11 that has specifically reacted with the serum of Egg-allergic patient 4 is indicated with a surrounding box.

DESCRIPTION OF EMBODIMENTS

[0102] The present invention will be described in detail below, but the present invention is not limited to them.

[0103] Unless otherwise defined herein, all scientific and technical terms used in relation to the present invention shall have meanings commonly understood by those skilled in the art.

[0104] As referred to herein, the "allergy" refers to the state in which, when a certain antigen enters the body of a living individual sensitized to said antigen, the living individual shows a hypersensitive reaction detrimental to him/her. In blood and tissues of individuals with many food-allergic diseases, IgE antibodies specific to antigens are produced. IgE antibodies bind to mast cells or basophils. When an antigen specific to such an IgE antibody enters again the body of a patient with an allergic disease, said antigen combines with the IgE antibody bound to mast cells or basophils, and the IgE antibody crosslinks said antigen on the cell surface, resulting in physiological effects of IgE antibody-antigen interaction. Examples of such physiological effects include release of histamine, serotonin, heparin, eosinophil chemotactic factors, leucotrienes, or the like. These released substances provoke an allergic reaction resulting from the combination of an IgE antibody with particular antigens. Such allergic reactions caused by particular antigens occur through the aforementioned pathway.

[0105] As referred herein, the "egg" refers to an egg of a bird, preferably a chicken egg.

[0106] As referred to herein, the "allergy to egg" refers to the state in which an individual has an allergic reaction caused by proteins, etc. present in egg which act as an antigen. The allergy to egg can produce an allergic reaction upon contact with, or consumption of, an antigen present in egg. In general, allergic reactions caused by consumption of foods are particularly referred to as "food allergies". The allergy to egg may be a food allergy.

[0107] As referred to herein, the "antigen" refers to a substance that provokes an allergic reaction, and is also referred to as an "allergen component". The antigen is preferably a protein.

[0108] As referred to herein, the "protein" refers to a molecule having a structure in which naturally occurring amino acids are joined together by peptide bond. The number of amino acids present in a protein is not particularly limited, but proteins having about 2 to 50 amino acids joined together by peptide bond are in some cases called "peptides". In the case where amino acids can form different enantiomers, the amino acids are understood to form an L-enantiomer, unless otherwise indicated. The amino acid sequences of proteins or peptides as used herein are represented by one-letter symbols of amino acids in accordance with standard usage and the notational convention commonly used in the art. The leftward direction represents the amino-terminal direction, and the rightward direction represents the carboxy-terminal direction.

[0109] Identification of Antigens

[0110] Proteins contained in egg were analyzed by the aforementioned technique to identify causative antigens of an allergy to egg. To be specific, raw chicken eggs were separated into egg yolk and egg white and the egg proteins contained in each of them were subjected to two-dimensional electrophoresis under the conditions described below.

[0111] The electrophoresis in the first dimension was isoelectric focusing, which was performed using isoelectric focusing gels with a gel-strip length of 5 to 10 cm and a gel pH range of 3 to 10. The pH gradient of the gels in the direction of electrophoresis was as follows: with the total gel-strip length being taken as 1, the gel-strip length up to pH 5 was "a=0.15 to 0.3", the gel-strip length from pH 5 to 7 was "b=0.4 to 0.7", and the gel-strip length above pH 7 was "c=0.15 to 0.3". More specifically, the isoelectric focusing was performed using the IPG gels, Immobiline Drystrip (pH3-10NL), produced by GE Healthcare Bio-Sciences Corporation (hereinafter abbreviated as "GE"). The electrophoresis system used was IPGphor produced by GE. The maximum current of the electrophoresis system was limited to 75 .mu.A per gel strip. The voltage program adopted to perform the first-dimensional isoelectric focusing was as follows: (1) a constant voltage step was performed at a constant voltage of 300 V until the volt-hours reached 750 Vhr (the current variation width during electrophoresis for 30 minutes before the end of this step was 5 .mu.A); (2) the voltage was increased gradually to 1000 V for 300 Vhr; (3) the voltage was further increased gradually to 5000 V for 4500 Vhr; and then (4) the voltage was held at a constant voltage of 5000 V until the total Vhr reached 12000.

[0112] The electrophoresis in the second dimension was SDS-PAGE, which was performed using polyacrylamide gels whose gel concentration at the distal end in the direction of electrophoresis was set to 3 to 6% and whose gel concentration at the proximal end was set to a higher value than that at the distal end. More specifically, the SDS-PAGE was performed using NuPAGE 4-12% Bris-Tris Gels (IPG well, Mini, 1 mm) produced by Life Technologies. The electrophoresis system used was XCell SureLock Mini-Cell produced by Life Technologies. The electrophoresis was run at a constant voltage of 200 V for about 45 minutes using an electrophoresis buffer composed of 50 mM MOPS, 50 mM Tris base, 0.1% (w/v) SDS and 1 mM EDTA.

[0113] As a result, the antigens of Spots 1 to 3 in the gel in which the chicken egg proteins have been separated by two-dimensional electrophoresis under the conditions described above have been revealed to exhibit specific binding to IgE antibodies from an egg-allergic patient diagnosed to be have food-dependent exercise-induced anaphylaxis (FIG. 3). Moreover, the antigens of Spots 4 to 11 have been revealed to exhibit specific binding to IgE antibodies from other egg-allergic patients (FIGS. 4 to 6).

[0114] Antigen

[0115] (1) Antigen in Spot 1

[0116] As the result of sequence identification of the antigen in spot 1 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 3-11 were detected.

[0117] Also, the mass spectroscopic data obtained for spot 1 (SEQ ID NOs: 3-11) on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, a C-terminal portion of Vitellogenin-3 (amino acid sequence: SEQ ID NO: 2, encoding nucleotide sequence: SEQ ID NO: 1) was identified.

[0118] Accordingly, in the present invention, the antigen in spot 1 can be any of (1A-a) to (1A-e) and (1B) as defined below:

(1A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 2; (1A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 2; (1A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 1; (1A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 1; (1A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 1; (1B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 2-11, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9 or all sequences of the amino acid sequences; more preferably a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4 and 9-11, preferably a protein comprising at least 2, 3, 4 or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs: 3-11 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0119] The proteins of (1A-a) to (1A-e) and (1B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 20 to 40 kDa, preferably around 30 to 35 kDa and an isoelectric point of 4.0 to 10.0, preferably an isoelectric point of 4.0 to 9.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0120] (2) Antigen in Spot 2

[0121] As the result of sequence identification of the antigen in spot 2 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 9-11, 14, 16 were detected.

[0122] Also, the mass spectroscopic data obtained for spot 2 (SEQ ID NOs: 9-11, 14, 16) on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, a C-terminal portion of Vitellogenin-3 (amino acid sequence: SEQ ID NO: 13, encoding nucleotide sequence: SEQ ID NO: 12) was identified.

[0123] Accordingly, in the present invention, the antigen in spot 2 can be any of (2A-a) to (2A-e) and (2B) as defined below:

(2A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 13; (2A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 13; (2A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 12; (2A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 12; (2A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 12; (2B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 9-11, 13, 14 and 16, preferably a protein comprising at least 2, 3, 4, 5 or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 9-11, 13, and 16, preferably a protein comprising at least 2, 3, 4, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs: 9-11, 13, 14, 16 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0124] The proteins of (2A-a) to (2A-e) and (2B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 30 to 60 kDa, preferably around 35 to 40 kDa and an isoelectric point of 5.0 to 10.0, preferably 6.0 to 9.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0125] (3) Antigen in Spot 3

[0126] As the result of sequence identification of the antigen in spot 3 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 19-45 were detected.

[0127] Also, the mass spectroscopic data obtained for spot 3 (SEQ ID NOs: 19-45) on a mass spectrometer was analyzed by comparing the data against the UniProt protein data, and as a result, a middle portion of Vitellogenin-1 or a C-terminal portion of Lipovitelin-1 (amino acid sequence: SEQ ID NO: 18, encoding nucleotide sequence: SEQ ID NO: 17) generated by N-terminal truncation of the protein was identified.

[0128] Accordingly, in the present invention, the antigen in spot 3 can be any of (3A-a) to (3A-e) and (3B) as defined below:

(3A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 18; (3A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 18; (3A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 17; (3A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 17. (3A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 17; (3B) A protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 18-45, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 19, 22-31, 33-35, 37, 39, 40, 42, 43, and 45, preferably, a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs:18-45 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0129] The proteins of (3A-a) to (3A-e) and (3B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 35 to 60 kDa, preferably around 40 to 50 kDa and an isoelectric point of 5.0 to 10.0, preferably 6.0 to 9.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0130] (4) Antigen in Spot 4

[0131] As the result of sequence identification of the antigen in spot 4 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 48-57 were detected.

[0132] Also, the mass spectroscopic data (SEQ ID NOs: 48-57) obtained for spot 4 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, the antigen in question was identified as Vitellogenin-3 (amino acid sequence: SEQ ID NO: 47, encoding nucleotide sequence: SEQ ID NO: 46).

[0133] Accordingly, in the present invention, the antigen in spot 4 can be any of (4A-a) to (4A-e) and (4B) as defined below:

(4A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 47; (4A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 47; (4A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 46; (4A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 46; (4A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 46; (4B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 47-57, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 47, 50, 51, 53, and 54, preferably a protein comprising at least 2, 3, 4, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs:47-57 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0134] The proteins of (4A-a) to (4A-e) and (4B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 20 to 50 kDa, preferably around 25 to 40 kDa, more preferably around 30 to 35 kDa and an isoelectric point of 3.0 to 8.0, preferably 3.5 to 7.0, more preferably 4.0 to 6.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0135] (5) Antigen in spots 5 and 6

[0136] As the result of sequence identification of the antigen in spots 5 and 6 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 60-104 were detected.

[0137] Also, the mass spectroscopic data (SEQ ID NOs: 60-104) obtained for spots 5 and 6 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, the antigen in question was identified as Vitellogenin-2 precursor (amino acid sequence: SEQ ID NO: 59, encoding nucleotide sequence: SEQ ID NO: 58).

[0138] Accordingly, in the present invention, the antigen in spots 5 and 6 can be any of (5A-a) to (5A-e) and (5B) as defined below:

(5A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 59; (5A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 59; (5A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 58; (5A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 58; (5A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 58; (5B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 59-104, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 59, 60, 63, 65, 68, 69, 71, 73, 75-79, 81, 83-88, 91-94, 96-99, and 101-103, preferably, a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs:59 to 104 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0139] The proteins of (5A-a) to (5A-e) and (5B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 80 to 260 kDa, preferably around 90 to 200 kDa, more preferably around 110 to 160 kDa and an isoelectric point of 1.0 to 8.0, preferably 2.0 to 7.0, more preferably 3.0 to 6.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0140] (6) Antigen in Spot 7

[0141] As the result of sequence identification of the antigen in spot 7 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 107-150 were detected.

[0142] Also, the mass spectroscopic data (SEQ ID NOs: 107-150) obtained for spot 7 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, the antigen in question was identified as Vitellogenin-2 precursor (amino acid sequence: SEQ ID NO: 106, encoding nucleotide sequence: SEQ ID NO: 105).

[0143] Accordingly, in the present invention, the antigen in spot 7 can be any of (6A-a) to (6A-e) and (6B) as defined below:

(6A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 106; (6A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 106; (6A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 105; (6A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 105; (6A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 105; (6B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 106-150, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 44 or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 106, 108, 110, 111, 113, 114, 116, 117, 120-124, 126-131, 133, 134, 136-138, 140-143, 145-147, and 149, preferably, a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 31, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs: 106-150 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0144] The proteins of (6A-a) to (6A-e) and (6B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 110 to 300 kDa, preferably around 130 to 280 kDa, more preferably around 160 to 260 kDa and an isoelectric point of 3.0 to 8.0, preferably 3.5 to 7.0, more preferably 4.0 to 6.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0145] (7) Antigen in Spot 8

[0146] As the result of sequence identification of the antigen in spot 8 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 153-235 were detected.

[0147] Also, the mass spectroscopic data (SEQ ID NOs: 153-235) obtained for spot 8 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, the antigen in question was identified as Apolipoprotein B precursor (amino acid sequence: SEQ ID NO: 152, encoding nucleotide sequence: SEQ ID NO: 151).

[0148] Accordingly, in the present invention, the antigen in spot 8 can be any of (7A-a) to (7A-e) and (7B) as defined below:

(7A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 152; (7A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 152; (7A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 151; (7A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 151; (7A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 151; (7B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 152-235, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 83 or all sequences of the amino acid sequences; more preferably a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 152, 154, 157-160, 163, 164, 167-172, 174, 175, 177, 178, 180, 182-185, 187, 189, 190, 192, 194-196, 198-200, 203-207, 209, 211, 212, 214-216, 220-229, 231 and 232, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs: 152-235 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0149] The proteins of (7A-a) to (7A-e) and (7B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 160 to 550 kDa, preferably around 180 to 400 kDa, more preferably around 200 to 300 kDa and an isoelectric point of 3.0 to 8.0, preferably 3.5 to 7.0, more preferably 4.0 to 6.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0150] (8) Antigen in Spot 9

[0151] As the result of sequence identification of the antigen in spot 9 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 238-249 were detected.

[0152] Also, the mass spectroscopic data (SEQ ID NOs: 238-249) obtained for spot 9 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, the antigen in question was identified as Apolipoprotein B precursor (amino acid sequence: SEQ ID NO: 237, encoding nucleotide sequence: SEQ ID NO: 236).

[0153] Accordingly, in the present invention, the antigen in spot 9 can be any of (8A-a) to (8A-e) and (8B) as defined below:

(8A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 237; (8A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 237; (8A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 236; (8A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 236; (8A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 236; (8B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 237-249, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 237-239, 241, 242, 244, and 246-249; preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs: 237-249 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0154] The proteins of (8A-a) to (8A-e) and (8B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 20 to 50 kDa, preferably around 25 to 45 kDa, more preferably around 30 to 40 kDa and an isoelectric point of 7.0 to 11.0, preferably 8.0 to 10.0, more preferably 9.0 to 10.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0155] (9) Antigen in Spot 10

[0156] As the result of sequence identification of the antigen in spot 10 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 252-260 were detected.

[0157] Also, the mass spectroscopic data (SEQ ID NOs: 252-260) obtained for spot 10 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, Apolipoprotein B precursor (amino acid sequence: SEQ ID NO: 251, encoding nucleotide sequence: SEQ ID NO: 250) was identified was identified.

[0158] Accordingly, the antigen in spot 10 in the present invention can be any of proteins selected from the group consisting of the proteins as defined below in (9A-a) to (9A-e), and (9B):

(9A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 251; (9A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 251; (9A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 250; (9A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 250; (9A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 250; (9B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 251-260, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9 or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 251-254, 256, 257, and 260; preferably a protein comprising at least 2, 3, 4, 5, 6, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs: 251-260 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids;

[0159] The proteins of (9A-a) to (9A-e) and (9B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 20 to 50 kDa, preferably 25 to 40 kDa, more preferably 30 to 40 kDa and an isoelectric point of 7.0 to 11.0, preferably 8.0 to 10.0, more preferably 9.0 to 10.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0160] (10) Antigen in Spot 11

[0161] As the result of sequence identification of the antigen in spot 11 by mass spectroscopy, the amino acid sequences of SEQ ID NOs: 263-271 were detected.

[0162] Also, the mass spectroscopic data (SEQ ID NOs: 263-271) obtained for spot 11 on a mass spectrometer was analyzed by comparing the data against the NCBI protein data, and as a result, Vitellogenin-2 precursor (amino acid sequence: SEQ ID NO: 262, encoding nucleotide sequence: SEQ ID NO: 261) was identified.

[0163] Accordingly, the antigen in spot 11 in the present invention can be any of proteins selected from the group consisting of the proteins as defined below in (10A-a) to (10A-e) and (10B):

(10A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 262; (10A-b) a protein comprising an amino acid sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 262; (10A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 261; (10A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, preferably at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identity to the nucleotide sequence of SEQ ID NO: 261; (10A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 261; (10B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 262-271, preferably a protein comprising at least 2, 3, 4, 5, 6, 7, 8, 9 or all sequences of the amino acid sequences. More preferably, a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 262-265, 268, and 269; preferably a protein comprising at least 2, 3, 4, 5, or all sequences of the amino acid sequences. As referred to above, the amino acid sequence of any of SEQ ID NOs:262 to 271 may be an amino acid sequence derived therefrom by deletion, substitution, insertion or addition of one or several amino acids.

[0164] The proteins of (10A-a) to (10A-e) and (10B) as defined above can be proteins that are found in a protein spot with a molecular weight of around 15 to 40 kDa, preferably 17 to 35 kDa, more preferably 20 to 30 kDa and an isoelectric point of 6.0 to 11.0, preferably 7.0 to 10.0, more preferably 8.0 to 10.0 on gels used in the two-dimensional electrophoresis performed under the conditions described above in the subsection titled "Identification of antigens".

[0165] The antigen proteins of (1) to (3) and (4) to (10) as defined above also include those proteins whose amino acid residues are modified by phosphorylation, sugar chain modification, aminoacylation, ring-opening, deamination or the like.

[0166] Preferably, the antigen proteins of (1) to (3) and (4) to (10) as defined above are antigens for an egg allergy.

[0167] By stating herein "deletion, substitution, insertion or addition of one or several amino acids" in relation to amino acid sequence, it is meant that in an amino acid sequence of interest, one or several amino acids (e.g., 30%, preferably 25%, 20%, 15%, 10%, 5%, 3%, 2%, or 1% of amino acids with respect to the total length of the amino acid sequence) are deleted, one or several amino acids are substituted by any other amino acids, any other amino acids are inserted, and/or any other amino acids are added.

[0168] Among the aforementioned modifications, substitution is preferably conservative substitution. The "conservative substitution" refers to the substitution of a certain amino acid residue by a different amino acid residue having similar physicochemical characteristics, and can be any type of substitution as long as it does not substantially change the characteristics of the structure of the original sequence for example, any type of substitution is acceptable as long as any substituted amino acids do not disrupt the helical structure of the original sequence or other secondary structures that characterize the original sequence. The following gives examples of separate groups of amino acid residues that are conservatively substitutable with each other, but substitutable amino acid residues are not limited to the examples given below.

Group A: leucine, isoleucine, valine, alanine, methionine Group B: aspartic acid, glutamic acid Group C: asparagine, glutamine Group D: lysine, arginine Group E: serine, threonine Group F: phenylalanine, tyrosine

[0169] In the case of non-conservative substitution, one member belonging to one of the aforementioned groups can be replaced with a member belonging to any other group. For example, in order to eliminate the possibility of unwanted sugar-chain modification, amino acids of group B, D or E as listed above may be substituted by those of any other group. Also, cysteines may be deleted or substituted by any other amino acids to prevent them from being folded into a protein in its tertiary structure. Also, in order to maintain the balance between hydrophilicity and hydrophobicity or to increase hydrophilicity for the purpose of facilitating synthesis, any amino acids may be substituted in consideration of the hydropathy scales of amino acids, which are a measure of the hydrophilic and hydrophobic properties of amino acids (J. Kyte and R. Doolittle, J. Mol. Biol., Vol. 157, p. 105-132, 1982).

[0170] As referred to herein, the percent identity between two amino acid sequences can be determined by visual inspection and mathematical calculation. Alternatively, the percent identity can be determined using a computer program. Examples of such computer programs include BLAST and ClustalW. In particular, various conditions (parameters) for identity searches with the BLAST program are described in Altschul, et al. (Nucl. Acids. Res., 25, p. 3389-3402, 1997), and are publicly available on the websites of the National Center for Biotechnology Information (NCBI) and DNA Data Bank of Japan (DDBJ) (Altschul, et al., BLAST Handbook, Altschul, et al., NCB/NLM/NIH Bethesda, Md. 20894). Also, the percent identity can be determined using a genetic information processing software program, such as GENETYX Ver. 7 (Genetyx Corporation), DINASIS Pro (Hitachi Software Engineering Co., Ltd.), or Vector NTI (Infomax Inc.).

[0171] By stating herein "deletion, substitution, insertion or addition of one or several nucleotides" in relation to nucleotide sequence, it is meant that in a nucleotide sequence of interest, one or several nucleotides (e.g., 30%, preferably 25%, 20%, 15%, 10%, 5%, 3%, 2% or 1%, of nucleotides with respect to the total length of the nucleotide sequence) are deleted, one or several nucleotides are substituted by any other nucleotides, any other nucleotides are inserted, and/or any other nucleotides are added. It is preferable that such a nucleotide deletion, substitution, insertion or addition should not give rise to a frame shift in an amino acid coding sequence.

[0172] As referred to herein, the percent identity between two nucleotide sequences can be determined by visual inspection and mathematical calculation. Alternatively, the percent identity can be determined using a computer program. Examples of such sequence comparison computer programs include the BLASTN program available on the website of the National Library of Medicine (http://blast.ncbi.nlm.nih.gov/Blast.cgi) (Altschul et al. (1990) J. Mol. Biol. 215: 403-10), and it can be determined by using default parameters.

[0173] As referred to herein, "under stringent conditions" means that hybridization takes place under moderately or highly stringent conditions. To be specific, the moderately stringent conditions can be easily determined by those having ordinary skill in the art on the basis of, for example, the length of DNA. Basic conditions are described in Sambrook, et al., Molecular Cloning: A Laboratory Manual, 3rd ed., ch. 6-7, Cold Spring Harbor Laboratory Press, 2001. The moderately stringent conditions include hybridization under the conditions of preferably 1.times.SSC to 6.times.SSC at 42.degree. C. to 55.degree. C., more preferably 1.times.SSC to 3.times.SSC at 45.degree. C. to 50.degree. C., most preferably 2.times.SSC at 50.degree. C. In the case of using a hybridization solution containing, for example, about 50% formamide, a temperature around 5 to 15.degree. C. lower than the foregoing should be adopted. Washing is also carried out under the conditions of 0.5.times.SSC to 6.times.SSC at 40.degree. C. to 60.degree. C. In the process of hybridization and washing, generally 0.05% to 0.2% SDS, preferably about 0.1% SDS, may be added. Likewise, the highly stringent conditions can be easily determined by those having ordinary skill in the art on the basis of, for example, the length of DNA. Generally, the highly stringent (high stringent) conditions include hybridization and/or washing at a higher temperature and/or a lower salt concentration than those adopted under the moderately stringent conditions. For example, hybridization is carried out under the conditions of 0.1.times.SSC to 2.times.SSC at 55.degree. C. to 65.degree. C., more preferably 0.1.times.SSC to 1.times.SSC at 60.degree. C. to 65.degree. C., most preferably 0.2.times.SSC at 63.degree. C. Washing is carried out under the conditions of 0.2.times.SSC to 2.times.SSC at 50.degree. C. to 68.degree. C., more preferably 0.2.times.SSC at 60 to 65.degree. C.

[0174] Antigens may be obtained by separating and purifying them from eggs (preferably chicken eggs) using a combination of protein purification methods well known to those skilled in the art. Also, antigens may be obtained by expressing them as recombinant proteins using a genetic recombination technique well known to those skilled in the art and by separating and purifying them using protein purification methods well known to those skilled in the art.

[0175] Exemplary protein purification methods include: solubility-based purification methods such as salt precipitation and solvent precipitation; purification methods based on molecular weight difference, such as dialysis, ultrafiltration, gel filtration and SDS-PAGE; charge-based purification methods such as ion exchange chromatography and hydroxylapatite chromatography; specific affinity-based purification methods such as affinity chromatography; purification methods based on hydrophobicity difference, such as reverse-phase high-performance liquid chromatography; and purification methods based on isoelectric point difference, such as isoelectric focusing.

[0176] Preparation of a protein by a genetic recombination technique is carried out by preparing an expression vector comprising an antigen-encoding nucleic acid, introducing the expression vector into appropriate host cells by gene transfer or genetic transformation, culturing the host cells under suitable conditions for expression of a recombinant protein, and recovering the recombinant protein expressed in the host cells.

[0177] The "vector" refers to a nucleic acid that can be used to introduce a nucleic acid attached thereto into host cells. The "expression vector" is a vector that can induce the expression of a protein encoded by a nucleic acid introduced therethrough. Exemplary vectors include plasmid vectors and viral vectors. Those skilled in the art can select an appropriate expression vector for the expression of a recombinant protein depending on the type of host cells to be used.

[0178] The "host cells" refers to cells that undergo gene transfer or genetic transformation by a vector. The host cells can be appropriately selected by those skilled in the art depending on the type of the vector to be used. The host cells can be derived from prokaryotes such as E. coli. When prokaryotic cells like E coli. are used as host cells, the antigen of the present invention may be designed to contain an N-terminal methionine residue in order to facilitate the expression of a recombinant protein in the prokaryotic cells. The N-terminal methionine can be cleaved from the recombinant protein after expression. Also, the host cells may be cells derived from eukaryotes, such as single-cell eukaryotes like yeast, plant cells and animal cells (e.g., human cells, monkey cells, hamster cells, rat cells, murine cells or insect cells) or silkworm.

[0179] Gene transfer or genetic transformation of an expression vector into host cells can be carried out as appropriate by following a technique known to those skilled in the art. Those skilled in the art can make possible the expression of a recombinant protein by selecting suitable conditions for the expression of the recombinant protein as appropriate depending on the type of host cells and culturing the host cells under the selected conditions. Then, those skilled in the art can homogenize the host cells having the expressed recombinant protein, and separate and purify an antigen expressed as the recombinant protein from the resulting homogenate by using an appropriate combination of such protein purification methods as mentioned above.

[0180] Diagnosis Kit and Method

[0181] The present invention provides a method for providing an indicator for diagnosing an allergy to an egg in a subject, the method comprising the steps of:

(i) contacting a sample obtained from the subject with an antigen, wherein the sample is a solution comprising an IgE antibody; (ii) detecting binding between an IgE antibody present in the sample from the subject and the antigen; and (iii) when the binding between the IgE antibody in the subject and the antigen is detected, an indicator of the fact that the subject is allergic to an egg is provided; wherein the antigen is at least one of proteins as defined above in any of (1) to (3) and (4) to (10).

[0182] The sample obtained from a subject is a solution containing an IgE antibody, as collected from the subject. Examples of such solutions include blood, saliva, sputum, snivel, urine, sweat, and tear. The sample obtained from the subject may be subjected to pretreatment for increasing the concentration of an IgE antibody in the sample before being contacted with an antigen. The pretreatment of a sample may involve, for example, collection of the serum, plasma from the blood. Furthermore, a Fab portion that is a binding portion with the antigen may be purified. In a particularly preferred mode, the step (i) mentioned above is carried out by contacting an IgE antibody present in the serum obtained from a subject with an antigen.

[0183] The IgE antibody may be the IgE antibody itself or mast cells or the like to which the IgE antibody is bound.

[0184] Detection of contact and binding between the sample obtained from a subject and an antigen can be carried out by using a known method. Examples of such methods that can be used include detection by ELISA (Enzyme-Linked Immunosorbent Assay), sandwich immunoassay, immunoblotting, immunoprecipitation, or immunochromatography. These are all techniques for detecting binding between an antigen and an IgE antibody from a subject by contacting and binding the IgE antibody from a subject with the antigen, allowing an enzymatically labelled secondary antibody to act on the IgE antibody specifically bound to the antigen, and adding an enzyme substrate (generally, chromogenic or luminescent reagent) to detect an enzymatic reaction product. Also, a method for detecting a fluorescently labeled secondary antibody can be used. Also, detection by a measurement method that permits the analysis of binding between an antigen and an IgE antibody, such as surface plasmon resonance (SPR), can be used. A plurality of antigen-specific IgE antibodies may be mixed.

[0185] The antigen may be provided as an isolated antigen in a state immobilized on a carrier. In this case, the steps (i) and (ii) mentioned above can be carried out using ELISA, sandwich immunoassay, immunochromatography, surface plasmon resonance, or the like. Also, the step (i) mentioned above is carried out by contacting the sample obtained from a subject with an antigen-immobilized surface. The isolated antigen may be obtained by separating and purifying it from egg (preferably chicken egg) using a combination of protein purification methods well known to those skilled in the art, or by preparing it using a genetic recombination technique. Moreover, the antibody may be in an immobilized state.

[0186] The antigen may be in a state unfixed on a carrier. In this case, the steps (i) and (ii) mentioned above can be carried out by flow cytometry or the like and the presence of the antigen bound to an antibody may be confirmed using a laser beam. Examples include basophil activation test (BAT) and the like. Another example is histamine release test (HRT) in which it is examined whether histamine is released or not by bringing an antigen further in contact with hemocytes in a sample.

[0187] The antigen may be detected by immunoblotting in a state separated by two-dimensional electrophoresis. The two-dimensional electrophoresis is a technique for separating a protein sample by performing isoelectric focusing in the first dimension and performing SDS-PAGE (SDS-polyacrylamide gel electrophoresis) in the second dimension. The conditions for two-dimensional electrophoresis are not particularly limited as long as the conditions permit the separation of the antigen of the present invention. For example, the conditions for two-dimensional electrophoresis as described above in the subsection titled "Identification of antigens" can be adopted. Also, the electrophoresis conditions may be defined by reference to the descriptions in PTLs 1 to 4 mentioned above. For example, two-dimensional electrophoresis can be carried out under the conditions that satisfy at least one selected from the group consisting of the following requirements:

(A) the isoelectric focusing gels used in the first dimension should have a gel-strip length of 5 to 10 cm and a gel pH range of 3 to 10, and the pH gradient of the gels in the direction of electrophoresis should be as follows: where the gel-strip length up to pH 5 is taken as "a", that length from pH 5 to 7 as "b", and that length above pH 7 as "c", the relations "a<b" and "b>c" are satisfied; (B) in the case of (A), when the total gel-strip length is taken as 1, "a" should be in the range of 0.15 to 0.3, "b" should be in the range of 0.4 to 0.7, and "c" should be in the range of 0.15 to 0.3; (C) in the first dimensional isoelectric focusing, a constant voltage step should be performed by applying a constant voltage ranging from 100 V to 600 V per gel strip containing a sample, and after the electrophoresis variation width during electrophoresis for 30 minutes falls within the range of 5 .mu.A, a voltage-increasing step should be started at which the voltage is increased from the aforementioned constant voltage; (D) in the case of (C), the final voltage at the voltage-increasing step should be in the range of 3000 V to 6000 V; (E) the isoelectric focusing gels used in the first dimension should have a longitudinal gel-strip length of 5 to 10 cm, and the electrophoresis gels used in the second dimension should have a gel concentration at the distal end in the direction of electrophoresis, which is in the range of 3 to 6%; and (F) in the case of (E), the electrophoresis gels used in the second dimension should have a gel concentration at the proximal end in the direction of electrophoresis, which is set to a higher value than that at the distal end in the direction of electrophoresis.

[0188] The aforementioned antigens (1) to (3) and (4) to (10) are antigens that specifically bind to IgE antibodies from patients with allergy to egg. Therefore, when binding between an IgE antibody from a subject and the antigen is detected, an indicator of the fact that the subject is allergic to egg is provided.

[0189] The present invention further provides a kit for diagnosing an allergy to an egg, comprising at least one of the aforementioned antigens (1) to (3) and (4) to (10). The diagnosis kit of this invention may be used in the aforementioned method for providing an indicator for diagnosing an allergy to an egg or in a diagnosis method as described later. The diagnosis kit of this invention may comprise not only the at least one of the aforementioned antigens (1) to (3) and (4) to (10), but also an anti-IgE antibody labeled with an enzyme and a chromogenic or luminescent substrate serving as a substrate for the enzyme. Also, a fluorescent-labeled anti-IgE antibody may be used. In the diagnosis kit of this invention, the antigen may be provided in a state immobilized on a carrier. The diagnosis kit of this invention may also be provided together with instructions on the procedure for diagnosis or a package containing said instructions.

[0190] In another aspect, the diagnosis kit includes a companion diagnostic agent for an egg allergy. The companion diagnostic agent is used to analyze the reactivity of a pharmaceutical product for the purpose of identifying a patient in which the pharmaceutical product is expected to work or a patient at risk for serious side effects from the pharmaceutical product, or optimizing a therapy using the pharmaceutical product. Here, examples of optimizing a therapy include determination of the usage and the volume, decision of stopping the administration, determination of the allergen component to be used for the induction of immune tolerance, and the like.

[0191] The present invention further provides a composition for diagnosing an allergy to an egg, comprising at least one of the aforementioned antigens (1) to (3) and (4) to (10). The diagnosis composition of this invention can be used in a diagnosis method as described below. The diagnosis composition of this invention may further comprise a pharmaceutically acceptable carrier and/or additives commonly used with the antigen of this invention depending on the need.

[0192] In one mode, the present invention provides a method for diagnosing an allergy to an egg in a subject, the method comprising:

(i) contacting a sample obtained from the subject with an antigen; (ii) detecting binding between an IgE antibody present in the sample from the subject and the antigen; and (iii) when the binding between the IgE antibody in the subject and the antigen is detected, diagnosing the subject as being allergic to an egg; wherein the antigen is at least one of proteins as defined above in any of (1) to (3) and (4) to (10). In this method, the steps (i) and (ii) are performed as described above regarding the corresponding steps of the method for providing an indicator for diagnosing an allergy to an egg.

[0193] In another mode, the present invention provides a method for diagnosing an allergy to an egg in a subject, the method comprising administering to the subject at least one of the aforementioned antigens (1) to (3) and (4) to (10). This method may be performed in the form of a skin test characterized by applying the antigen onto the skin. Examples of the skin test include various forms of tests, such as: a prick test in which a diagnosis composition is applied onto the skin and then a tiny prick to such an extent as not to provoke bleeding is made in the skin to allow an antigen to penetrate the skin, thereby observing a skin reaction; a scratch test in which a diagnosis composition is applied onto the skin and then the skin is lightly scratched to observe a reaction; a patch test in which a diagnosis composition in the form of cream, ointment, etc. is applied onto the skin to observe a reaction; and an intracutaneous test in which an antigen is administered intracutaneously to observe a reaction. If a skin reaction such as swelling occurs in a skin portion to which the antigen has been applied, the subject of interest is diagnosed as having an allergy to an egg. The amount of the antigen to be applied to the skin in such tests can be, for example, not more than 100 .mu.g per dose.

[0194] In the allergic diagnosis, a load test for the purpose of identifying the antigen is often performed. At least one of the aforementioned antigens (1) to (3) and (4) to (10) can be used as an active ingredient(s) in such a load test for diagnosing an egg allergy. Here, the antigen protein to be used in the load test may be a protein that has been expressed and purified and may be a protein that has been expressed in a food and a food material, for example, rice-based vaccine produced by transforming rice with a gene of a cedar pollen antigen to express the antigen protein therein.

[0195] In yet another mode, the present invention provides at least one of the aforementioned antigens (1) to (3) and (4) to (10), intended for use in the diagnosis of an allergy to an egg. Here, the present invention encompasses the provision of at least one of the aforementioned antigens (1) to (3) and (4) to (10) mixed with a known antigen.

[0196] In still another mode, the present invention provides use of at least one of the aforementioned antigens (1) to (3) and (4) to (10) for the production of a diagnostic agent for an allergy to an egg.

[0197] Pharmaceutical Composition and Treatment Method

[0198] The present invention provides a pharmaceutical composition comprising at least one of the aforementioned antigens (1) to (3) and (4) to (10).

[0199] In one mode, the aforementioned pharmaceutical composition is used for the treatment of an allergy to an egg.

[0200] The present invention also provides a method for treating an allergy to an egg, the method comprising administering at least one of the aforementioned antigens (1) to (3) and (4) to (10) to a patient in need of a treatment for an allergy to an egg.

[0201] In another mode, the present invention provides at least one of the aforementioned antigens (1) to (3) and (4) to (10), intended for use in the treatment for an allergy to an egg. In yet another mode, the present invention provides use of at least one of the aforementioned antigens (1) to (3) and (4) to (10) for the production of a therapeutic agent for an allergy to an egg.

[0202] In the process of allergy treatment, a hyposensitization therapy aiming to induce immunological tolerance by administering an antigen to a patient is often adopted. The at least one of the aforementioned antigens (1) to (3) and (4) to (10) can be used as an active ingredient for a hyposensitization therapy for an allergy to an egg. Here, the antigen protein to be used in the hyposensitization therapy may be a protein that has been expressed and purified and may be a protein that has been expressed in a food and a food material, for example, rice-based vaccine produced by transforming rice with a gene of a cedar pollen antigen to express the antigen protein therein.

[0203] The pharmaceutical composition of the present invention can be administered by common administration routes. Examples of common administration routes include oral, sublingual, percutaneous, intracutaneous, subcutaneous, intravascular, intranasal, intramuscular, intraperitoneal, and intrarectal administrations.

[0204] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition to which a commonly used pharmaceutically acceptable adjuvant or excipient or any other additives (e.g., stabilizer, solubilizer, emulsifier, buffer, preservative, colorant) are added by a conventional method together with the antigen of this invention depending on the need. The dosage form of the pharmaceutical composition can be selected by those skilled in the art as appropriate depending on the administration route. The pharmaceutical composition can be in the form of, for example, tablet, capsule, troche, sublingual tablet, injection, intranasal spray, poultice, solution, cream, lotion, or suppository. The administration dose, frequency and/or period of the pharmaceutical composition of this invention can be selected by a physician as appropriate depending on the administration route and the patient's condition and characteristics such as age and body weight. For example, the pharmaceutical composition may be administered to an adult patient at a dose of not more than 100 .mu.g per dose. The administration interval can be, for example, once daily, once weekly, twice weekly, once per three months or so. The administration period can be, for example, several weeks to several years. The pharmaceutical composition may be administered in such a manner that the dose is increased in incremental steps over the administration period.

Tester

[0205] The present invention provides a tester comprising an antibody for at least one of the aforementioned antigens (1) to (3) and (4) to (10).

[0206] The antibody can be prepared by a conventional method. For example, the antibody may be prepared by immunizing a mammal such as rabbit with one of the aforementioned antigens (1) to (3) and (4) to (10). The antibody may be an IgE antibody, a polyclonal antibody, a monoclonal antibody, or an antigen-binding fragment thereof (e.g., Fab, F(ab').sub.2, Fab').

[0207] Further, in the aforementioned tester, the antibody may be provided in a form bound to a carrier. The type of the carrier is not particularly limited as long as it is usable for detection of binding between an antibody and an antigen. Any given carrier known to those skilled in the art can be used.

[0208] Examples of a method for determining the presence or absence of an antigen include the following:

[0209] A method in which a prepared tester comprising an IgE antibody is contacted with a sample obtained from a food, food material, etc., ELISA or the like method is used to detect whether there is a binding between the IgE antibody and an antigen in the sample, and if the binding between the IgE antibody and the antigen is detected, it is determined that the antibody is present in the food, food material, etc. of interest.

[0210] A method in which a food or a food material is infiltrated into a filter paper or the like and an antibody solution is reacted with the filter paper to detect an antigen present in the food or food material.

[0211] In another aspect, the present invention encompasses a tester for determining the presence or absence of an antigen for an egg allergy in an object of interest, comprising a primer having a nucleotide sequence complementary to a part of at least one of the nucleotide sequences set forth in SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261. Without limiting, the primer has a nucleotide sequence complementary to preferably 12 bases, 15 bases, 20 bases, or 25 bases in the sequence of a 3' terminal or middle portion of a part of at least one sequence of the nucleotide sequences set forth in, for example, SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261. Particularly when mRNA is targeted, the tester comprises a poly A tail-complementarity primer. In a preferred aspect, the tester including the primer may further comprise a primer comprising a nucleotide sequence of a 5' terminal portion of at least one sequence of the nucleotide sequences set forth in SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261, preferably a nucleotide sequence consisting of 12 bases, 15 bases, 20 bases, 25 bases.

[0212] For example, the presence or absence of the antigen is determined by amplifying cDNA by polymerase chain reaction (PCR) including RT-PCR with DNA or mRNA obtained from an egg or a bird as a template and the complementary primer and comparing the amplified cDNA sequence(s) with SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261. Examples of the method of the amplification by PCR include RACE and the like. In the determination, the antigen is determined to be present when the comparison between the amplified cDNA and SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261 indicates the presence of one or more point mutations encoding the same amino acid, or when the amino acid sequence encoded by the amplified cDNA has 70% or more, preferably 80, 90, 95, 98, or 99% or more identity with an amino acid sequence of SEQ ID NO: 2, 13, 18, 47, 59, 106, 152, 237, 251 or 262, even if the nucleotide sequence of the amplified cDNA is modified from a nucleotide sequence of SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261 by insertion, deletion, substitution, or addition of one or more nucleotides.

[0213] In one mode, the aforementioned tester is used to determine the presence or absence of an antigen in foods or in products of interest in a food material (egg or bird) or a food production line. The tester may also be used for quality inspection of production lines and pre-shipment products by manufacturers, or may be used for self-checking of the presence or absence of an antigen in a food, food material of interest by consumers.

[0214] Antigen-Free Food and the Like

[0215] The present invention provides an egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which at least one of the aforementioned antigens (1) to (3) and (4) to (10) is eliminated or reduced.

[0216] The method for eliminating or reducing the antigen of the present invention in an egg, a processed product of an egg, or a bird which lays or has hatched from the egg is not limited. The elimination or reduction of the antigen may be conducted by any method, as long as the method permits the elimination or reduction of the antigen.

[0217] For example, the egg of the present invention whose antigen is eliminated or reduced may be obtained by preparing an egg in which the expression of the antigen of the present invention is knocked out, using a gene knock-out technique.

[0218] As the gene knock-out technique, there can be used any methods known to those skilled in the art. For example, Oishi, et al. (Scientific Reports, Vol. 6, Article number: 23980, 2016, doi:10.1038/srep23980) describes that the genome editing technique CRISPER/Cas9 is applied to chicken primordial germ cells to obtain individual animals deficient in ovomucoid gene. The egg devoid of the antigen of this invention may also be obtained by using the same technique as above. Moreover, a bird or an egg in which the antigen of the present invention is eliminated or decreased may be obtained by mating by artificial insemination with a bird or an egg that does not contain the antigen or contains a low content of the antigen. The artificial mating of birds or eggs can be performed by a conventional method.

[0219] An antigen of the present invention may be the artefact that an antigen of the present invention assumed the removal or a reduced egg raw material as for the removal or the reduced processed products of egg. In the case of using an ordinary egg as a source ingredient, a treatment for removing or reducing the antigen of this invention is performed before or after preparation of a processed product of egg. Examples of a method of eliminating or decreasing the antigen of the present invention in a processed product made from a common egg include methods for eliminating the protein component in a food or a food material, such as elution with a high pressure treatment and a neutral salt solution and hot steam and methods for hydrolysis, denaturation, or amino acid modification (chemical modification or elimination of side chains) by heat treatment and acid treatment.

[0220] The bird in which the antigen of the present invention is eliminated or reduced may be a bird that has hatched and grown from an egg in which the aforementioned antigen of the present invention is eliminated or reduced. The birds include birds at growth stages of nestling, juvenile, young bird, adult bird and old bird. As used herein, the bird means an animal belonging to Ayes, preferably a chicken.

[0221] Method for Producing Antigen-Free Processed Product of Egg

[0222] The present invention provides a method for producing a processed product of an egg in which an antigen is eliminated or reduced, comprising the step of confirming that the antigen is eliminated or reduced in the process of producing the processed product, wherein the antigen is at least one of the aforementioned antigens (1) to (3) and (4) to (10).

[0223] The step of confirming that the antigen is eliminated or reduced in the process of producing the processed product of an egg in which an antigen is eliminated or reduced may be performed by examining whether the antigen is contained or not by the method described in the section of "Tester" above.

[0224] The method for producing a processed product of an egg in which an antigen is eliminated or reduced may be performed by the method described in the section "Antigen-free food and the like" above.

EXAMPLES

[0225] The following describes examples of the present invention. The technical scope of this invention is not limited by these examples.

Example 1: Confirmation of a Protein Pattern

[0226] Proteins contained in egg were investigated using a two-dimensional electrophoresis method described below.

[0227] Protein Extraction

[0228] Raw chicken eggs were separated into egg white and egg yolk.

[0229] The extraction and the purification of proteins contained in the egg white and the egg yolk were performed as follows. A solubilization agent was added to the egg white to extract proteins and then water or a urea buffer was added to obtain a protein extract. The composition of the urea buffer is as follows.

[0230] 30 mM Tris

[0231] 2 M Thiourea

[0232] 7 M Urea

[0233] 4% (w/v) CHAPS:

[0234] 3-[(3-Cholamidopropyl)dimethylammonio]propanesulfonate

[0235] A proper quantity of dilute hydrochloric acid

Distilled water was added and the total volume was adjusted to 100 mL. PH was 8.5. Subsequently, 25 .mu.g each in terms of protein weight was mixed to obtain an extract. A surfactant buffer (Mammalian Lysis Buffer (MCLI), SIGMA) was added as a solubilization agent to the egg yolk to extract proteins.

[0236] Thereafter, the precipitation procedure was repeated twice using a 2D-CleanUP Kit (produced by GE). In the first round of precipitation, the collected liquid protein extract was precipitated by adding TCA (trichloroacetic acid) thereto and the precipitated product produced by this procedure (TCA-precipitated product) was collected. In the second round of precipitation, the TCA-precipitated product collected above was further precipitated by adding acetone thereto and the precipitated product (sample) produced by this procedure was collected.

[0237] Preparation of a Sample Solution

[0238] Part of the collected sample (50 .mu.g on a protein weight basis) was dissolved in 150 .mu.L of a DeStreak Rehydration Solution (produced by GE), which is a swelling buffer for first-dimensional isoelectric focusing gels, thereby obtaining a sample solution for first-dimensional isoelectric focusing (sample solution for swelling). The constituents of the DeStreak Rehydration Solution are as mentioned below.

[0239] 7M thiourea

[0240] 2M urea

[0241] 4% (w/v) of CHAPS

[0242] 0.5% (v/v) IPG buffer; produced by GE

[0243] Moderate amount of BPB (bromophenol blue)

[0244] Penetration of the Sample into First-Dimensional Isoelectric Focusing Gels

[0245] First-dimensional isoelectric focusing gel strips (Immobiline Drystrip IPG gels (pH3-10NL); produced by GE) were immersed in 140 .mu.L of the foregoing sample solution for first-dimensional isoelectric focusing (sample solution for swelling) and impregnated with the solution at room temperature overnight.

[0246] In this example, an IPGphor electrophoresis system produced by GE was used.

[0247] An electrophoresis tray was filled with silicone oil. Filter paper moisten with water was positioned at both ends of the gel strips impregnated with the sample, and the gel strips were set in the electrophoresis tray such that the gel strips were covered with silicone oil. Electrodes were placed on the gel strips with the filter paper intervening therebetween.

[0248] The maximum current of the isoelectric focusing system was set to 75 .mu.A per gel strip, and the first-dimensional isoelectric focusing was carried out according to the following voltage program: (1) a constant voltage step was performed at a constant voltage of 300 V until the volt-hours reached 750 Vhr (the current variation width during electrophoresis for 30 minutes before the end of this step was 5 .mu.A); (2) the voltage was increased gradually to 1000 V for 300 Vhr; (3) the voltage was further increased gradually to 5000 V for 4500 Vhr; and then (4) the voltage was held at a constant voltage of 5000 V until the total Vhr reached 12000.

[0249] SDS Equilibration of Isoelectric Focusing Gels

[0250] After the aforementioned first-dimensional isoelectric focusing was done, the gel strips were taken out of the isoelectric focusing system, immersed in an equilibration buffer containing a reducing agent, and shaken at room temperature for 15 minutes. The constituents of the equilibration buffer containing the reducing agent are as mentioned below.

[0251] 100 mM Tris-HCl (pH 8.0)

[0252] 6M urea

[0253] 30% (v/v) glycerol

[0254] 2% (w/v) SDS

[0255] 1% (w/v) DTT

[0256] Next, the equilibration buffer containing the reducing agent was removed, and then the gel strips were immersed in an equilibration buffer containing an alkylating agent and shaken at room temperature for 15 minutes to obtain SDS-equilibrated gels. The constituents of the equilibration buffer containing the alkylating agent are as mentioned below.

[0257] 100 mM Tris-HCl (pH 8.0)

[0258] 6M urea

[0259] 30% (v/v) glycerol

[0260] 2% (w/v) SDS

[0261] 2.5% (w/v) iodoacetamide

[0262] Second-dimensional SDS-PAGE

[0263] In this example, the XCell SureLock Mini-Cell electrophoresis system produced by Life Technologies was used. The second-dimensional electrophoresis gels used were NuPAGE 4-12% Bis-Tris Gels produced by Life Technologies. Also, an electrophoresis buffer composed of the following constituents was prepared and used.

[0264] 50 mM MOPS

[0265] 50 mM Tris base

[0266] 0.1% (w/v) SDS

[0267] 1 mM EDTA

[0268] Further, an agarose solution for gel adhesion was used in this example, which was prepared by dissolving 0.5% (w/v) Agarose S (produced by Nippon Gene Co., Ltd.) and a moderate amount of BPB (bromophenol blue) in the electrophoresis buffer.

[0269] SDS-PAGE wells were washed well with the electrophoresis buffer, and then the buffer used for the washing was removed. Next, the washed wells were charged with the fully dissolved agarose solution for gel adhesion. Next, the SDS-equilibrated gel strips were immersed in agarose and closely adhered to second-dimensional electrophoresis gels using tweezers. After it was confirmed that agarose was fully fixed with the gels being closely adhered to each other, electrophoresis was performed at a constant voltage of 200 V for about 45 minutes.

[0270] Fluorescent Staining of Gels

[0271] The gels were fluorescently stained with SYPRO Ruby (produced by Life Technologies).

[0272] First, an airtight container to be used was washed well in advance with 98% (v/v) ethanol. The electrophoresed second-dimensional electrophoresis gel strips were taken out of the SDS-PAGE system, placed onto the washed airtight container, and treated twice by immersion in 50% (v/v) methanol and 7% (v/v) aqueous solution containing acetic acid for 30 minutes. Then, a further immersion treatment was done for 10 minutes, with the solution being replaced by water. Next, the second-dimensional electrophoresis gel strips were immersed in 40 mL of SYPRO Ruby and shaken at room temperature overnight. Thereafter, the SYPRO Ruby was removed, and then the second-dimensional electrophoresis gel strips were washed with water and shaken in 10% (v/v) methanol and 7% (v/v) aqueous solution containing acetic acid for 30 minutes. Further shaking was done for at least 30 minutes, with the solution being replaced by water.

[0273] Analysis

[0274] The second-dimensional electrophoresis gels obtained through the foregoing series of treatments were subjected to fluorescent image scanning on Typhoon 9400 (produced by GE). FIG. 1 illustrates the result of two-dimensional electrophoresis of proteins contained in the egg yolk (the result of the egg white is not illustrated). Molecular weight marker bands are found at the left of the photograph of the gel. The positions of the bands indicate particular molecular weights (KDa).

Example 2: Identification of Antigens by Immunoblotting (1)

[0275] Identification of antigens by immunoblotting was carried out by taking all the steps up to the step of "Second-dimensional SDS-PAGE" as described above in Example 1, followed by the steps of "Transfer to membrane", "Immunoblotting" and "Analysis" as described below.

[0276] Transfer to Membrane

[0277] Transfer to membrane was done using the following transfer system and transfer buffer.

Transfer system: XCell SureLock Mini-Cell and XCell II Blot Module (produced by Life Technologies) Transfer buffer: NuPAGE Transfer Buffer (X20) (produced by Life Technologies), used in a form diluted 20-fold with milliQ water.

[0278] To be specific, proteins in the two-dimensional electrophoresis gels were transferred to a membrane (PVDF membrane) according to the following procedure.

[0279] (1) The PVDF membrane was immersed in 100% methanol followed by milliQ water, and then moved into the transfer buffer to hydrophilize the PVDF membrane.

[0280] (2) After sponge, filter paper, the gels treated by second-dimensional SDS-PAGE, the hydrophilized PVDF membrane, filter paper, and sponge were put in place in this order, the transfer system was energized at a constant voltage of 30 V for one hour.

[0281] Immunoblotting

[0282] Immunoblotting of the membrane was carried out using, as a primary antibody, the serum from a patient with an egg allergy (patient 1) or the serum from a non-egg-allergic subject. This egg-allergic patient is a patient diagnosed as food-dependent exercise-induced anaphylaxis (FDEIA) by chicken egg. This patient was negative for raw egg, boiled egg, and soft-boiled egg in a prick test and also negative for egg white, egg yolk, and ovomucoid in an allergen-specific IgE antibody test.

[0283] Immunoblotting of the membrane was carried out according to the following procedure.

(1) The transferred membrane was shaken in a 5% skim milk/PBST solution (a PBS buffer containing 0.1% Tween 20 nonionic surfactant) at room temperature for one hour. (2) The membrane was left to stand in a solution of 5% primary antibody serum in 5% skim milk/PBST at room temperature for one hour. (3) The membrane was washed with a PBST solution (5 min..times.3 times). (4) The membrane was left to stand in a 1:5000 dilution of the secondary antibody, anti-human IgE-HRP (horseradish peroxidase), with a 5% skim milk/PBST solution at room temperature for one hour. (5) The membrane was washed with a PBST solution (5 min..times.3 times). (6) The membrane was left to stand in Pierce Western Blotting Substrate Plus (produced by Thermo Fisher Scientific) for 5 minutes.

[0284] Analysis

[0285] The membrane obtained through the foregoing series of treatments was subjected to fluorescent image scanning on Typhoon 9500 (produced by GE).

[0286] The immunoblot obtained with the serum from the egg-allergic patient was compared with that obtained with the control serum from the non-egg-allergic subject. Three spots that are different from those with the serum of the non-egg-allergic patient and different from the known chicken egg allergen proteins were detected on an immunoblot of the proteins contained in raw egg yolk with the serum of the egg-allergic patient (FIG. 2).

[0287] The molecular weights and isoelectric points of the three spots are as follows (FIG. 3).

Spot 1: Molecular weight 20 to 40 kDa, pI 4.0 to 10.0 Spot 2: Molecular weight 30 to 60 kDa, pI 5.0 to 10.0 Spot 3: Molecular weight 35 to 60 kDa, pI 5.0 to 10.0

Example 3: Mass Spectrometry and Identification of Antigens (1)

[0288] The amino acid sequences of the antigens that form the three protein spots of Example 2 were identified by mass spectroscopy.

[0289] To be specific, protein extraction and mass spectroscopy were done by the following procedure.

(1) Egg yolk of raw chicken egg was subjected to protein extraction, two-dimensional electrophoresis and transfer to membrane by following the procedures described in Examples 1 and 2, and the resulting membrane was stained by shaking in a solution of 0.008% Direct blue in 40% ethanol and 10% acetic acid. (2) Then, the membrane was decolorized by repeating a 5-minute treatment with 40% ethanol and 10% acetic acid three times, washed with water for 5 minutes, and then dried by air. (3) A protein spot of interest was cut out with a clean cutter blade and put into a centrifugal tube. The cut membrane was subjected to hydrophilization with 50 .mu.L of methanol, followed by washing with 100 .mu.L of water twice and then centrifugal cleaning. Thereafter, 20 .mu.L of 20 mM NH.sub.4HCO.sub.3 and 50% acetonitrile were added. (4) 1 .mu.L of 1 pmol/.mu.L lysyl endopeptidase (produced by WAKO) was added, and the solution was left to stand at 37.degree. C. for 60 minutes and then collected in a new centrifugal tube. After 20 .mu.L of 20 mM NH.sub.4HCO.sub.3 and 70% acetonitrile were added to the membrane, the membrane was immersed therein at room temperature for 10 minutes, and the resulting solution was further collected. The solution was dissolved with 0.1% formic acid and 10 .mu.L of 4% acetonitrile and transferred to a tube. (5) The collected solution was dried under reduced pressure, dissolved with 15 .mu.L of solution A (a 0.1% formic acid/4% acetonitrile solution), and analyzed by mass spectroscopy (ESI-TOF6600, produced by AB Sciex). (6) Identification of proteins based on the MS data obtained with the mass spectrometer was done by searching the NCBI or Uniprot database.

[0290] Results

[0291] The mass spectrometry of the spots resulted in the detection of the following amino acid sequences.

Spot 1: The amino acid sequences set forth in SEQ ID NOs: 3 to 11 Spot 2: The amino acid sequences set forth in SEQ ID NOs: 9 to 11, 14, 16 Spot 3: The amino acid sequences set forth in SEQ ID NOs: 19 to 45

[0292] Furthermore, the spots were identified as the following proteins by the analysis of the mass data obtained from the mass spectrometer for spots 1 and 2 at NCBI and for spot 3 with UniProt.

Spot 1: A C-terminal portion (amino acid sequence: SEQ ID NO: 2, encoding nucleotide sequence: SEQ ID NO: 1) of Vitellogenin-3 (amino acid sequence: NCBI accession number XP_015146355, encoding nucleotide sequence: GenBank accession number XM_015290869.1): Spot 2: A C-terminal portion (amino acid sequence: SEQ ID NO: 13, encoding nucleotide sequence: SEQ ID NO: 12) of Vitellogenin-3 (amino acid sequence: NCBI accession number XP_015146355, encoding nucleotide sequence: GenBank accession number XM_015290869.1) Spot 3: A middle portion of Vitellogenin-1 (amino acid sequence: UniProt accession number P87498, encoding nucleotide sequence: ENA(EMBL) accession number D89547.1) or a C-terminal portion of Lipovitelin-1 (amino acid sequence: SEQ ID NO: 18, encoding nucleotide sequence: SEQ ID NO: 17)

Example 4: Identification of Antigens by Immunoblotting (2)

[0293] The Identification of antigens was performed by immunoblotting using the serum of three different egg-allergic patients (Patient 2, Patient 3, Patient 4), in the same manner as in Example 2. Spots that are different from those with the serum of the non-egg-allergic patient and different from the known chicken egg allergen proteins were detected on immunoblots of the proteins contained in raw egg yolk with the serums of the egg-allergic patients (FIG. 4 for Patient 2, FIG. 5 for Patient 3, FIG. 6 for Patient 4). Specifically, Spots 4 to 8, Spots 9 and 10, and Spot 11 were respectively detected for patient 2, Patient 3, and Patient 4.

[0294] The molecular weights and isoelectric points of Spots 4 to 11 are as follows (FIGS. 4 to 6).

Spot 4: Molecular weight 20 to 50 kDa, pI 3.0 to 8.0 Spots 5, 6: Molecular weight 80 to 260 kDa, pI 1.0 to 8.0 Spot 7: Molecular weight 110 to 300 kDa, pI 3.0 to 8.0 Spot 8: Molecular weight 160 to 550 kDa, pI 3.0 to 8.0 Spot 9: Molecular weight 20 to 50 kDa, pI 7.0 to 11.0 Spot 10: Molecular weight 20 to 50 kDa, pI 7.0 to 11.0 Spot 11: Molecular weight 15 to 40 kDa, pI 6.0 to 11.0

Example 5: Mass Spectrometry and Identification of Antigens (2)

[0295] The identification of the amino acid sequences of antigens producing spots 4 to 11 in Example 4 by the mass spectrometry was performed in the same manner as in Example 3.

[0296] The mass spectrometry of the spots resulted in the detection of the following amino acid sequences.

Spot 4: The amino acid sequences set forth in SEQ ID NOs: 48 to 57 Spots 5, 6: The amino acid sequences set forth in SEQ ID NOs: 60 to 104 Spot 7: The amino acid sequences set forth in SEQ ID NOs: 107 to 150 Spot 8: The amino acid sequences set forth in SEQ ID NOs: 153 to 235 Spot 9: The amino acid sequences set forth in SEQ ID NOs: 238 to 249 Spot 10: The amino acid sequences set forth in SEQ ID NOs: 252 to 260 Spot 11: The amino acid sequences set forth in SEQ ID NOs: 263 to 271

[0297] Furthermore, the spots were identified as the following proteins by the analysis of the mass data obtained from the mass spectrometer for the spots at NCBI.

Spot 4: Vitellogenin-3 (amino acid sequence: NCBI accession number XP_015146355, encoding nucleotide sequence: GenBank accession number XM_015290869.1) (amino acid sequence: SEQ ID NO: 47, encoding nucleotide sequence: SEQ ID NO: 46). Spots 5, 6: A Vitellogenin-2 precursor (amino acid sequence: NCBI accession number NP_001026447.1, encoding nucleotide sequence: GenBank accession number NM_001031276.1) (amino acid sequence: SEQ ID NO: 59, encoding nucleotide sequence: SEQ ID NO: 58). Spot 7: A Vitellogenin-2 precursor (amino acid sequence: NCBI accession number NP_001026447.1, encoding nucleotide sequence: GenBank accession number NM_001031276.1) (amino acid sequence: SEQ ID NO: 106, encoding nucleotide sequence: SEQ ID NO: 105) Spot 8: An Apolipoprotein B precursor (amino acid sequence: NCBI accession number NP_001038098.1, encoding nucleotide sequence: GenBank accession number NM_001044633.1) (amino acid sequence: SEQ ID NO: 152, encoding nucleotide sequence: SEQ ID NO: 151) Spot 9: An Apolipoprotein B precursor (amino acid sequence: NCBI accession number NP_001038098.1, encoding nucleotide sequence: GenBank accession number NM_001044633.1) (amino acid sequence: SEQ ID NO: 237, encoding nucleotide sequence: SEQ ID NO: 236). Spot 10: An Apolipoprotein B precursor (amino acid sequence: NCBI accession number NP_001038098.1, encoding nucleotide sequence: GenBank accession number NM_001044633.1) (amino acid sequence: SEQ ID NO: 251, encoding nucleotide sequence: SEQ ID NO: 250) Spot 11: A Vitellogenin-2 precursor (amino acid sequence: NCBI accession number NP_001026447.1, encoding nucleotide sequence: GenBank accession number NM_001031276.1) (amino acid sequence: SEQ ID NO: 262, encoding nucleotide sequence: SEQ ID NO: 261).

INDUSTRIAL APPLICABILITY

[0298] The present invention can provide a novel antigen of an egg allergy, a method for diagnosing an egg allergy and a kit for diagnosing an egg allergy, a pharmaceutical composition comprising the antigen, an egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which the antigen is eliminated or reduced, and a method for producing a processed product of an egg in which the antigen is eliminated or reduced. The present invention can further provide testers for determining the presence or absence of an egg antigen in an object of interest.

Sequence CWU 1

1

2711831DNAGallus gallus 1tcaatcattg aaaaccttaa agctcgttgt tcagtttcac aaaatatgat aacaaccttc 60aatggagttg agtttaacta ttcaatgcct gcaaattgct accacatctt ggcacaggat 120tgtagtccag aactgaagtt cctggtaatg atgaaaagac ttggagaatc tgctgatctc 180acagcaataa gtgtcagact tgccagccat gaggttgaca tgtatgtttc caatggacta 240atccagctga agattaatgg tgttcaaacc ccaacagacg ttccatacac atctaagtct 300ggtctgctga taagcagtga gaaggaaggt ttgtcattaa aagcccctga atatggtgta 360gaaaaactat attacgatag acgtaaactt gagattcggg ttgctttctg gatggttgga 420aaaacatgtg gtatttgtgg aaaatatgat gctgagaaga aaagggagta tcaaatgccc 480agtggatatt tagctaaaga tgcagtgagt tttgctcagt cctgggtcat ctcagaagac 540acgtgtactg gagcttgcaa gctgcagagg aaatttgtca aaattgagaa gccggttgca 600tttaacaaaa aggcctcaaa atgcttttcc attgagccag ttttacgctg tgcagaaggc 660tgttcagcaa ccaggactgt tcctgtctct gtgggtttcc actgtgtccc atctgactcc 720acactcgagc tggaggaaga gcaggtgagg ttagaccaga agtctgagga cttggtgagc 780agggtcgatg cccatacggc gtgttcctgc gcccagcagc tgtgctcagc g 8312277PRTGallus gallus 2Ser Ile Ile Glu Asn Leu Lys Ala Arg Cys Ser Val Ser Gln Asn Met1 5 10 15Ile Thr Thr Phe Asn Gly Val Glu Phe Asn Tyr Ser Met Pro Ala Asn 20 25 30Cys Tyr His Ile Leu Ala Gln Asp Cys Ser Pro Glu Leu Lys Phe Leu 35 40 45Val Met Met Lys Arg Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile Ser 50 55 60Val Arg Leu Ala Ser His Glu Val Asp Met Tyr Val Ser Asn Gly Leu65 70 75 80Ile Gln Leu Lys Ile Asn Gly Val Gln Thr Pro Thr Asp Val Pro Tyr 85 90 95Thr Ser Lys Ser Gly Leu Leu Ile Ser Ser Glu Lys Glu Gly Leu Ser 100 105 110Leu Lys Ala Pro Glu Tyr Gly Val Glu Lys Leu Tyr Tyr Asp Arg Arg 115 120 125Lys Leu Glu Ile Arg Val Ala Phe Trp Met Val Gly Lys Thr Cys Gly 130 135 140Ile Cys Gly Lys Tyr Asp Ala Glu Lys Lys Arg Glu Tyr Gln Met Pro145 150 155 160Ser Gly Tyr Leu Ala Lys Asp Ala Val Ser Phe Ala Gln Ser Trp Val 165 170 175Ile Ser Glu Asp Thr Cys Thr Gly Ala Cys Lys Leu Gln Arg Lys Phe 180 185 190Val Lys Ile Glu Lys Pro Val Ala Phe Asn Lys Lys Ala Ser Lys Cys 195 200 205Phe Ser Ile Glu Pro Val Leu Arg Cys Ala Glu Gly Cys Ser Ala Thr 210 215 220Arg Thr Val Pro Val Ser Val Gly Phe His Cys Val Pro Ser Asp Ser225 230 235 240Thr Leu Glu Leu Glu Glu Glu Gln Val Arg Leu Asp Gln Lys Ser Glu 245 250 255Asp Leu Val Ser Arg Val Asp Ala His Thr Ala Cys Ser Cys Ala Gln 260 265 270Gln Leu Cys Ser Ala 27538PRTGallus gallus 3Ala Pro Glu Tyr Gly Val Glu Lys1 5413PRTGallus gallus 4Gly Val Gln Thr Pro Thr Asp Val Pro Tyr Thr Ser Lys1 5 1058PRTGallus gallus 5Ile Glu Lys Pro Val Ala Phe Asn1 565PRTGallus gallus 6Pro Val Ala Phe Asn1 576PRTGallus gallus 7Ser Ile Ile Glu Asn Leu1 589PRTGallus gallus 8Ile Glu Lys Pro Val Ala Phe Asn Lys1 5915PRTGallus gallus 9Ile Asn Gly Val Gln Thr Pro Thr Asp Val Pro Tyr Thr Ser Lys1 5 10 151013PRTGallus gallus 10Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile Ser Val Arg1 5 101114PRTGallus gallus 11Arg Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile Ser Val Arg1 5 10121314DNAGallus gallus 12gtgcaggtgt ttgtttcaag catcacagaa tcagataggt ggaaactctg tgctgatgct 60tcagtagtaa attcccataa agcatcgggt acccttaaat ggggtaaaga ttgccaggac 120tatcaggttg ctactcagat tgcaacaggg caatttgctg cacacccggc tatacaggtg 180aagctggagt ggtcagaagt gccttcaagt gtccgaaaaa ctgccagatg gttctacaca 240tatcttccag gagctgcgta tatgcttggc tactcccaga agcagcagcg tggtccttct 300caccaggcag ccatggtgat ggctctgacg tctccaagaa cctgcgatgt ggtcctgaag 360ctacctgagc tcacagttta caacagagcc atcaggcttc ccctgccact cccttcaagt 420tcagatacac caacctcaac actaccatcc tccaaatgga acgtctttta ccaagcagcc 480ttttcaatca ttgaaaacct taaagctcgt tgttcagttt cacaaaatat gataacaacc 540ttcaatggag ttgagtttaa ctattcaatg cctgcaaatt gctaccacat cttggcacag 600gattgtagtc cagaactgaa gttcctggta atgatgaaaa gacttggaga atctgctgat 660ctcacagcaa taagtgtcag acttgccagc catgaggttg acatgtatgt ttccaatgga 720ctaatccagc tgaagattaa tggtgttcaa accccaacag acgttccata cacatctaag 780tctggtctgc tgataagcag tgagaaggaa ggtttgtcat taaaagcccc tgaatatggt 840gtagaaaaac tatattacga tagacgtaaa cttgagattc gggttgcttt ctggatggtt 900ggaaaaacat gtggtatttg tggaaaatat gatgctgaga agaaaaggga gtatcaaatg 960cccagtggat atttagctaa agatgcagtg agttttgctc agtcctgggt catctcagaa 1020gacacgtgta ctggagcttg caagctgcag aggaaatttg tcaaaattga gaagccggtt 1080gcatttaaca aaaaggcctc aaaatgcttt tccattgagc cagttttacg ctgtgcagaa 1140ggctgttcag caaccaggac tgttcctgtc tctgtgggtt tccactgtgt cccatctgac 1200tccacactcg agctggagga agagcaggtg aggttagacc agaagtctga ggacttggtg 1260agcagggtcg atgcccatac ggcgtgttcc tgcgcccagc agctgtgctc agcg 131413438PRTGallus gallus 13Val Gln Val Phe Val Ser Ser Ile Thr Glu Ser Asp Arg Trp Lys Leu1 5 10 15Cys Ala Asp Ala Ser Val Val Asn Ser His Lys Ala Ser Gly Thr Leu 20 25 30Lys Trp Gly Lys Asp Cys Gln Asp Tyr Gln Val Ala Thr Gln Ile Ala 35 40 45Thr Gly Gln Phe Ala Ala His Pro Ala Ile Gln Val Lys Leu Glu Trp 50 55 60Ser Glu Val Pro Ser Ser Val Arg Lys Thr Ala Arg Trp Phe Tyr Thr65 70 75 80Tyr Leu Pro Gly Ala Ala Tyr Met Leu Gly Tyr Ser Gln Lys Gln Gln 85 90 95Arg Gly Pro Ser His Gln Ala Ala Met Val Met Ala Leu Thr Ser Pro 100 105 110Arg Thr Cys Asp Val Val Leu Lys Leu Pro Glu Leu Thr Val Tyr Asn 115 120 125Arg Ala Ile Arg Leu Pro Leu Pro Leu Pro Ser Ser Ser Asp Thr Pro 130 135 140Thr Ser Thr Leu Pro Ser Ser Lys Trp Asn Val Phe Tyr Gln Ala Ala145 150 155 160Phe Ser Ile Ile Glu Asn Leu Lys Ala Arg Cys Ser Val Ser Gln Asn 165 170 175Met Ile Thr Thr Phe Asn Gly Val Glu Phe Asn Tyr Ser Met Pro Ala 180 185 190Asn Cys Tyr His Ile Leu Ala Gln Asp Cys Ser Pro Glu Leu Lys Phe 195 200 205Leu Val Met Met Lys Arg Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile 210 215 220Ser Val Arg Leu Ala Ser His Glu Val Asp Met Tyr Val Ser Asn Gly225 230 235 240Leu Ile Gln Leu Lys Ile Asn Gly Val Gln Thr Pro Thr Asp Val Pro 245 250 255Tyr Thr Ser Lys Ser Gly Leu Leu Ile Ser Ser Glu Lys Glu Gly Leu 260 265 270Ser Leu Lys Ala Pro Glu Tyr Gly Val Glu Lys Leu Tyr Tyr Asp Arg 275 280 285Arg Lys Leu Glu Ile Arg Val Ala Phe Trp Met Val Gly Lys Thr Cys 290 295 300Gly Ile Cys Gly Lys Tyr Asp Ala Glu Lys Lys Arg Glu Tyr Gln Met305 310 315 320Pro Ser Gly Tyr Leu Ala Lys Asp Ala Val Ser Phe Ala Gln Ser Trp 325 330 335Val Ile Ser Glu Asp Thr Cys Thr Gly Ala Cys Lys Leu Gln Arg Lys 340 345 350Phe Val Lys Ile Glu Lys Pro Val Ala Phe Asn Lys Lys Ala Ser Lys 355 360 365Cys Phe Ser Ile Glu Pro Val Leu Arg Cys Ala Glu Gly Cys Ser Ala 370 375 380Thr Arg Thr Val Pro Val Ser Val Gly Phe His Cys Val Pro Ser Asp385 390 395 400Ser Thr Leu Glu Leu Glu Glu Glu Gln Val Arg Leu Asp Gln Lys Ser 405 410 415Glu Asp Leu Val Ser Arg Val Asp Ala His Thr Ala Cys Ser Cys Ala 420 425 430Gln Gln Leu Cys Ser Ala 435149PRTGallus gallus 14Leu Pro Glu Leu Thr Val Tyr Asn Arg1 51513PRTGallus gallus 15Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile Ser Val Arg1 5 101613PRTGallus gallus 16Val Gln Val Phe Val Ser Ser Ile Thr Glu Ser Asp Arg1 5 1017996DNAGallus gallus 17gacaaacctt ttgcatcagg ttacttgaag atgtttggcc aggagttgct ctttggtaga 60ctcgataaag acaccctcca aaatgtattg caggtatggt atggacctga tgaaaaaatc 120ccttcaataa ggagattaat cagtagcctt caaactggca taggaagaca atggactaag 180gctttactat tgtctgagat tcgttgtatt gtgcctacct gtgttgggtt cccgatggag 240accagcttct attactcttc tgtcacaaaa gtggcaggaa acgttcaagc gcaaattaca 300ccttcaccga ggtctgattt cagattgact gagttactaa attccaacgt taggctgcga 360tccaaaatga gtctaagcat ggctaaacat atgacctttg taattgggat caacacaaac 420atgatccagg cagggctgga agcacacacc aaagtaaatg ctcatgtacc tgtgaatgtt 480gttgccacta ttcaaatgaa ggaaaaaagt atcaaagctg aaattccacc atgcaaagaa 540gagactaact taattattgt aagctctaag acatttgctg ttacacgaaa tattgaagat 600ttggctgcta gtaagatgac tccagttctt ctacctgaag cagtgcctga cataatgaag 660atgtccttcg actcagattc tgcatcaggc gagactgata acatcaggga cagacagtct 720gtagaagatg tttcgtctgg aaattccttc tcctttggac atccttcttc cgggaaggag 780ccatttattc agtccatgtg ctccaacgca agtacatttg gggttcaagt gtgcattgag 840aagaaaagtg tacatgcagc attcatcaga aatgtgcctc tttataacgc tattggagaa 900catgccctta gaatgagctt caagccagtc tactcagatg tacctattga aaaaatacaa 960gtcacaattc aagcaggaga tcaagctcct acaaaa 99618332PRTGallus gallus 18Asp Lys Pro Phe Ala Ser Gly Tyr Leu Lys Met Phe Gly Gln Glu Leu1 5 10 15Leu Phe Gly Arg Leu Asp Lys Asp Thr Leu Gln Asn Val Leu Gln Val 20 25 30Trp Tyr Gly Pro Asp Glu Lys Ile Pro Ser Ile Arg Arg Leu Ile Ser 35 40 45Ser Leu Gln Thr Gly Ile Gly Arg Gln Trp Thr Lys Ala Leu Leu Leu 50 55 60Ser Glu Ile Arg Cys Ile Val Pro Thr Cys Val Gly Phe Pro Met Glu65 70 75 80Thr Ser Phe Tyr Tyr Ser Ser Val Thr Lys Val Ala Gly Asn Val Gln 85 90 95Ala Gln Ile Thr Pro Ser Pro Arg Ser Asp Phe Arg Leu Thr Glu Leu 100 105 110Leu Asn Ser Asn Val Arg Leu Arg Ser Lys Met Ser Leu Ser Met Ala 115 120 125Lys His Met Thr Phe Val Ile Gly Ile Asn Thr Asn Met Ile Gln Ala 130 135 140Gly Leu Glu Ala His Thr Lys Val Asn Ala His Val Pro Val Asn Val145 150 155 160Val Ala Thr Ile Gln Met Lys Glu Lys Ser Ile Lys Ala Glu Ile Pro 165 170 175Pro Cys Lys Glu Glu Thr Asn Leu Ile Ile Val Ser Ser Lys Thr Phe 180 185 190Ala Val Thr Arg Asn Ile Glu Asp Leu Ala Ala Ser Lys Met Thr Pro 195 200 205Val Leu Leu Pro Glu Ala Val Pro Asp Ile Met Lys Met Ser Phe Asp 210 215 220Ser Asp Ser Ala Ser Gly Glu Thr Asp Asn Ile Arg Asp Arg Gln Ser225 230 235 240Val Glu Asp Val Ser Ser Gly Asn Ser Phe Ser Phe Gly His Pro Ser 245 250 255Ser Gly Lys Glu Pro Phe Ile Gln Ser Met Cys Ser Asn Ala Ser Thr 260 265 270Phe Gly Val Gln Val Cys Ile Glu Lys Lys Ser Val His Ala Ala Phe 275 280 285Ile Arg Asn Val Pro Leu Tyr Asn Ala Ile Gly Glu His Ala Leu Arg 290 295 300Met Ser Phe Lys Pro Val Tyr Ser Asp Val Pro Ile Glu Lys Ile Gln305 310 315 320Val Thr Ile Gln Ala Gly Asp Gln Ala Pro Thr Lys 325 3301913PRTGallus gallus 19Ala Gly Asn Val Gln Ala Gln Ile Thr Pro Ser Pro Arg1 5 10208PRTGallus gallus 20Ala Leu Leu Leu Ser Glu Ile Arg1 5218PRTGallus gallus 21Asp Lys Pro Phe Ala Ser Gly Tyr1 52210PRTGallus gallus 22Asp Lys Pro Phe Ala Ser Gly Tyr Leu Lys1 5 102316PRTGallus gallus 23Asp Thr Leu Gln Asn Val Leu Gln Val Trp Tyr Gly Pro Asp Glu Lys1 5 10 152411PRTGallus gallus 24Glu Glu Thr Asn Leu Ile Ile Val Ser Ser Lys1 5 102512PRTGallus gallus 25Gly Asn Val Gln Ala Gln Ile Thr Pro Ser Pro Arg1 5 102610PRTGallus gallus 26Ile Gln Ala Gly Asp Gln Ala Pro Thr Lys1 5 102713PRTGallus gallus 27Ile Gln Val Thr Ile Gln Ala Gly Asp Gln Ala Pro Thr1 5 102814PRTGallus gallus 28Ile Gln Val Thr Ile Gln Ala Gly Asp Gln Ala Pro Thr Lys1 5 102920PRTGallus gallus 29Ile Thr Pro Ser Pro Arg Ser Asp Phe Arg Leu Thr Glu Leu Leu Asn1 5 10 15Ser Asn Val Arg 203012PRTGallus gallus 30Lys Glu Glu Thr Asn Leu Ile Ile Val Ser Ser Lys1 5 103111PRTGallus gallus 31Lys Pro Val Tyr Ser Asp Val Pro Ile Glu Lys1 5 10328PRTGallus gallus 32Leu Asp Lys Asp Thr Leu Gln Asn1 53311PRTGallus gallus 33Leu Asp Lys Asp Thr Leu Gln Asn Val Leu Gln1 5 103419PRTGallus gallus 34Leu Asp Lys Asp Thr Leu Gln Asn Val Leu Gln Val Trp Tyr Gly Pro1 5 10 15Asp Glu Lys3511PRTGallus gallus 35Leu Ile Ser Ser Leu Gln Thr Gly Ile Gly Arg1 5 10368PRTGallus gallus 36Leu Thr Glu Leu Leu Asn Ser Asn1 53710PRTGallus gallus 37Leu Thr Glu Leu Leu Asn Ser Asn Val Arg1 5 10389PRTGallus gallus 38Asn Ile Glu Asp Leu Ala Ala Ser Lys1 53914PRTGallus gallus 39Asn Val Pro Leu Tyr Asn Ala Ile Gly Glu His Ala Leu Arg1 5 104011PRTGallus gallus 40Asn Val Gln Ala Gln Ile Thr Pro Ser Pro Arg1 5 10418PRTGallus gallus 41Pro Ser Ser Gly Lys Glu Pro Phe1 54210PRTGallus gallus 42Pro Val Tyr Ser Asp Val Pro Ile Glu Lys1 5 104312PRTGallus gallus 43Arg Leu Ile Ser Ser Leu Gln Thr Gly Ile Gly Arg1 5 10448PRTGallus gallus 44Ser Val His Ala Ala Phe Ile Arg1 54510PRTGallus gallus 45Val Gln Ala Gln Ile Thr Pro Ser Pro Arg1 5 10461023DNAGallus gallus 46ggtccttctc accaggcagc catggtgatg gctctgacgt ctccaagaac ctgcgatgtg 60gtcctgaagc tacctgagct cacagtttac aacagagcca tcaggcttcc cctgccactc 120ccttcaagtt cagatacacc aacctcaaca ctaccatcct ccaaatggaa cgtcttttac 180caagcagcct tttcaatcat tgaaaacctt aaagctcgtt gttcagtttc acaaaatatg 240ataacaacct tcaatggagt tgagtttaac tattcaatgc ctgcaaattg ctaccacatc 300ttggcacagg attgtagtcc agaactgaag ttcctggtaa tgatgaaaag acttggagaa 360tctgctgatc tcacagcaat aagtgtcaga cttgccagcc atgaggttga catgtatgtt 420tccaatggac taatccagct gaagattaat ggtgttcaaa ccccaacaga cgttccatac 480acatctaagt ctggtctgct gataagcagt gagaaggaag gtttgtcatt aaaagcccct 540gaatatggtg tagaaaaact atattacgat agacgtaaac ttgagattcg ggttgctttc 600tggatggttg gaaaaacatg tggtatttgt ggaaaatatg atgctgagaa gaaaagggag 660tatcaaatgc ccagtggata tttagctaaa gatgcagtga gttttgctca gtcctgggtc 720atctcagaag acacgtgtac tggagcttgc aagctgcaga ggaaatttgt caaaattgag 780aagccggttg catttaacaa aaaggcctca aaatgctttt ccattgagcc agttttacgc 840tgtgcagaag gctgttcagc aaccaggact gttcctgtct ctgtgggttt ccactgtgtc 900ccatctgact ccacactcga gctggaggaa gagcaggtga ggttagacca gaagtctgag 960gacttggtga gcagggtcga tgcccatacg gcgtgttcct gcgcccagca gctgtgctca 1020gcg 102347341PRTGallus gallus 47Gly Pro Ser His Gln Ala Ala Met Val Met Ala Leu Thr Ser Pro Arg1 5 10 15Thr Cys Asp Val Val Leu Lys Leu Pro Glu Leu Thr Val Tyr Asn Arg 20 25 30Ala Ile Arg Leu Pro Leu Pro Leu Pro Ser Ser Ser Asp Thr Pro Thr 35 40 45Ser Thr Leu Pro Ser Ser Lys Trp Asn Val Phe Tyr Gln Ala Ala Phe 50 55 60Ser Ile Ile Glu Asn Leu Lys Ala Arg Cys Ser Val Ser Gln Asn Met65 70 75 80Ile Thr Thr Phe Asn Gly Val Glu Phe Asn Tyr Ser Met Pro Ala Asn 85 90 95Cys Tyr His Ile Leu Ala Gln Asp Cys Ser Pro Glu Leu Lys Phe Leu 100 105 110Val Met Met Lys Arg Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile Ser 115 120 125Val Arg Leu Ala Ser His Glu Val Asp Met Tyr Val Ser Asn Gly Leu 130 135 140Ile Gln Leu Lys Ile Asn Gly Val Gln Thr Pro Thr Asp Val Pro Tyr145 150 155 160Thr Ser Lys Ser Gly Leu Leu Ile Ser Ser Glu Lys Glu Gly Leu Ser 165 170

175Leu Lys Ala Pro Glu Tyr Gly Val Glu Lys Leu Tyr Tyr Asp Arg Arg 180 185 190Lys Leu Glu Ile Arg Val Ala Phe Trp Met Val Gly Lys Thr Cys Gly 195 200 205Ile Cys Gly Lys Tyr Asp Ala Glu Lys Lys Arg Glu Tyr Gln Met Pro 210 215 220Ser Gly Tyr Leu Ala Lys Asp Ala Val Ser Phe Ala Gln Ser Trp Val225 230 235 240Ile Ser Glu Asp Thr Cys Thr Gly Ala Cys Lys Leu Gln Arg Lys Phe 245 250 255Val Lys Ile Glu Lys Pro Val Ala Phe Asn Lys Lys Ala Ser Lys Cys 260 265 270Phe Ser Ile Glu Pro Val Leu Arg Cys Ala Glu Gly Cys Ser Ala Thr 275 280 285Arg Thr Val Pro Val Ser Val Gly Phe His Cys Val Pro Ser Asp Ser 290 295 300Thr Leu Glu Leu Glu Glu Glu Gln Val Arg Leu Asp Gln Lys Ser Glu305 310 315 320Asp Leu Val Ser Arg Val Asp Ala His Thr Ala Cys Ser Cys Ala Gln 325 330 335Gln Leu Cys Ser Ala 340488PRTGallus gallus 48Ala Pro Glu Tyr Gly Val Glu Lys1 5497PRTGallus gallus 49Ile Glu Lys Pro Val Ala Phe1 55015PRTGallus gallus 50Ile Asn Gly Val Gln Thr Pro Thr Asp Val Pro Tyr Thr Ser Lys1 5 10 155113PRTGallus gallus 51Leu Gly Glu Ser Ala Asp Leu Thr Ala Ile Ser Val Arg1 5 10529PRTGallus gallus 52Leu Pro Glu Leu Thr Val Tyr Asn Arg1 55316PRTGallus gallus 53Leu Pro Leu Pro Leu Pro Ser Ser Ser Asp Thr Pro Thr Ser Thr Leu1 5 10 155412PRTGallus gallus 54Pro Ser Asp Ser Thr Leu Glu Leu Glu Glu Glu Gln1 5 10559PRTGallus gallus 55Ser Gly Leu Leu Ile Ser Ser Glu Lys1 5567PRTGallus gallus 56Ser Ile Glu Pro Val Leu Arg1 5579PRTGallus gallus 57Thr Val Pro Val Ser Val Gly Phe His1 5583363DNAGallus gallus 58atgaggggga tcatactggc attagtgctc acccttgtag gcagccagaa gtttgacatt 60gacccaggat tcaatagcag aaggagttac ctgtacaact atgaaggttc tatgttgaat 120gggcttcaag acagaagttt gggcaaagct ggtgtgcgct tgagcagcaa gctagagatc 180agtgggctac cagagaatgc ttacctcctc aaggtccgct ctccacaagt ggaggagtac 240aatggggtct ggcccaggga tcccttcact cgatcttcca aaatcaccca agtgatctca 300tcgtgtttca cccggctctt caaatttgaa tacagcagtg gacggatcgg aaacatttat 360gccccagaag actgcccaga tctgtgtgtt aacatagtga gaggaatatt gaacatgttc 420cagatgacca ttaaaaaatc acagaacgtc tacgaattac aagaggctgg aattggaggt 480atttgtcatg caaggtatgt cattcaggaa gacaggaaga atagccgaat ctatgttacc 540agaactgtgg acttgaataa ttgccaggaa aaggtgcaaa aaagcattgg aatggcttac 600atctatccct gccctgtgga cgtgatgaaa gaaaggctca ccaaagggac caccgctttc 660tcctacaagc tgaagcagtc agacagcggc acgctgatca cagatgtctc gtcgcggcag 720gtgtatcaga tctccccatt caatgagccc actggggtgg ctgtcatgga agcaagacag 780cagctcactt tggtcgaggt gagaagtgag cggggcagtg ccccagatgt ccccatgcag 840aactatggca gccttcgcta ccgcttccca gccgtactgc cacagatgcc acttcagctg 900atcaagacaa aaaaccctga gcaacggata gtagaaacgc tgcagcacat agtcctgaat 960aaccaacaag atttccatga cgatgtttca tacagattct tagaggtggt ccagctttgc 1020cggatagcaa atgctgacaa tcttgagtct atctggagac aagtttcaga taaacctcgt 1080tacaggcgat ggctcctgag cgcagtttct gcgagtggca ccacagaaac actaaaattc 1140cttaagaaca gaattcgcaa tgatgacctc aactacattc agacccttct aactgtttct 1200ttgactcttc atttattgca agctgatgaa cacacacttc caatagcagc agatttaatg 1260accagctctc gaattcagaa aaatcctgtg cttcagcaag tggcctgctt gggatatagc 1320tctgtagtca acagatactg ctctcagacc tcagcatgtc ctaaggaagc tcttcagccc 1380atccatgacc tggcagatga agcaatcagc aggggccgtg aagacaaaat gaaattagct 1440ctaaagtgca ttggtaacat gggagaacca gccagcttaa agcgcatcct gaagttcctt 1500ccaatatctt catccagtgc tgctgatatc ccagtccaca ttcagataga tgccataacg 1560gccttgaaaa agatagcttg gaaggacccc aaaacagtgc agggctatct catccagatc 1620cttgcagacc aatcacttcc ccctgaggtg cgaatgatgg cttgtgctgt tatctttgag 1680acaaggcctg cccttgcttt gataacgact atagctaacg tggcaatgaa ggagagcaat 1740atgcaagtgg ccagttttgt atattcccac atgaagtctt tgtcaaagag cagattgcca 1800tttatgtaca acatatcttc cgcttgtaac attgccctta agctcctgtc ccccaaactg 1860gacagtatga gctatcggta cagcaaggtc attcgagcag acacttactt tgataactat 1920agagttggtg ctactggaga aatctttgtt gtgaacagcc caagaactat gttcccatca 1980gcaataattt ccaaattgat ggcaaattct gcaggttcag tggctgatct ggtagaggtt 2040ggcatccgag tggaaggcct cgcagatgtc ataatgaaaa gaaacatccc atttgctgaa 2100tatcccacat acaagcagat aaaggagctt ggaaaagctc tgcagggatg gaaagagctg 2160ccgacagaaa cccctttggt atcagcctac ttgaaaatac ttggccaaga agtggccttc 2220atcaacatca acaaggaact cctgcaacag gtcatgaaga ctgtagtgga acctgctgat 2280cgaaacgcag caataaagag aatcgccaac cagatccgca acagcattgc agggcagtgg 2340acgcagccgg tgtggatggg agagctgcga tacgtggttc ccagctgtct cggcctgccg 2400ctggagtacg ggtcctacac caccgccctg gcacgagctg cagtcagcgt tgagggaaag 2460atgacgccgc ctttaaccgg agatttcaga ctttctcagt tgcttgaatc caccatgcag 2520attcggtctg acttaaagcc cagtttatat gtgcatacag ttgcaacgat gggtgtcaac 2580acagaatact ttcaacatgc tgttgaaatt caaggcgagg tccagacaag aatgccaatg 2640aagtttgatg ccaagataga tgtgaaattg aaaaacctta agattgaaac gaacccatgc 2700cgtgaggaaa ctgagatagt ggttggaaga cataaggctt ttgctgtatc aaggaacata 2760ggagaactag gtgttgaaaa gaggacctca attctgccgg aagatgctcc attagatgtt 2820acagaagaac ctttccaaac atcagagaga gcttccaggg aacacttcgc aatgcaaggg 2880cctgacagca tgccaaggaa acagtcccat agttctcgag aagatcttcg ccgtagcaca 2940ggaaaaagag cacataaacg agacatttgc ctcaaaatgc atcatattgg ttgccagctt 3000tgcttttcca gaaggtcaag agatgccagt ttcatacaga atacgtattt gcacaaatta 3060attggagaac atgaagctaa aatagttttg atgccagttc atacagatgc tgatattgac 3120aaaattcagc tggagattca ggcaggatct agagcagctg ccagaataat tactgaggta 3180aacccagagt ctgaggaaga ggatgaatca tctccatatg aggacattca agctaaactg 3240aagaggattc taggcattga cagtatgttc aaggttgcaa acaaaacacg gcacccgaaa 3300aatcgaccat ctaagaaagg aaacactgtg ctagcagagt ttgggacaga gcctgatgca 3360aaa 3363591121PRTGallus gallus 59Met Arg Gly Ile Ile Leu Ala Leu Val Leu Thr Leu Val Gly Ser Gln1 5 10 15Lys Phe Asp Ile Asp Pro Gly Phe Asn Ser Arg Arg Ser Tyr Leu Tyr 20 25 30Asn Tyr Glu Gly Ser Met Leu Asn Gly Leu Gln Asp Arg Ser Leu Gly 35 40 45Lys Ala Gly Val Arg Leu Ser Ser Lys Leu Glu Ile Ser Gly Leu Pro 50 55 60Glu Asn Ala Tyr Leu Leu Lys Val Arg Ser Pro Gln Val Glu Glu Tyr65 70 75 80Asn Gly Val Trp Pro Arg Asp Pro Phe Thr Arg Ser Ser Lys Ile Thr 85 90 95Gln Val Ile Ser Ser Cys Phe Thr Arg Leu Phe Lys Phe Glu Tyr Ser 100 105 110Ser Gly Arg Ile Gly Asn Ile Tyr Ala Pro Glu Asp Cys Pro Asp Leu 115 120 125Cys Val Asn Ile Val Arg Gly Ile Leu Asn Met Phe Gln Met Thr Ile 130 135 140Lys Lys Ser Gln Asn Val Tyr Glu Leu Gln Glu Ala Gly Ile Gly Gly145 150 155 160Ile Cys His Ala Arg Tyr Val Ile Gln Glu Asp Arg Lys Asn Ser Arg 165 170 175Ile Tyr Val Thr Arg Thr Val Asp Leu Asn Asn Cys Gln Glu Lys Val 180 185 190Gln Lys Ser Ile Gly Met Ala Tyr Ile Tyr Pro Cys Pro Val Asp Val 195 200 205Met Lys Glu Arg Leu Thr Lys Gly Thr Thr Ala Phe Ser Tyr Lys Leu 210 215 220Lys Gln Ser Asp Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg Gln225 230 235 240Val Tyr Gln Ile Ser Pro Phe Asn Glu Pro Thr Gly Val Ala Val Met 245 250 255Glu Ala Arg Gln Gln Leu Thr Leu Val Glu Val Arg Ser Glu Arg Gly 260 265 270Ser Ala Pro Asp Val Pro Met Gln Asn Tyr Gly Ser Leu Arg Tyr Arg 275 280 285Phe Pro Ala Val Leu Pro Gln Met Pro Leu Gln Leu Ile Lys Thr Lys 290 295 300Asn Pro Glu Gln Arg Ile Ile Glu Thr Leu Gln His Ile Val Leu Asn305 310 315 320Asn Gln Gln Asp Phe His Asp Asp Val Ser Tyr Arg Phe Leu Glu Val 325 330 335Val Gln Leu Cys Arg Ile Ala Asn Ala Asp Asn Leu Glu Ser Ile Trp 340 345 350Arg Gln Val Ser Asp Lys Pro Arg Tyr Arg Arg Trp Leu Leu Ser Ala 355 360 365Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys Phe Leu Lys Asn Arg 370 375 380Ile Arg Asn Asp Asp Leu Asn Tyr Ile Gln Thr Leu Leu Thr Val Ser385 390 395 400Leu Thr Leu His Leu Leu Gln Ala Asp Glu His Thr Leu Pro Ile Ala 405 410 415Ala Asp Leu Met Thr Ser Ser Arg Ile Gln Lys Asn Pro Val Leu Gln 420 425 430Gln Val Ala Cys Leu Gly Tyr Ser Ser Val Val Asn Arg Tyr Cys Ser 435 440 445Gln Thr Ser Ala Cys Pro Lys Glu Ala Leu Gln Pro Ile His Asp Leu 450 455 460Ala Asp Glu Ala Ile Ser Arg Gly Arg Glu Asp Lys Met Lys Leu Ala465 470 475 480Leu Lys Cys Ile Gly Asn Met Gly Glu Pro Ala Ser Leu Lys Arg Ile 485 490 495Leu Lys Phe Leu Pro Ile Ser Ser Ser Ser Ala Ala Asp Ile Pro Val 500 505 510His Ile Gln Ile Asp Ala Ile Thr Ala Leu Lys Lys Ile Ala Trp Lys 515 520 525Asp Pro Lys Thr Val Gln Gly Tyr Leu Ile Gln Ile Leu Ala Asp Gln 530 535 540Ser Leu Pro Pro Glu Val Arg Met Met Ala Cys Ala Val Ile Phe Glu545 550 555 560Thr Arg Pro Ala Leu Ala Leu Ile Thr Thr Ile Ala Asn Val Ala Met 565 570 575Lys Glu Ser Asn Met Gln Val Ala Ser Phe Val Tyr Ser His Met Lys 580 585 590Ser Leu Ser Lys Ser Arg Leu Pro Phe Met Tyr Asn Ile Ser Ser Ala 595 600 605Cys Asn Ile Ala Leu Lys Leu Leu Ser Pro Lys Leu Asp Ser Met Ser 610 615 620Tyr Arg Tyr Ser Lys Val Ile Arg Ala Asp Thr Tyr Phe Asp Asn Tyr625 630 635 640Arg Val Gly Ala Thr Gly Glu Ile Phe Val Val Asn Ser Pro Arg Thr 645 650 655Met Phe Pro Ser Ala Ile Ile Ser Lys Leu Met Ala Asn Ser Ala Gly 660 665 670Ser Val Ala Asp Leu Val Glu Val Gly Ile Arg Val Glu Gly Leu Ala 675 680 685Asp Val Ile Met Lys Arg Asn Ile Pro Phe Ala Glu Tyr Pro Thr Tyr 690 695 700Lys Gln Ile Lys Glu Leu Gly Lys Ala Leu Gln Gly Trp Lys Glu Leu705 710 715 720Pro Thr Glu Thr Pro Leu Val Ser Ala Tyr Leu Lys Ile Leu Gly Gln 725 730 735Glu Val Ala Phe Ile Asn Ile Asn Lys Glu Leu Leu Gln Gln Val Met 740 745 750Lys Thr Val Val Glu Pro Ala Asp Arg Asn Ala Ala Ile Lys Arg Ile 755 760 765Ala Asn Gln Ile Arg Asn Ser Ile Ala Gly Gln Trp Thr Gln Pro Val 770 775 780Trp Met Gly Glu Leu Arg Tyr Val Val Pro Ser Cys Leu Gly Leu Pro785 790 795 800Leu Glu Tyr Gly Ser Tyr Thr Thr Ala Leu Ala Arg Ala Ala Val Ser 805 810 815Val Glu Gly Lys Met Thr Pro Pro Leu Thr Gly Asp Phe Arg Leu Ser 820 825 830Gln Leu Leu Glu Ser Thr Met Gln Ile Arg Ser Asp Leu Lys Pro Ser 835 840 845Leu Tyr Val His Thr Val Ala Thr Met Gly Val Asn Thr Glu Tyr Phe 850 855 860Gln His Ala Val Glu Ile Gln Gly Glu Val Gln Thr Arg Met Pro Met865 870 875 880Lys Phe Asp Ala Lys Ile Asp Val Lys Leu Lys Asn Leu Lys Ile Glu 885 890 895Thr Asn Pro Cys Arg Glu Glu Thr Glu Ile Val Val Gly Arg His Lys 900 905 910Ala Phe Ala Val Ser Arg Asn Ile Gly Glu Leu Gly Val Glu Lys Arg 915 920 925Thr Ser Ile Leu Pro Glu Asp Ala Pro Leu Asp Val Thr Glu Glu Pro 930 935 940Phe Gln Thr Ser Glu Arg Ala Ser Arg Glu His Phe Ala Met Gln Gly945 950 955 960Pro Asp Ser Met Pro Arg Lys Gln Ser His Ser Ser Arg Glu Asp Leu 965 970 975Arg Arg Ser Thr Gly Lys Arg Ala His Lys Arg Asp Ile Cys Leu Lys 980 985 990Met His His Ile Gly Cys Gln Leu Cys Phe Ser Arg Arg Ser Arg Asp 995 1000 1005Ala Ser Phe Ile Gln Asn Thr Tyr Leu His Lys Leu Ile Gly Glu 1010 1015 1020His Glu Ala Lys Ile Val Leu Met Pro Val His Thr Asp Ala Asp 1025 1030 1035Ile Asp Lys Ile Gln Leu Glu Ile Gln Ala Gly Ser Arg Ala Ala 1040 1045 1050Ala Arg Ile Ile Thr Glu Val Asn Pro Glu Ser Glu Glu Glu Asp 1055 1060 1065Glu Ser Ser Pro Tyr Glu Asp Ile Gln Ala Lys Leu Lys Arg Ile 1070 1075 1080Leu Gly Ile Asp Ser Met Phe Lys Val Ala Asn Lys Thr Arg His 1085 1090 1095Pro Lys Asn Arg Pro Ser Lys Lys Gly Asn Thr Val Leu Ala Glu 1100 1105 1110Phe Gly Thr Glu Pro Asp Ala Lys 1115 11206010PRTGallus gallus 60Ala Asp Gln Ser Leu Pro Pro Glu Val Arg1 5 10619PRTGallus gallus 61Ala Asp Thr Tyr Phe Asp Asn Tyr Arg1 5627PRTGallus gallus 62Ala Val Ile Phe Glu Thr Arg1 56312PRTGallus gallus 63Asp Ala Ser Phe Ile Gln Asn Thr Tyr Leu His Lys1 5 10649PRTGallus gallus 64Asp Leu Ala Asp Glu Ala Ile Ser Arg1 56516PRTGallus gallus 65Glu Ala Leu Gln Pro Ile His Asp Leu Ala Asp Glu Ala Ile Ser Arg1 5 10 15669PRTGallus gallus 66Glu Glu Thr Glu Ile Val Val Gly Arg1 5679PRTGallus gallus 67Glu Ile Phe Val Val Asn Ser Pro Arg1 56814PRTGallus gallus 68Glu Leu Pro Thr Glu Thr Pro Leu Val Ser Ala Tyr Leu Lys1 5 106910PRTGallus gallus 69Phe Asp Ile Asp Pro Gly Phe Asn Ser Arg1 5 10707PRTGallus gallus 70Phe Glu Tyr Ser Ser Gly Arg1 57125PRTGallus gallus 71Phe Leu Pro Ile Ser Ser Ser Ser Ala Ala Asp Ile Pro Val His Ile1 5 10 15Gln Ile Asp Ala Ile Thr Ala Leu Lys 20 25728PRTGallus gallus 72Gly Tyr Ser Ser Val Val Asn Arg1 57312PRTGallus gallus 73Ile Ala Asn Ala Asp Asn Leu Glu Ser Ile Trp Arg1 5 10748PRTGallus gallus 74Ile Asp Ala Ile Thr Ala Leu Lys1 57524PRTGallus gallus 75Ile Ile Thr Glu Val Asn Pro Glu Ser Glu Glu Glu Asp Glu Ser Ser1 5 10 15Pro Tyr Glu Asp Ile Gln Ala Lys 207612PRTGallus gallus 76Ile Leu Ala Asp Gln Ser Leu Pro Pro Glu Val Arg1 5 107713PRTGallus gallus 77Ile Leu Gly Gln Glu Val Ala Phe Ile Asn Ile Asn Lys1 5 107810PRTGallus gallus 78Ile Gln Leu Glu Ile Gln Ala Gly Ser Arg1 5 107913PRTGallus gallus 79Ile Arg Asn Asp Asp Leu Asn Tyr Ile Gln Thr Leu Leu1 5 10808PRTGallus gallus 80Leu Ala Asp Glu Ala Ile Ser Arg1 58114PRTGallus gallus 81Leu Glu Ile Ser Gly Leu Pro Glu Asn Ala Tyr Leu Leu Lys1 5 10829PRTGallus gallus 82Leu Gly Tyr Ser Ser Val Val Asn Arg1 58315PRTGallus gallus 83Leu Ile Gln Ile Leu Ala Asp Gln Ser Leu Pro Pro Glu Val Arg1 5 10 158416PRTGallus gallus 84Leu Lys Gln Ser Asp Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg1 5 10 158515PRTGallus gallus 85Leu Leu Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 10 158614PRTGallus gallus 86Leu Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 108711PRTGallus gallus 87Asn Ile Pro Phe Ala Glu Tyr Pro Thr Tyr Lys1 5 108811PRTGallus gallus 88Pro Ala Leu Ala Leu Ile Thr Thr Ile Ala Asn1 5 10898PRTGallus gallus 89Pro Pro Leu Thr Gly Asp Phe Arg1 5909PRTGallus gallus 90Gln Gln Leu Thr Leu Val Glu Val Arg1 59114PRTGallus gallus 91Gln Ser Asp Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg1 5 109212PRTGallus gallus 92Arg Asn Ile Pro Phe Ala Glu Tyr Pro Thr Tyr Lys1 5 109314PRTGallus gallus 93Ser Ala Gly Ser Val Ala Asp Leu Val Glu Val Gly Ile Arg1 5

109413PRTGallus gallus 94Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 10958PRTGallus gallus 95Ser Asp Leu Lys Pro Ser Leu Tyr1 59611PRTGallus gallus 96Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg1 5 109713PRTGallus gallus 97Ser Pro Gln Val Glu Glu Tyr Asn Gly Val Trp Pro Arg1 5 109822PRTGallus gallus 98Thr Ser Ile Leu Pro Glu Asp Ala Pro Leu Asp Val Thr Glu Glu Pro1 5 10 15Phe Gln Thr Ser Glu Arg 209920PRTGallus gallus 99Thr Val Gln Gly Tyr Leu Ile Gln Ile Leu Ala Asp Gln Ser Leu Pro1 5 10 15Pro Glu Val Arg 201008PRTGallus gallus 100Thr Val Val Glu Pro Ala Asp Arg1 510114PRTGallus gallus 101Val Gly Ala Thr Gly Glu Ile Phe Val Val Asn Ser Pro Arg1 5 1010211PRTGallus gallus 102Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 1010316PRTGallus gallus 103Trp Leu Leu Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 10 151048PRTGallus gallus 104Tyr Val Ile Gln Glu Asp Arg Lys1 51055550DNAGallus gallus 105atgaggggga tcatactggc attagtgctc acccttgtag gcagccagaa gtttgacatt 60gacccaggat tcaatagcag aaggagttac ctgtacaact atgaaggttc tatgttgaat 120gggcttcaag acagaagttt gggcaaagct ggtgtgcgct tgagcagcaa gctagagatc 180agtgggctac cagagaatgc ttacctcctc aaggtccgct ctccacaagt ggaggagtac 240aatggggtct ggcccaggga tcccttcact cgatcttcca aaatcaccca agtgatctca 300tcgtgtttca cccggctctt caaatttgaa tacagcagtg gacggatcgg aaacatttat 360gccccagaag actgcccaga tctgtgtgtt aacatagtga gaggaatatt gaacatgttc 420cagatgacca ttaaaaaatc acagaacgtc tacgaattac aagaggctgg aattggaggt 480atttgtcatg caaggtatgt cattcaggaa gacaggaaga atagccgaat ctatgttacc 540agaactgtgg acttgaataa ttgccaggaa aaggtgcaaa aaagcattgg aatggcttac 600atctatccct gccctgtgga cgtgatgaaa gaaaggctca ccaaagggac caccgctttc 660tcctacaagc tgaagcagtc agacagcggc acgctgatca cagatgtctc gtcgcggcag 720gtgtatcaga tctccccatt caatgagccc actggggtgg ctgtcatgga agcaagacag 780cagctcactt tggtcgaggt gagaagtgag cggggcagtg ccccagatgt ccccatgcag 840aactatggca gccttcgcta ccgcttccca gccgtactgc cacagatgcc acttcagctg 900atcaagacaa aaaaccctga gcaacggata gtagaaacgc tgcagcacat agtcctgaat 960aaccaacaag atttccatga cgatgtttca tacagattct tagaggtggt ccagctttgc 1020cggatagcaa atgctgacaa tcttgagtct atctggagac aagtttcaga taaacctcgt 1080tacaggcgat ggctcctgag cgcagtttct gcgagtggca ccacagaaac actaaaattc 1140cttaagaaca gaattcgcaa tgatgacctc aactacattc agacccttct aactgtttct 1200ttgactcttc atttattgca agctgatgaa cacacacttc caatagcagc agatttaatg 1260accagctctc gaattcagaa aaatcctgtg cttcagcaag tggcctgctt gggatatagc 1320tctgtagtca acagatactg ctctcagacc tcagcatgtc ctaaggaagc tcttcagccc 1380atccatgacc tggcagatga agcaatcagc aggggccgtg aagacaaaat gaaattagct 1440ctaaagtgca ttggtaacat gggagaacca gccagcttaa agcgcatcct gaagttcctt 1500ccaatatctt catccagtgc tgctgatatc ccagtccaca ttcagataga tgccataacg 1560gccttgaaaa agatagcttg gaaggacccc aaaacagtgc agggctatct catccagatc 1620cttgcagacc aatcacttcc ccctgaggtg cgaatgatgg cttgtgctgt tatctttgag 1680acaaggcctg cccttgcttt gataacgact atagctaacg tggcaatgaa ggagagcaat 1740atgcaagtgg ccagttttgt atattcccac atgaagtctt tgtcaaagag cagattgcca 1800tttatgtaca acatatcttc cgcttgtaac attgccctta agctcctgtc ccccaaactg 1860gacagtatga gctatcggta cagcaaggtc attcgagcag acacttactt tgataactat 1920agagttggtg ctactggaga aatctttgtt gtgaacagcc caagaactat gttcccatca 1980gcaataattt ccaaattgat ggcaaattct gcaggttcag tggctgatct ggtagaggtt 2040ggcatccgag tggaaggcct cgcagatgtc ataatgaaaa gaaacatccc atttgctgaa 2100tatcccacat acaagcagat aaaggagctt ggaaaagctc tgcagggatg gaaagagctg 2160ccgacagaaa cccctttggt atcagcctac ttgaaaatac ttggccaaga agtggccttc 2220atcaacatca acaaggaact cctgcaacag gtcatgaaga ctgtagtgga acctgctgat 2280cgaaacgcag caataaagag aatcgccaac cagatccgca acagcattgc agggcagtgg 2340acgcagccgg tgtggatggg agagctgcga tacgtggttc ccagctgtct cggcctgccg 2400ctggagtacg ggtcctacac caccgccctg gcacgagctg cagtcagcgt tgagggaaag 2460atgacgccgc ctttaaccgg agatttcaga ctttctcagt tgcttgaatc caccatgcag 2520attcggtctg acttaaagcc cagtttatat gtgcatacag ttgcaacgat gggtgtcaac 2580acagaatact ttcaacatgc tgttgaaatt caaggcgagg tccagacaag aatgccaatg 2640aagtttgatg ccaagataga tgtgaaattg aaaaacctta agattgaaac gaacccatgc 2700cgtgaggaaa ctgagatagt ggttggaaga cataaggctt ttgctgtatc aaggaacata 2760ggagaactag gtgttgaaaa gaggacctca attctgccgg aagatgctcc attagatgtt 2820acagaagaac ctttccaaac atcagagaga gcttccaggg aacacttcgc aatgcaaggg 2880cctgacagca tgccaaggaa acagtcccat agttctcgag aagatcttcg ccgtagcaca 2940ggaaaaagag cacataaacg agacatttgc ctcaaaatgc atcatattgg ttgccagctt 3000tgcttttcca gaaggtcaag agatgccagt ttcatacaga atacgtattt gcacaaatta 3060attggagaac atgaagctaa aatagttttg atgccagttc atacagatgc tgatattgac 3120aaaattcagc tggagattca ggcaggatct agagcagctg ccagaataat tactgaggta 3180aacccagagt ctgaggaaga ggatgaatca tctccatatg aggacattca agctaaactg 3240aagaggattc taggcattga cagtatgttc aaggttgcaa acaaaacacg gcacccgaaa 3300aatcgaccat ctaagaaagg aaacactgtg ctagcagagt ttgggacaga gcctgatgca 3360aaaacttcct ccagctcatc ttctgcctcc tcaactgcca cctcttcttc ctcatcatct 3420gcctcctctc ctaatcgtaa aaagcctatg gatgaagagg agaatgatca agtaaagcaa 3480gcaagaaaca aagatgcaag cagcagcagc aggagcagca agagcagtaa cagcagcaag 3540agaagcagca gcaagagcag taacagcagc aagagaagca gcagcagcag tagcagtagc 3600agtagcagca gcaggagcag cagcagtagc agcagtagta gcagtaacag caagagcagc 3660agtagcagca gcaagagcag cagtagcagc agcaggagca gaagcagcag caagagcagc 3720agtagcagca gcagcagtag cagcagcagc agcagcaaaa gtagcagtag taggagcagt 3780agcagcagca gcaagtcaag cagtcaccat agccatagcc atcattcagg gcatctaaat 3840ggcagcagca gcagcagcag cagcagcagg tcagtgagtc accacagcca tgagcatcac 3900tcaggacatc tggaagatga cagcagtagc agcagcagca gcagcgtgct ttccaaaata 3960tgggggcgtc atgagattta tcagtatcgc tttagatcag cacacagaca agagttcccc 4020aaaagaaaac tcccaggtga ccgcgctacc agcagatact cctctaccag atccagccat 4080gacacatccc gagctgcttc ctggcctaag tttctgggtg acatcaaaac cccagtgtta 4140gctgcttttc tccatggcat tagtaacaat aagaagacag gaggcctcca gcttgtggta 4200tatgctgata ccgactcggt caggccgcgg gtgcaggtat ttgtgacaaa cctcacagat 4260tcgagcaagt ggaagctctg cgcagatgct tcggtccgca atgctcacaa ggcagtggcc 4320tacgtgaaat ggggctggga ctgccgggac tacaaggttt ctactgagct ggtaactggg 4380cggtttgctg ggcaccctgc tgcacaagtg aagctggagt ggcccaaggt tccttcgaat 4440gtcagatcag tggttgaatg gttttacgag tttgtccctg gggctgcatt tatgctgggt 4500ttctctgaga gaatggacaa gaatccttct cgacaagcca ggatggttgt ggctctaact 4560tctccgagga catgtgatgt tgttgtcaag ctgcctgata taatcctcta tcaaaaagcc 4620gtgaggcttc ctctatcact ccctgtgggt ccaaggatcc cagcttcaga gctgcagcct 4680ccaatctgga acgtctttgc tgaagccccc tctgccgtgc tcgagaattt gaaagctcgc 4740tgctcagttt cgtacaacaa gatcaaaacc tttaatgaag tcaagttcaa ctactcgatg 4800cccgcaaact gctatcacat cttggttcag gattgcagct ctgaacttaa gttcctggtg 4860atgatgaaaa gtgctggaga agctacaaac cttaaagcca tcaacatcaa gattggcagt 4920catgaaattg atatgcatcc tgtgaatgga caggtgaaac tgctggtaga tggggctgag 4980agccccacag ccaacatttc cctcatatct gctggtgctt ctctgtggat tcacaatgaa 5040aaccaagggt ttgcacttgc tgccccaggc catggtatcg ataaattgta cttcgatgga 5100aaaacaatca cgattcaagt tcctttatgg atggcaggga aaacatgtgg aatctgtgga 5160aaatatgatg cagaatgcga acaggagtat cggatgccca atggatatct agctaaaaat 5220gccgtgagct ttggtcattc ttggatcttg gaagaagcgc cctgtagagg agcttgtaaa 5280ctgcatcgtt cattcgtgaa gcttgagaag acggttcagc tggcgggtgt tgattccaag 5340tgctactcta cagagcctgt gctgcgctgt gcaaagggat gctctgctac caagacaact 5400ccagtaactg ttggcttcca ctgcctccca gctgattcag ctaacagcct aactgacaaa 5460cagatgaagt acgaccagaa gtcagaagac atgcaggata ctgttgatgc acacacaacg 5520tgttcatgtg agaatgagga atgcagtaca 55501061850PRTGallus gallus 106Met Arg Gly Ile Ile Leu Ala Leu Val Leu Thr Leu Val Gly Ser Gln1 5 10 15Lys Phe Asp Ile Asp Pro Gly Phe Asn Ser Arg Arg Ser Tyr Leu Tyr 20 25 30Asn Tyr Glu Gly Ser Met Leu Asn Gly Leu Gln Asp Arg Ser Leu Gly 35 40 45Lys Ala Gly Val Arg Leu Ser Ser Lys Leu Glu Ile Ser Gly Leu Pro 50 55 60Glu Asn Ala Tyr Leu Leu Lys Val Arg Ser Pro Gln Val Glu Glu Tyr65 70 75 80Asn Gly Val Trp Pro Arg Asp Pro Phe Thr Arg Ser Ser Lys Ile Thr 85 90 95Gln Val Ile Ser Ser Cys Phe Thr Arg Leu Phe Lys Phe Glu Tyr Ser 100 105 110Ser Gly Arg Ile Gly Asn Ile Tyr Ala Pro Glu Asp Cys Pro Asp Leu 115 120 125Cys Val Asn Ile Val Arg Gly Ile Leu Asn Met Phe Gln Met Thr Ile 130 135 140Lys Lys Ser Gln Asn Val Tyr Glu Leu Gln Glu Ala Gly Ile Gly Gly145 150 155 160Ile Cys His Ala Arg Tyr Val Ile Gln Glu Asp Arg Lys Asn Ser Arg 165 170 175Ile Tyr Val Thr Arg Thr Val Asp Leu Asn Asn Cys Gln Glu Lys Val 180 185 190Gln Lys Ser Ile Gly Met Ala Tyr Ile Tyr Pro Cys Pro Val Asp Val 195 200 205Met Lys Glu Arg Leu Thr Lys Gly Thr Thr Ala Phe Ser Tyr Lys Leu 210 215 220Lys Gln Ser Asp Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg Gln225 230 235 240Val Tyr Gln Ile Ser Pro Phe Asn Glu Pro Thr Gly Val Ala Val Met 245 250 255Glu Ala Arg Gln Gln Leu Thr Leu Val Glu Val Arg Ser Glu Arg Gly 260 265 270Ser Ala Pro Asp Val Pro Met Gln Asn Tyr Gly Ser Leu Arg Tyr Arg 275 280 285Phe Pro Ala Val Leu Pro Gln Met Pro Leu Gln Leu Ile Lys Thr Lys 290 295 300Asn Pro Glu Gln Arg Ile Val Glu Thr Leu Gln His Ile Val Leu Asn305 310 315 320Asn Gln Gln Asp Phe His Asp Asp Val Ser Tyr Arg Phe Leu Glu Val 325 330 335Val Gln Leu Cys Arg Ile Ala Asn Ala Asp Asn Leu Glu Ser Ile Trp 340 345 350Arg Gln Val Ser Asp Lys Pro Arg Tyr Arg Arg Trp Leu Leu Ser Ala 355 360 365Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys Phe Leu Lys Asn Arg 370 375 380Ile Arg Asn Asp Asp Leu Asn Tyr Ile Gln Thr Leu Leu Thr Val Ser385 390 395 400Leu Thr Leu His Leu Leu Gln Ala Asp Glu His Thr Leu Pro Ile Ala 405 410 415Ala Asp Leu Met Thr Ser Ser Arg Ile Gln Lys Asn Pro Val Leu Gln 420 425 430Gln Val Ala Cys Leu Gly Tyr Ser Ser Val Val Asn Arg Tyr Cys Ser 435 440 445Gln Thr Ser Ala Cys Pro Lys Glu Ala Leu Gln Pro Ile His Asp Leu 450 455 460Ala Asp Glu Ala Ile Ser Arg Gly Arg Glu Asp Lys Met Lys Leu Ala465 470 475 480Leu Lys Cys Ile Gly Asn Met Gly Glu Pro Ala Ser Leu Lys Arg Ile 485 490 495Leu Lys Phe Leu Pro Ile Ser Ser Ser Ser Ala Ala Asp Ile Pro Val 500 505 510His Ile Gln Ile Asp Ala Ile Thr Ala Leu Lys Lys Ile Ala Trp Lys 515 520 525Asp Pro Lys Thr Val Gln Gly Tyr Leu Ile Gln Ile Leu Ala Asp Gln 530 535 540Ser Leu Pro Pro Glu Val Arg Met Met Ala Cys Ala Val Ile Phe Glu545 550 555 560Thr Arg Pro Ala Leu Ala Leu Ile Thr Thr Ile Ala Asn Val Ala Met 565 570 575Lys Glu Ser Asn Met Gln Val Ala Ser Phe Val Tyr Ser His Met Lys 580 585 590Ser Leu Ser Lys Ser Arg Leu Pro Phe Met Tyr Asn Ile Ser Ser Ala 595 600 605Cys Asn Ile Ala Leu Lys Leu Leu Ser Pro Lys Leu Asp Ser Met Ser 610 615 620Tyr Arg Tyr Ser Lys Val Ile Arg Ala Asp Thr Tyr Phe Asp Asn Tyr625 630 635 640Arg Val Gly Ala Thr Gly Glu Ile Phe Val Val Asn Ser Pro Arg Thr 645 650 655Met Phe Pro Ser Ala Ile Ile Ser Lys Leu Met Ala Asn Ser Ala Gly 660 665 670Ser Val Ala Asp Leu Val Glu Val Gly Ile Arg Val Glu Gly Leu Ala 675 680 685Asp Val Ile Met Lys Arg Asn Ile Pro Phe Ala Glu Tyr Pro Thr Tyr 690 695 700Lys Gln Ile Lys Glu Leu Gly Lys Ala Leu Gln Gly Trp Lys Glu Leu705 710 715 720Pro Thr Glu Thr Pro Leu Val Ser Ala Tyr Leu Lys Ile Leu Gly Gln 725 730 735Glu Val Ala Phe Ile Asn Ile Asn Lys Glu Leu Leu Gln Gln Val Met 740 745 750Lys Thr Val Val Glu Pro Ala Asp Arg Asn Ala Ala Ile Lys Arg Ile 755 760 765Ala Asn Gln Ile Arg Asn Ser Ile Ala Gly Gln Trp Thr Gln Pro Val 770 775 780Trp Met Gly Glu Leu Arg Tyr Val Val Pro Ser Cys Leu Gly Leu Pro785 790 795 800Leu Glu Tyr Gly Ser Tyr Thr Thr Ala Leu Ala Arg Ala Ala Val Ser 805 810 815Val Glu Gly Lys Met Thr Pro Pro Leu Thr Gly Asp Phe Arg Leu Ser 820 825 830Gln Leu Leu Glu Ser Thr Met Gln Ile Arg Ser Asp Leu Lys Pro Ser 835 840 845Leu Tyr Val His Thr Val Ala Thr Met Gly Val Asn Thr Glu Tyr Phe 850 855 860Gln His Ala Val Glu Ile Gln Gly Glu Val Gln Thr Arg Met Pro Met865 870 875 880Lys Phe Asp Ala Lys Ile Asp Val Lys Leu Lys Asn Leu Lys Ile Glu 885 890 895Thr Asn Pro Cys Arg Glu Glu Thr Glu Ile Val Val Gly Arg His Lys 900 905 910Ala Phe Ala Val Ser Arg Asn Ile Gly Glu Leu Gly Val Glu Lys Arg 915 920 925Thr Ser Ile Leu Pro Glu Asp Ala Pro Leu Asp Val Thr Glu Glu Pro 930 935 940Phe Gln Thr Ser Glu Arg Ala Ser Arg Glu His Phe Ala Met Gln Gly945 950 955 960Pro Asp Ser Met Pro Arg Lys Gln Ser His Ser Ser Arg Glu Asp Leu 965 970 975Arg Arg Ser Thr Gly Lys Arg Ala His Lys Arg Asp Ile Cys Leu Lys 980 985 990Met His His Ile Gly Cys Gln Leu Cys Phe Ser Arg Arg Ser Arg Asp 995 1000 1005Ala Ser Phe Ile Gln Asn Thr Tyr Leu His Lys Leu Ile Gly Glu 1010 1015 1020His Glu Ala Lys Ile Val Leu Met Pro Val His Thr Asp Ala Asp 1025 1030 1035Ile Asp Lys Ile Gln Leu Glu Ile Gln Ala Gly Ser Arg Ala Ala 1040 1045 1050Ala Arg Ile Ile Thr Glu Val Asn Pro Glu Ser Glu Glu Glu Asp 1055 1060 1065Glu Ser Ser Pro Tyr Glu Asp Ile Gln Ala Lys Leu Lys Arg Ile 1070 1075 1080Leu Gly Ile Asp Ser Met Phe Lys Val Ala Asn Lys Thr Arg His 1085 1090 1095Pro Lys Asn Arg Pro Ser Lys Lys Gly Asn Thr Val Leu Ala Glu 1100 1105 1110Phe Gly Thr Glu Pro Asp Ala Lys Thr Ser Ser Ser Ser Ser Ser 1115 1120 1125Ala Ser Ser Thr Ala Thr Ser Ser Ser Ser Ser Ser Ala Ser Ser 1130 1135 1140Pro Asn Arg Lys Lys Pro Met Asp Glu Glu Glu Asn Asp Gln Val 1145 1150 1155Lys Gln Ala Arg Asn Lys Asp Ala Ser Ser Ser Ser Arg Ser Ser 1160 1165 1170Lys Ser Ser Asn Ser Ser Lys Arg Ser Ser Ser Lys Ser Ser Asn 1175 1180 1185Ser Ser Lys Arg Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser 1190 1195 1200Ser Arg Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Asn Ser Lys 1205 1210 1215Ser Ser Ser Ser Ser Ser Lys Ser Ser Ser Ser Ser Ser Arg Ser 1220 1225 1230Arg Ser Ser Ser Lys Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser 1235 1240 1245Ser Ser Ser Ser Lys Ser Ser Ser Ser Arg Ser Ser Ser Ser Ser 1250 1255 1260Ser Lys Ser Ser Ser His His Ser His Ser His His Ser Gly His 1265 1270 1275Leu Asn Gly Ser Ser Ser Ser Ser Ser Ser Ser Arg Ser Val Ser 1280 1285 1290His His Ser His Glu His His Ser Gly His Leu Glu Asp Asp Ser 1295 1300 1305Ser Ser Ser Ser Ser Ser Ser Val Leu Ser Lys Ile Trp Gly Arg 1310 1315 1320His Glu Ile Tyr Gln Tyr Arg Phe Arg Ser Ala His Arg Gln Glu 1325 1330 1335Phe Pro Lys Arg Lys Leu Pro Gly Asp Arg Ala Thr Ser Arg Tyr 1340 1345 1350Ser Ser Thr Arg Ser Ser His Asp Thr Ser Arg Ala Ala Ser Trp 1355 1360 1365Pro Lys

Phe Leu Gly Asp Ile Lys Thr Pro Val Leu Ala Ala Phe 1370 1375 1380Leu His Gly Ile Ser Asn Asn Lys Lys Thr Gly Gly Leu Gln Leu 1385 1390 1395Val Val Tyr Ala Asp Thr Asp Ser Val Arg Pro Arg Val Gln Val 1400 1405 1410Phe Val Thr Asn Leu Thr Asp Ser Ser Lys Trp Lys Leu Cys Ala 1415 1420 1425Asp Ala Ser Val Arg Asn Ala His Lys Ala Val Ala Tyr Val Lys 1430 1435 1440Trp Gly Trp Asp Cys Arg Asp Tyr Lys Val Ser Thr Glu Leu Val 1445 1450 1455Thr Gly Arg Phe Ala Gly His Pro Ala Ala Gln Val Lys Leu Glu 1460 1465 1470Trp Pro Lys Val Pro Ser Asn Val Arg Ser Val Val Glu Trp Phe 1475 1480 1485Tyr Glu Phe Val Pro Gly Ala Ala Phe Met Leu Gly Phe Ser Glu 1490 1495 1500Arg Met Asp Lys Asn Pro Ser Arg Gln Ala Arg Met Val Val Ala 1505 1510 1515Leu Thr Ser Pro Arg Thr Cys Asp Val Val Val Lys Leu Pro Asp 1520 1525 1530Ile Ile Leu Tyr Gln Lys Ala Val Arg Leu Pro Leu Ser Leu Pro 1535 1540 1545Val Gly Pro Arg Ile Pro Ala Ser Glu Leu Gln Pro Pro Ile Trp 1550 1555 1560Asn Val Phe Ala Glu Ala Pro Ser Ala Val Leu Glu Asn Leu Lys 1565 1570 1575Ala Arg Cys Ser Val Ser Tyr Asn Lys Ile Lys Thr Phe Asn Glu 1580 1585 1590Val Lys Phe Asn Tyr Ser Met Pro Ala Asn Cys Tyr His Ile Leu 1595 1600 1605Val Gln Asp Cys Ser Ser Glu Leu Lys Phe Leu Val Met Met Lys 1610 1615 1620Ser Ala Gly Glu Ala Thr Asn Leu Lys Ala Ile Asn Ile Lys Ile 1625 1630 1635Gly Ser His Glu Ile Asp Met His Pro Val Asn Gly Gln Val Lys 1640 1645 1650Leu Leu Val Asp Gly Ala Glu Ser Pro Thr Ala Asn Ile Ser Leu 1655 1660 1665Ile Ser Ala Gly Ala Ser Leu Trp Ile His Asn Glu Asn Gln Gly 1670 1675 1680Phe Ala Leu Ala Ala Pro Gly His Gly Ile Asp Lys Leu Tyr Phe 1685 1690 1695Asp Gly Lys Thr Ile Thr Ile Gln Val Pro Leu Trp Met Ala Gly 1700 1705 1710Lys Thr Cys Gly Ile Cys Gly Lys Tyr Asp Ala Glu Cys Glu Gln 1715 1720 1725Glu Tyr Arg Met Pro Asn Gly Tyr Leu Ala Lys Asn Ala Val Ser 1730 1735 1740Phe Gly His Ser Trp Ile Leu Glu Glu Ala Pro Cys Arg Gly Ala 1745 1750 1755Cys Lys Leu His Arg Ser Phe Val Lys Leu Glu Lys Thr Val Gln 1760 1765 1770Leu Ala Gly Val Asp Ser Lys Cys Tyr Ser Thr Glu Pro Val Leu 1775 1780 1785Arg Cys Ala Lys Gly Cys Ser Ala Thr Lys Thr Thr Pro Val Thr 1790 1795 1800Val Gly Phe His Cys Leu Pro Ala Asp Ser Ala Asn Ser Leu Thr 1805 1810 1815Asp Lys Gln Met Lys Tyr Asp Gln Lys Ser Glu Asp Met Gln Asp 1820 1825 1830Thr Val Asp Ala His Thr Thr Cys Ser Cys Glu Asn Glu Glu Cys 1835 1840 1845Ser Thr 18501079PRTGallus gallus 107Ala Asp Thr Tyr Phe Asp Asn Tyr Arg1 510810PRTGallus gallus 108Ala Glu Phe Gly Thr Glu Pro Asp Ala Lys1 5 101097PRTGallus gallus 109Ala Glu Tyr Pro Thr Tyr Lys1 511012PRTGallus gallus 110Ala Thr Gly Glu Ile Phe Val Val Asn Ser Pro Arg1 5 1011111PRTGallus gallus 111Ala Val Glu Ile Gln Gly Glu Val Gln Thr Arg1 5 101127PRTGallus gallus 112Ala Val Ile Phe Glu Thr Arg1 511312PRTGallus gallus 113Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 1011416PRTGallus gallus 114Glu Ala Leu Gln Pro Ile His Asp Leu Ala Asp Glu Ala Ile Ser Arg1 5 10 151159PRTGallus gallus 115Glu Glu Thr Glu Ile Val Val Gly Arg1 511614PRTGallus gallus 116Glu Leu Pro Thr Glu Thr Pro Leu Val Ser Ala Tyr Leu Lys1 5 1011710PRTGallus gallus 117Phe Asp Ile Asp Pro Gly Phe Asn Ser Arg1 5 101187PRTGallus gallus 118Phe Glu Tyr Ser Ser Gly Arg1 51198PRTGallus gallus 119Gly Thr Thr Ala Phe Ser Tyr Lys1 512010PRTGallus gallus 120Ile Ala Asn Ala Asp Asn Leu Glu Ser Ile1 5 1012112PRTGallus gallus 121Ile Leu Ala Asp Gln Ser Leu Pro Pro Glu Val Arg1 5 1012213PRTGallus gallus 122Ile Leu Gly Gln Glu Val Ala Phe Ile Asn Ile Asn Lys1 5 1012310PRTGallus gallus 123Ile Gln Leu Glu Ile Gln Ala Gly Ser Arg1 5 1012414PRTGallus gallus 124Leu Glu Ile Ser Gly Leu Pro Glu Asn Ala Tyr Leu Leu Lys1 5 101259PRTGallus gallus 125Leu Gly Tyr Ser Ser Val Val Asn Arg1 512615PRTGallus gallus 126Leu Ile Gln Ile Leu Ala Asp Gln Ser Leu Pro Pro Glu Val Arg1 5 10 1512716PRTGallus gallus 127Leu Lys Gln Ser Asp Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg1 5 10 1512815PRTGallus gallus 128Leu Leu Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 10 1512910PRTGallus gallus 129Leu Pro Leu Ser Leu Pro Val Gly Pro Arg1 5 1013014PRTGallus gallus 130Leu Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 1013111PRTGallus gallus 131Asn Asp Asp Leu Asn Tyr Ile Gln Thr Leu Leu1 5 101329PRTGallus gallus 132Asn Ile Gly Glu Leu Gly Val Glu Lys1 513311PRTGallus gallus 133Asn Ile Pro Phe Ala Glu Tyr Pro Thr Tyr Lys1 5 1013411PRTGallus gallus 134Pro Ala Leu Ala Leu Ile Thr Thr Ile Ala Asn1 5 101359PRTGallus gallus 135Gln Gln Leu Thr Leu Val Glu Val Arg1 513614PRTGallus gallus 136Gln Ser Asp Ser Gly Thr Leu Ile Thr Asp Val Ser Ser Arg1 5 1013714PRTGallus gallus 137Ser Ala Gly Ser Val Ala Asp Leu Val Glu Val Gly Ile Arg1 5 1013813PRTGallus gallus 138Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 101398PRTGallus gallus 139Ser Asp Leu Lys Pro Ser Leu Tyr1 514018PRTGallus gallus 140Thr Gly Gly Leu Gln Leu Val Val Tyr Ala Asp Thr Asp Ser Val Arg1 5 10 15Pro Arg14115PRTGallus gallus 141Thr Pro Val Leu Ala Ala Phe Leu His Gly Ile Ser Asn Asn Lys1 5 10 1514220PRTGallus gallus 142Thr Val Gln Gly Tyr Leu Ile Gln Ile Leu Ala Asp Gln Ser Leu Pro1 5 10 15Pro Glu Val Arg 2014310PRTGallus gallus 143Thr Val Gln Leu Ala Gly Val Asp Ser Lys1 5 101448PRTGallus gallus 144Thr Val Val Glu Pro Ala Asp Arg1 514510PRTGallus gallus 145Val Glu Ile Gln Gly Glu Val Gln Thr Arg1 5 1014614PRTGallus gallus 146Val Gly Ala Thr Gly Glu Ile Phe Val Val Asn Ser Pro Arg1 5 1014711PRTGallus gallus 147Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 101489PRTGallus gallus 148Val Ser Thr Glu Leu Val Thr Gly Arg1 514916PRTGallus gallus 149Trp Leu Leu Ser Ala Val Ser Ala Ser Gly Thr Thr Glu Thr Leu Lys1 5 10 151508PRTGallus gallus 150Tyr Val Ile Gln Glu Asp Arg Lys1 51517875PRTGallus gallus 151Ala Thr Gly Gly Gly Cys Cys Cys Thr Gly Thr Gly Cys Gly Gly Cys1 5 10 15Thr Cys Thr Thr Gly Cys Thr Gly Cys Thr Cys Thr Thr Gly Cys Thr 20 25 30Gly Cys Thr Gly Cys Thr Cys Ala Gly Cys Ala Gly Thr Gly Gly Thr 35 40 45Gly Thr Thr Cys Thr Cys Ala Cys Ala Cys Ala Gly Gly Ala Ala Gly 50 55 60Gly Ala Ala Cys Ala Cys Cys Thr Gly Ala Ala Ala Ala Thr Gly Gly65 70 75 80Ala Ala Ala Cys Cys Cys Ala Gly Gly Ala Thr Gly Thr Thr Cys Ala 85 90 95Ala Ala Ala Gly Ala Thr Gly Cys Gly Gly Cys Cys Cys Gly Ala Thr 100 105 110Thr Thr Ala Ala Ala Ala Gly Cys Cys Thr Thr Ala Gly Ala Ala Ala 115 120 125Ala Thr Ala Thr Gly Thr Thr Thr Ala Cys Thr Thr Ala Thr Ala Thr 130 135 140Gly Ala Ala Gly Cys Ala Gly Ala Ala Ala Cys Ala Thr Cys Ala Ala145 150 155 160Gly Thr Gly Gly Gly Ala Thr Cys Ala Cys Gly Gly Gly Ala Ala Cys 165 170 175Ala Gly Cys Ala Gly Ala Thr Thr Cys Thr Cys Gly Ala Ala Gly Cys 180 185 190Gly Gly Thr Thr Cys Ala Ala Ala Gly Ala Thr Cys Ala Cys Cys Thr 195 200 205Gly Thr Ala Ala Ala Gly Thr Thr Gly Ala Gly Thr Thr Gly Gly Ala 210 215 220Gly Gly Thr Ala Cys Cys Ala Cys Ala Gly Cys Thr Gly Thr Gly Cys225 230 235 240Cys Ala Gly Thr Thr Cys Ala Thr Cys Cys Thr Gly Ala Gly Gly Ala 245 250 255Cys Ala Ala Thr Gly Cys Ala Thr Thr Gly Cys Thr Cys Cys Cys Thr 260 265 270Ala Ala Gly Gly Gly Ala Gly Ala Cys Ala Thr Thr Thr Gly Gly Thr 275 280 285Gly Thr Thr Gly Ala Cys Ala Gly Thr Gly Ala Gly Ala Gly Ala Ala 290 295 300Gly Ala Gly Cys Cys Ala Thr Gly Cys Thr Gly Ala Gly Gly Ala Ala305 310 315 320Gly Thr Cys Ala Ala Ala Gly Ala Ala Cys Thr Cys Thr Gly Ala Thr 325 330 335Gly Ala Cys Thr Thr Thr Gly Cys Ala Ala Ala Thr Gly Cys Cys Ala 340 345 350Thr Gly Thr Cys Cys Ala Ala Ala Cys Ala Thr Gly Ala Gly Cys Thr 355 360 365Ala Ala Gly Ala Thr Thr Cys Ala Gly Cys Ala Cys Thr Cys Ala Gly 370 375 380Gly Ala Thr Gly Gly Ala Ala Cys Ala Ala Ala Ala Gly Thr Thr Ala385 390 395 400Ala Ala Cys Thr Ala Thr Ala Thr Cys Cys Ala Gly Ala Gly Ala Ala 405 410 415Gly Gly Ala Thr Gly Ala Ala Cys Cys Thr Cys Thr Gly Ala Ala Thr 420 425 430Gly Thr Cys Cys Thr Cys Ala Ala Thr Cys Thr Cys Ala Ala Gly Ala 435 440 445Gly Ala Gly Gly Ala Ala Thr Thr Ala Thr Cys Thr Cys Ala Gly Cys 450 455 460Thr Cys Thr Cys Cys Thr Thr Gly Cys Ala Cys Cys Ala Ala Cys Ala465 470 475 480Gly Ala Ala Ala Cys Ala Gly Ala Gly Gly Ala Ala Ala Ala Cys Ala 485 490 495Thr Ala Ala Ala Ala Ala Cys Ala Ala Thr Thr Thr Cys Cys Ala Thr 500 505 510Gly Gly Ala Thr Ala Cys Thr Gly Thr Ala Thr Ala Thr Gly Gly Ala 515 520 525Ala Ala Gly Thr Gly Thr Gly Ala Cys Ala Gly Thr Gly Ala Gly Gly 530 535 540Thr Thr Gly Ala Gly Thr Thr Cys Ala Ala Ala Thr Cys Cys Ala Gly545 550 555 560Ala Ala Gly Ala Gly Gly Ala Ala Gly Thr Gly Thr Thr Gly Cys Ala 565 570 575Gly Ala Ala Gly Ala Thr Ala Thr Thr Thr Cys Ala Ala Thr Thr Ala 580 585 590Ala Cys Ala Gly Gly Ala Ala Cys Cys Thr Gly Ala Ala Ala Gly Cys 595 600 605Cys Thr Gly Thr Gly Ala Cys Ala Ala Cys Thr Thr Cys Ala Gly Thr 610 615 620Cys Cys Ala Ala Thr Cys Ala Gly Ala Gly Ala Thr Thr Ala Thr Gly625 630 635 640Thr Cys Ala Gly Cys Cys Cys Thr Gly Thr Thr Gly Cys Cys Ala Thr 645 650 655Thr Gly Thr Ala Ala Ala Ala Gly Gly Ala Cys Thr Ala Ala Ala Cys 660 665 670Ala Thr Cys Cys Cys Ala Cys Thr Ala Thr Cys Thr Ala Cys Cys Cys 675 680 685Thr Thr Cys Thr Gly Ala Gly Thr Ala Gly 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Cys Cys Thr Cys Cys Ala Thr Thr 5600 5605 5610Ala Cys Thr Ala Thr Gly Ala Ala Cys Ala Cys Ala Ala Ala Thr 5615 5620 5625Thr Gly Thr Gly Ala Thr Thr Cys Cys Ala Ala Ala Thr Cys Thr 5630 5635 5640Cys Thr Cys Cys Gly Thr Thr Thr Cys Ala Gly Cys Ala Ala Thr 5645 5650 5655Gly Cys Thr Cys Thr Gly Cys Gly Thr Thr Cys Cys Ala Cys Thr 5660 5665 5670Ala Thr Gly Gly Cys Cys Cys Cys Ala Thr Thr Cys Ala Cys Thr 5675 5680 5685Ala Thr Cys Ala Cys Gly Gly Cys Thr Gly Ala Thr Gly Thr Thr 5690 5695 5700Cys Ala Cys Ala Cys Cys Ala Ala Cys Gly Gly Thr Ala Ala Thr 5705 5710 5715Gly Gly Gly Ala Ala Gly Cys Thr Gly Ala Thr Thr Gly Cys Thr 5720 5725 5730Cys Thr Gly Gly Gly Thr Gly Ala Ala Cys Ala Thr Ala Cys Ala 5735 5740 5745Gly Gly Ala Gly Ala Cys Cys Thr Thr Thr Ala Cys Ala Gly Cys 5750 5755 5760Ala Ala Ala Ala Thr Cys Cys Thr Gly Thr Thr Cys Ala Ala Ala 5765 5770 5775Gly Cys Ala Gly Ala Ala Cys Cys Thr Cys Thr Thr Gly Cys Thr 5780 5785 5790Thr Thr Cys Ala Cys Thr Thr Thr Cys Thr Cys Cys Cys Ala Thr 5795 5800 5805Gly Ala Thr Thr Ala Cys Ala Gly Ala Gly Gly Ala Thr Cys Thr 5810 5815 5820Ala Cys Cys Ala Gly Thr Cys Ala Thr Ala Gly Cys Thr Thr Cys 5825 5830 5835Ala Ala Gly Thr Cys Thr Ala Thr Gly Ala Gly Ala Ala Gly Ala 5840 5845 5850Thr Ala Cys Thr Cys Thr Ala Cys Ala Cys Ala Gly Cys Thr Thr 5855 5860 5865Gly Ala Thr Ala Ala Cys Ala Ala Ala Thr Thr Thr Cys Ala Thr 5870 5875 5880Ala Thr Gly Cys Thr Thr Thr Thr Thr Ala Cys Thr Cys Cys Ala 5885 5890 5895Thr Cys Ala Gly Ala Gly Cys Ala Gly Thr Cys Gly Ala Gly Thr 5900 5905 5910Gly Cys Thr Thr Gly Gly Ala Ala Ala Thr Thr Gly Ala Ala Ala 5915 5920 5925Ala Gly Thr Cys Ala Gly Cys Thr Ala Ala Ala Cys Ala Ala Cys 5930 5935 5940Ala Ala Cys Ala Thr Ala Thr Ala Thr Thr Cys Ala Cys Ala Ala 5945 5950 5955Gly Ala Thr Ala Thr Cys Ala Ala Thr Gly Cys Thr Thr Ala Cys 5960 5965 5970Ala Ala Thr Gly Ala Thr Gly Cys Ala Gly Ala Ala Ala Ala Gly 5975 5980 5985Ala Thr Thr Gly Gly Thr Gly Thr Gly Gly Ala Ala Cys Thr Thr 5990 5995 6000Ala Gly Thr Gly Gly Ala Ala Gly Ala Gly Cys Thr Thr Thr Ala 6005 6010 6015Gly Cys Ala Gly Ala Thr Cys Thr Cys Thr Cys Thr Gly Thr Gly 6020 6025 6030Gly Thr Gly Gly Ala Thr Ala Cys Ala Gly Cys Ala Ala Thr Cys 6035 6040 6045Ala Gly Ala Cys Thr Ala Cys Cys Ala Thr Thr Cys Ala Thr Gly 6050 6055 6060Thr Cys Thr Gly Ala Ala Gly Ala Ala Gly Thr Thr Ala Ala Thr 6065 6070 6075Gly Thr Ala Ala Thr Thr Gly Ala Thr Gly Thr Ala Thr Thr Ala 6080 6085 6090Gly Gly Cys Cys Thr Cys Ala Gly Gly Gly Ala Cys Ala Gly Thr 6095 6100 6105Gly Thr Gly Thr Cys Ala Gly Ala Gly Cys Cys Thr Cys Ala Ala 6110 6115 6120Gly Ala Ala Thr Thr Cys Ala Gly Cys Ala Thr Cys Thr Cys Thr 6125 6130 6135Gly Gly Cys Thr Cys Thr Gly Thr Gly Ala Ala Gly Thr Ala Thr 6140 6145 6150Gly Ala Cys Ala Ala Ala Ala Ala Thr Ala Ala Ala Gly Ala Thr 6155 6160 6165Ala Thr Gly Cys Ala Thr Gly Thr Thr Ala Thr Thr Ala Ala Cys 6170 6175 6180Cys Thr Ala Cys Cys Ala Thr Thr Cys Thr Thr Gly Gly Ala Ala 6185 6190 6195Cys Ala Cys Thr Thr Thr Cys Cys Ala Gly Thr Cys Thr Ala Cys 6200 6205 6210Thr Thr Thr Gly

Ala Ala Cys Ala Ala Ala Thr Cys Ala Gly Ala 6215 6220 6225Gly Gly Thr Gly Cys Cys Ala Thr Thr Cys Thr Ala Thr Cys Cys 6230 6235 6240Ala Cys Ala Cys Thr Gly Cys Ala Gly Gly Cys Thr Gly Thr Ala 6245 6250 6255Cys Ala Gly Ala Ala Thr Thr Ala Cys Cys Thr Gly Ala Ala Ala 6260 6265 6270Ala Ala Cys Ala Thr Thr Gly Ala Cys Gly Thr Ala Gly Ala Thr 6275 6280 6285Cys Ala Ala Thr Ala Thr Ala Thr Gly Ala Ala Ala Ala Ala Ala 6290 6295 6300Thr Ala Cys Ala Ala Gly Gly Cys Ala Ala Cys Thr Thr Thr Ala 6305 6310 6315Gly Ala Thr Gly Ala Ala Thr Thr Cys Cys Cys Ala Cys Ala Gly 6320 6325 6330Cys Ala Cys Cys Thr Thr Ala Ala Thr Gly Ala Thr Thr Ala Cys 6335 6340 6345Ala Thr Gly Gly Ala Cys Ala Ala Ala Thr Thr Ala Gly Ala Thr 6350 6355 6360Cys Thr Gly Ala Ala Ala Gly Gly Cys Ala Gly Ala Gly Cys Thr 6365 6370 6375Ala Gly Cys Ala Cys Cys Ala Thr Ala Ala Ala Ala Ala Cys Thr 6380 6385 6390Ala Ala Thr Thr Thr Gly Ala Thr Thr Gly Cys Thr Thr Thr Cys 6395 6400 6405Ala Cys Gly Ala Ala Gly Gly Ala Cys Thr Ala Thr Ala Gly Ala 6410 6415 6420Ala Thr Ala Ala Cys Ala Thr Cys Thr Gly Ala Thr Gly Ala Thr 6425 6430 6435Cys Thr Cys Gly Ala Ala Ala Thr Thr Ala Thr Thr Cys Thr Gly 6440 6445 6450Gly Ala Ala Ala Ala Ala Gly Cys Cys Cys Thr Gly Gly Ala Thr 6455 6460 6465Ala Ala Thr Cys Thr Thr Cys Ala Ala Gly Ala Ala Ala Thr Ala 6470 6475 6480Cys Thr Gly Cys Thr Cys Cys Ala Gly Cys Thr Thr Cys Ala Ala 6485 6490 6495Gly Thr Thr Thr Ala Thr Cys Thr Thr Gly Thr Gly Cys Ala Ala 6500 6505 6510Ala Thr Ala Gly Ala Gly Cys Ala Gly Thr Ala Cys Ala Thr Cys 6515 6520 6525Ala Ala Ala Gly Ala Gly Ala Ala Thr Thr Ala Cys Gly Ala Thr 6530 6535 6540Cys Ala Gly Thr Thr Thr Gly Ala Cys Ala Thr Thr Ala Ala Thr 6545 6550 6555Gly Cys Ala Cys Thr Thr Ala Thr Thr Gly Cys Ala Cys Ala Ala 6560 6565 6570Cys Thr Thr Cys Thr Thr Gly Ala Cys Ala Ala Ala Ala Thr Ala 6575 6580 6585Gly Thr Thr Gly Ala Ala Ala Ala Ala Ala Thr Gly Ala Cys Ala 6590 6595 6600Gly Cys Thr Cys Thr Ala Gly Ala Thr Gly Ala Ala Ala Ala Ala 6605 6610 6615Thr Ala Thr Ala Ala Gly Ala Thr Ala Ala Gly Ala Gly Thr Gly 6620 6625 6630Ala Cys Thr Gly Thr Ala Gly Thr Thr Gly Ala Cys Ala Cys Thr 6635 6640 6645Ala Thr Thr Cys Ala Gly Ala Ala Gly Thr Thr Ala Cys Ala Ala 6650 6655 6660Thr Thr Thr Thr Thr Thr Thr Thr Ala Ala Ala Thr Cys Ala Ala 6665 6670 6675Thr Ala Thr Thr Ala Cys Cys Cys Cys Ala Gly Cys Ala Ala Cys 6680 6685 6690Ala Thr Thr Gly Gly Ala Ala Gly Cys Ala Ala Cys Ala Cys Thr 6695 6700 6705Ala Thr Gly Ala Cys Thr Thr Gly Gly Ala Thr Thr Ala Ala Ala 6710 6715 6720Ala Ala Thr Ala Thr Ala Gly Ala Thr Gly Ala Thr Gly Ala Gly 6725 6730 6735Thr Ala Thr Ala Gly Gly Ala Thr Cys Ala Cys Ala Gly Gly Thr 6740 6745 6750Ala Gly Ala Ala Thr Ala Ala Ala Gly Gly Ala Gly Ala Ala Cys 6755 6760 6765Cys Thr Ala Gly Ala Ala Cys Ala Gly Cys Thr Cys Ala Ala Gly 6770 6775 6780Ala Thr Thr Cys Ala Gly Ala Thr Thr Cys Ala Gly Ala Ala Cys 6785 6790 6795Ala Thr Thr Gly Ala Thr Ala Thr Cys Ala Gly Ala Ala Gly Cys 6800 6805 6810Thr Thr Thr Gly Cys Ala Gly Ala Ala Ala Ala Thr Thr Thr Gly 6815 6820 6825Ala Ala Ala Ala Gly Gly Ala Ala Gly Ala Thr Thr Ala Ala Ala 6830 6835 6840Ala Thr Ala Ala Thr Thr Gly Ala Thr Gly Thr Thr Ala Ala Ala 6845 6850 6855Cys Ala Ala Cys Thr Ala Thr Thr Ala Gly Ala Ala Ala Ala Ala 6860 6865 6870Thr Thr Ala Ala Ala Gly Cys Gly Thr Thr Cys Ala Thr Thr Ala 6875 6880 6885Cys Cys Ala Ala Thr Thr Ala Ala Ala Ala Ala Ala Ala Thr Gly 6890 6895 6900Ala Ala Gly Gly Ala Ala Gly Thr Thr Cys Thr Thr Gly Ala Ala 6905 6910 6915Cys Ala Ala Ala Thr Cys Ala Ala Ala Gly Ala Cys Thr Thr Thr 6920 6925 6930Ala Thr Thr Cys Thr Gly Ala Gly Thr Thr Gly Gly Ala Thr Gly 6935 6940 6945Gly Ala Gly Gly Ala Gly Thr Ala Cys Gly Ala Ala Gly Thr Gly 6950 6955 6960Thr Cys Thr Gly Ala Gly Ala Ala Gly Ala Thr Cys Ala Gly Thr 6965 6970 6975Gly Cys Thr Thr Thr Cys Cys Gly Ala Gly Gly Thr Cys Ala Thr 6980 6985 6990Ala Thr Gly Cys Ala Thr Ala Ala Ala Cys Thr Gly Ala Thr Thr 6995 7000 7005Gly Thr Ala Ala Ala Ala Thr Ala Thr Gly Ala Ala Ala Thr Thr 7010 7015 7020Gly Ala Thr Ala Ala Gly Cys Ala Thr Gly Thr Gly Thr Ala Thr 7025 7030 7035Thr Thr Thr Thr Thr Ala Thr Thr Gly Gly Ala Cys Ala Gly Ala 7040 7045 7050Ala Thr Gly Ala Thr Ala Gly Ala Ala Cys Thr Ala Cys Thr Thr 7055 7060 7065Ala Ala Cys Cys Ala Gly Thr Ala Cys Ala Gly Ala Ala Thr Ala 7070 7075 7080Ala Gly Ala Gly Ala Ala Ala Cys Gly Gly Thr Ala Cys Gly Gly 7085 7090 7095Ala Ala Ala Ala Thr Gly Ala Cys Gly Ala Cys Cys Thr Ala Cys 7100 7105 7110Cys Thr Ala Ala Gly Ala Ala Ala Ala Ala Thr Thr Gly Ala Cys 7115 7120 7125Gly Thr Gly Ala Ala Gly Ala Cys Ala Thr Gly Cys Thr Thr Thr 7130 7135 7140Gly Ala Cys Ala Ala Ala Ala Thr Thr Gly Thr Gly Thr Cys Thr 7145 7150 7155Thr Thr Ala Ala Thr Thr Gly Ala Thr Gly Ala Thr Gly Cys Thr 7160 7165 7170Gly Thr Gly Ala Ala Gly Ala Ala Ala Gly Thr Gly Cys Ala Ala 7175 7180 7185Ala Cys Cys Thr Thr Thr Gly Ala Thr Thr Ala Thr Gly Ala Ala 7190 7195 7200Ala Thr Gly Ala Thr Gly Ala Thr Ala Ala Ala Gly Ala Ala Ala 7205 7210 7215Cys Thr Cys Ala Ala Cys Ala Ala Ala Thr Thr Cys Cys Thr Thr 7220 7225 7230Gly Ala Cys Ala Thr Gly Ala Thr Thr Ala Thr Ala Ala Ala Gly 7235 7240 7245Ala Ala Ala Cys Thr Cys Ala Ala Ala Thr Cys Thr Thr Thr Thr 7250 7255 7260Gly Ala Cys Thr Ala Thr Ala Ala Cys Cys Ala Gly Thr Thr Thr 7265 7270 7275Gly Thr Thr Gly Ala Thr Gly Ala Cys Ala Cys Ala Ala Ala Thr 7280 7285 7290Ala Ala Cys Ala Ala Ala Ala Thr Cys Cys Ala Ala Gly Ala Ala 7295 7300 7305Ala Thr Thr Ala Thr Ala Cys Ala Gly Ala Ala Ala Ala Thr Ala 7310 7315 7320Ala Ala Thr Gly Ala Gly Gly Ala Ala Cys Thr Cys Ala Gly Ala 7325 7330 7335Ala Ala Thr Cys Thr Ala Gly Ala Ala Cys Thr Gly Cys Cys Ala 7340 7345 7350Cys Ala Gly Ala Ala Ala Gly Cys Ala Gly Ala Ala Gly Cys Ala 7355 7360 7365Thr Thr Gly Ala Ala Ala Cys Ala Gly Thr Ala Thr Ala Thr Gly 7370 7375 7380Ala Gly Ala Gly Ala Thr Thr Thr Thr Ala Ala Thr Gly Cys Thr 7385 7390 7395Gly Thr Ala Gly Thr Thr Thr Cys Ala Ala Ala Ala Thr Ala Cys 7400 7405 7410Gly Thr Ala Gly Ala Ala Cys Ala Ala Cys Thr Ala Ala Gly Gly 7415 7420 7425Gly Ala Cys Ala Cys Cys Ala Ala Gly Cys Thr Thr Gly Thr Cys 7430 7435 7440Gly Cys Thr Ala Thr Ala Ala Thr Thr Ala Ala Cys Thr Gly Gly 7445 7450 7455Cys Thr Cys Ala Ala Gly Gly Ala Gly Cys Thr Cys Ala Thr Cys 7460 7465 7470Gly Ala Cys Thr Cys Ala Ala Cys Ala Ala Cys Ala Thr Thr Thr 7475 7480 7485Ala Cys Thr Ala Ala Thr Cys Thr Gly Ala Ala Ala Gly Cys Cys 7490 7495 7500Ala Ala Ala Gly Thr Ala Ala Ala Thr Gly Ala Gly Cys Ala Thr 7505 7510 7515Cys Thr Gly Gly Ala Ala Gly Gly Thr Cys Thr Gly Cys Gly Ala 7520 7525 7530Gly Ala Gly Ala Gly Ala Ala Thr Thr Thr Cys Thr Gly Ala Cys 7535 7540 7545Ala Thr Gly Gly Ala Thr Ala Thr Cys Gly Cys Cys Ala Ala Gly 7550 7555 7560Gly Ala Ala Thr Thr Thr Gly Ala Ala Thr Gly Gly Thr Ala Thr 7565 7570 7575Cys Thr Thr Cys Ala Ala Ala Ala Gly Ala Thr Ala Ala Gly Cys 7580 7585 7590Cys Ala Gly Thr Thr Cys Thr Ala Cys Ala Ala Thr Thr Cys Thr 7595 7600 7605Gly Thr Thr Gly Thr Cys Ala Thr Ala Thr Ala Cys Ala Thr Thr 7610 7615 7620Thr Cys Thr Gly Ala Ala Cys Ala Gly Thr Gly Gly Ala Ala Cys 7625 7630 7635Ala Thr Ala Gly Cys Thr Thr Thr Thr Ala Ala Ala Ala Ala Ala 7640 7645 7650Ala Thr Cys Gly Thr Thr Ala Cys Thr Thr Thr Gly Gly Cys Thr 7655 7660 7665Gly Ala Gly Ala Ala Gly Thr Ala Thr Gly Ala Cys Cys Thr Ala 7670 7675 7680Ala Ala Ala Ala Ala Thr Thr Gly Gly Gly Cys Thr Gly Ala Ala 7685 7690 7695Ala Ala Thr Thr Thr Ala Ala Ala Cys Cys Ala Gly Thr Thr Cys 7700 7705 7710Ala Thr Thr Gly Ala Ala Ala Cys Ala Gly Gly Ala Thr Thr Thr 7715 7720 7725Ala Ala Ala Gly Thr Cys Cys Cys Thr Gly Ala Ala Ala Thr Ala 7730 7735 7740Ala Gly Ala Ala Cys Ala Gly Thr Thr Ala Thr Ala Gly Thr Cys 7745 7750 7755Ala Cys Thr Ala Thr Ala Cys Cys Thr Gly Cys Cys Thr Thr Thr 7760 7765 7770Gly Ala Ala Thr Thr Cys Ala Gly Thr Cys Thr Thr Cys Gly Ala 7775 7780 7785Ala Gly Thr Cys Thr Thr Cys Gly Gly Gly Ala Ala Gly Cys Ala 7790 7795 7800Ala Cys Thr Thr Thr Cys Cys Gly Ala Ala Cys Ala Cys Cys Gly 7805 7810 7815Gly Ala Cys Thr Thr Cys Ala Thr Thr Gly Thr Thr Cys Cys Ala 7820 7825 7830Cys Thr Gly Ala Cys Thr Gly Ala Thr Cys Thr Gly Ala Ala Ala 7835 7840 7845Ala Thr Cys Cys Cys Cys Thr Cys Cys Thr Ala Thr Gly Ala Ala 7850 7855 7860Ala Thr Ala Ala Ala Thr Ala Thr Thr Ala Gly Gly 7865 7870 78751522625PRTGallus gallus 152Met Gly Pro Val Arg Leu Leu Leu Leu Leu Leu Leu Leu Ser Ser Gly1 5 10 15Val Leu Thr Gln Glu Gly Thr Pro Glu Asn Gly Asn Pro Gly Cys Ser 20 25 30Lys Asp Ala Ala Arg Phe Lys Ser Leu Arg Lys Tyr Val Tyr Leu Tyr 35 40 45Glu Ala Glu Thr Ser Ser Gly Ile Thr Gly Thr Ala Asp Ser Arg Ser 50 55 60Gly Ser Lys Ile Thr Cys Lys Val Glu Leu Glu Val Pro Gln Leu Cys65 70 75 80Gln Phe Ile Leu Arg Thr Met His Cys Ser Leu Arg Glu Thr Phe Gly 85 90 95Val Asp Ser Glu Arg Arg Ala Met Leu Arg Lys Ser Lys Asn Ser Asp 100 105 110Asp Phe Ala Asn Ala Met Ser Lys His Glu Leu Arg Phe Ser Thr Gln 115 120 125Asp Gly Thr Lys Val Lys Leu Tyr Pro Glu Lys Asp Glu Pro Leu Asn 130 135 140Val Leu Asn Leu Lys Arg Gly Ile Ile Ser Ala Leu Leu Ala Pro Thr145 150 155 160Glu Thr Glu Glu Asn Ile Lys Thr Ile Ser Met Asp Thr Val Tyr Gly 165 170 175Lys Cys Asp Ser Glu Val Glu Phe Lys Ser Arg Arg Gly Ser Val Ala 180 185 190Glu Asp Ile Ser Ile Asn Arg Asn Leu Lys Ala Cys Asp Asn Phe Ser 195 200 205Pro Ile Arg Asp Tyr Val Ser Pro Val Ala Ile Val Lys Gly Leu Asn 210 215 220Ile Pro Leu Ser Thr Leu Leu Ser Ser Thr Gln Ser Cys His Tyr Ser225 230 235 240Ile Asp Ala Lys Lys Lys His Ile Arg Asp Val Val Cys Ser Glu Lys 245 250 255His Leu Phe Leu Pro Ser Ser Tyr Lys Asn Gln Tyr Gly Met Met Thr 260 265 270Glu Val Asn Gln Thr Leu Lys Leu Glu Asp Asn Gln Arg Met Asn Asn 275 280 285Arg Asn Pro Asp Gly Asp Glu Leu Glu Glu Lys Gly Leu Ala Leu Glu 290 295 300Ser Thr Asp Ala Lys Phe Ser Arg Gln Gly Asp Ala Val Leu Lys Ile305 310 315 320Leu Gln Glu Leu Gln Lys Leu Thr Ala Ser Gln Gln Asn Gln Gln Arg 325 330 335Ala Lys Leu Phe Tyr Lys Phe Val Ser Gly Leu Arg Ser Leu His Asn 340 345 350Ser Thr Leu Gly Ser Leu Val Pro Lys Met Met Glu Thr Ser Ser Ser 355 360 365Ile Thr Ile Gln Ala Leu Ile Gln Cys Gly Thr Pro Glu Cys Tyr Ser 370 375 380Ala Val Leu Gln Ile Leu Arg Thr Gly Asn Val Asn Pro Leu Val Val385 390 395 400Asp Leu Val Thr Tyr Thr Leu Gly Leu Leu Pro Ser Pro Thr Pro Lys 405 410 415Arg Ile Arg Glu Ile Leu Asn Met Ala Gln Tyr Gln Pro Ser Arg Ala 420 425 430Ser Phe Tyr Gly Leu Ser His Ala Val Thr Lys Phe Tyr Asn Glu Lys 435 440 445Met Ile Val Thr Glu Glu Ile Thr Asp Val Ala Asp Phe Met Val Ser 450 455 460Leu Leu Gly Thr Asp Cys Ser Gly Asp Ala Glu Leu Thr Tyr Leu Thr465 470 475 480Leu Arg Ala Ile Gly Asn Met Gly Ala Val Met Glu Lys Ala Lys Pro 485 490 495Ser Leu Lys Ala Ser Leu Lys Thr Cys Ile Arg Asn Gln Ala Ala Ser 500 505 510Leu Ser Val Gln Lys Ala Ala Ile Gln Ala Phe Arg Lys Met Thr Ile 515 520 525Thr Glu Glu Asp Arg Ser Ala Leu Leu Lys Glu Phe Gln Glu Gly Asp 530 535 540Ala Pro Thr Asp Lys Arg Leu Ala Thr Tyr Leu Ile Leu Met Lys Asn545 550 555 560Pro Ser Pro Ala Asp Leu Ala Lys Ile Met Arg Ile Leu Thr Arg Glu 565 570 575Lys Asn Glu Gln Val Lys Ser Phe Val Ala Ser His Ile Ala Asn Ile 580 585 590Leu Asp Ser Asp Glu Val Gly Ile Glu Asp Leu Lys Ser His Val Glu 595 600 605Glu Ala Leu Lys Gly Asn Glu Val Pro Thr Ala Lys Asp Phe Arg Lys 610 615 620Phe Ser Gln Asn Tyr Gln Val Ser Lys Arg Val Ser Val Pro Gly Leu625 630 635 640Asn Pro Ile Ser Ala Lys Val Glu Gly Asn Val Ile Phe Asp Pro Ser 645 650 655Ser Tyr Val Pro Lys Glu Thr Met Leu Lys Thr Thr Leu Asn Leu Tyr 660 665 670Gly Phe Gly Pro Ser Asp Ile Phe Glu Leu Gly Leu Asp Gly Lys Gly 675 680 685Phe Glu Pro Thr Leu Glu Ala Leu Phe Gly Glu Lys Gly Phe Phe Pro 690 695 700Asp Thr Ala Ser Lys Ala Leu Tyr Trp Val Asp Gly Lys Val Pro Glu705 710 715 720Gln Val Ser Lys Ala Leu Phe Asp Tyr Phe Gly Tyr Ser His Asp Gly 725 730 735Lys Gln Asp Gln Glu Ile Thr Lys Ala Val Ile Leu Asn Leu Glu Lys 740 745 750Leu Ile Lys Glu Leu Ser Lys Lys Glu Ala Pro Glu Gly Arg Ala Phe 755 760 765Leu Arg Ile Leu Gly Glu Glu Leu Gly Tyr Met Lys Leu Ser Asp Phe 770 775 780Lys Leu Leu

Gly Ser Val Ala Leu Glu Cys Ile Lys Thr Leu Gln Arg785 790 795 800Ile Pro Glu Ile Ile Ala Gln Ala Ile Ser Lys Gly Val Asp Lys Asp 805 810 815Leu Phe Val His Tyr Met Phe Met Asp Asn Glu Phe Glu Leu Pro Thr 820 825 830Gly Ala Gly Leu Gln Leu Lys Phe Ala Leu Ser Gly Ile Val Thr Pro 835 840 845Gly Ala Lys Val Ala Val Lys Leu His Gln Lys Ser Met Gln Ala Glu 850 855 860Leu Ile Ala Lys Pro Ser Val Ala Val Glu Phe Val Thr His Leu Gly865 870 875 880Ile Asn Met Pro Glu Phe Ala Arg Ser Gly Val Glu Met Asn Ser Asn 885 890 895Ile Phe His Glu Ser Gly Ile Glu Ala His Val Ser Val Lys Ala Gly 900 905 910Gln Leu Lys Phe Ser Ile Pro Ala Pro Lys Thr Pro Thr Lys Leu Leu 915 920 925Ser Ile Ser Asn Thr Leu His Leu Val Ser Pro Ala Lys Thr Glu Glu 930 935 940Ile Pro Pro Leu Ile Glu Asn Arg Glu Phe Ser Thr Ser Cys Lys Pro945 950 955 960Phe Ile Ser Gly Leu Asn Phe Cys Thr Lys Leu Leu Tyr Ser Asn Ala 965 970 975Ser Ser Met Glu Ala Ala Pro Tyr Tyr Pro Leu Thr Gly Glu Thr Arg 980 985 990Phe Glu Val Glu Ile Val Ser Thr Gly Glu Val Lys Glu Tyr Ser Ala 995 1000 1005Ser Ala Asn Tyr Asp Leu Gln Arg Glu Gly Thr Asp Leu Val Asp 1010 1015 1020Thr Leu Lys Phe Ala Val Gln Ala Glu Gly Val Lys Gln His Glu 1025 1030 1035Ala Thr Leu Thr Phe Lys Tyr Asn Arg Asp Arg Lys Ile Leu Thr 1040 1045 1050Ser Asp Val Ser Ile Pro Asp Val Asp Val Asp Phe Gly Thr Asn 1055 1060 1065Phe Arg Ile Thr Asp Glu Ser Val Ser Gly Lys Lys Ala Tyr Ile 1070 1075 1080Phe Val Ile Asp Phe Asn Asn Lys Lys Ile Ser Glu Val Thr Leu 1085 1090 1095Thr Gly Gln Ile Arg Tyr Ala Gly Ile Glu Glu Ala Met Leu Arg 1100 1105 1110Gly Thr Val Ser Ile Pro Arg Leu Gln Thr Glu Leu Lys Thr Glu 1115 1120 1125Ala Leu Val Asn Tyr Ser Pro Thr Lys Gly Tyr Leu Gln Met Ser 1130 1135 1140Ser Ser Val Gly Thr His Gly Asn Thr Val Ser Lys Arg Val Leu 1145 1150 1155Leu Arg Tyr Asp Ser Glu Lys Ala Glu Leu Glu Trp Asn Ser Gly 1160 1165 1170Ala Thr Ala Ala Val Gly Arg Met Ser Ser Ala Phe Gln Val Asp 1175 1180 1185Phe Ser Asp Tyr Ser Lys Thr Leu Glu Lys Tyr Ala Asn Glu Leu 1190 1195 1200Leu Asp Arg Lys Val Ala Leu Thr Asp Met Thr Met Arg His Ile 1205 1210 1215Val Ser Gln Phe Ile Val Ala Thr Asn Thr Trp Leu Gln Lys Ala 1220 1225 1230Ser Lys Asp Val Pro Tyr Ala Gln Thr Leu Gln Ala Lys Leu Ser 1235 1240 1245Gly Leu Gln Glu Leu Asn Ile Gln Lys Ile Lys Leu Pro Val Ile 1250 1255 1260Thr Ile Pro Glu Glu Leu Phe Leu Lys Ser Glu Gly Arg Ile Lys 1265 1270 1275Tyr Ser Phe Asn Lys Asn Ser Phe Leu Ile Asn Ile Pro Leu Pro 1280 1285 1290Phe Gly Gly Arg Ser Ser His Asp Ile Arg Val Pro Gln Thr Val 1295 1300 1305Lys Thr Pro Arg Leu Val Ile Glu Ser Met Gly Ile Asn Ile Pro 1310 1315 1320Ser Gln Glu Tyr Arg Met Pro Thr Phe Thr Val Pro Glu Ser Tyr 1325 1330 1335Pro Leu Leu Val Pro Leu Phe Gly Ala Leu Glu Ala Ser Ala Ser 1340 1345 1350Val His Ser Asn Tyr Tyr Asn Trp Thr Ala Ala Tyr Thr Leu Thr 1355 1360 1365Asn Ser Ser Thr Glu Lys Thr Ala Arg Ile Gly Thr Thr Tyr Ala 1370 1375 1380Val Asn Ala Asp Ser Val Phe Glu Leu Leu Ser Tyr Asn Met Lys 1385 1390 1395Gly Ser Gly Glu Ala Ser Ser Ser Arg Asn Gly Phe Thr Cys Ala 1400 1405 1410Tyr Glu Asn His Leu Lys His Arg Leu Leu Thr Ser Asp Phe Lys 1415 1420 1425Met Ser Arg Thr Lys Ser Tyr Glu Pro Thr Ser Val Ser Asn Cys 1430 1435 1440Thr Ile Phe Leu Met Ala Ser Ser Ala Leu Gly Pro Gln Leu Ser 1445 1450 1455Phe Ser Ser Asp Val Val Ser Glu Lys Thr Asn Asn Met Asn Ile 1460 1465 1470Asn Asn Val Arg Ile Glu Gly Gln Leu Glu Val Ala Ser Val Phe 1475 1480 1485Ala Arg Ser Val Tyr Thr Met Ser Ser Ser Tyr Asn Glu Lys Arg 1490 1495 1500Arg Val Leu Glu Gly Lys Ser Asn Leu Arg Leu Asp Ser Ser Tyr 1505 1510 1515Leu Gln Ala Thr Asn His Leu Ser Gly Arg Tyr Thr Asp Gly Val 1520 1525 1530Phe Ser Ile Thr Ser Ala Ser Asp Val Gln Asn Gly Leu Leu Lys 1535 1540 1545Asn Thr Ala Ser Leu Lys Tyr Glu Asn Ser Gln Leu Lys Ile Thr 1550 1555 1560Ser Glu Thr Asn Gly Arg Tyr Leu His Leu Ala Ala Val Asn Lys 1565 1570 1575Leu Glu Phe Leu Leu Ser Lys Lys Met Ala Ala Leu Arg Ser Glu 1580 1585 1590Tyr Gln Ala Thr Tyr Lys Gln Thr Gln Cys Tyr Ala Leu Phe Ala 1595 1600 1605Gly Ser Leu Asn Ser Gln Asp Leu Val Phe Asn Thr Asp Phe Ser 1610 1615 1620Leu Thr Asp Gln Arg Asn Arg Ala Ala His Lys Ser Ser Leu Asn 1625 1630 1635Val Asn Gln Tyr Gly Leu Ala Ser Ser Ala Thr Thr Asn Val Gln 1640 1645 1650Phe Ser Pro Leu Thr Met Gln Ser Glu Met Asn Ala Lys Leu Asp 1655 1660 1665Thr Ser Gly Gly Ser Val Ser Leu Ser Ser Ser Gly Arg Tyr Gly 1670 1675 1680Lys Asn Asn Ala Lys Phe Asn Val Gly Gly Arg Val Ser Leu Thr 1685 1690 1695Glu Ile Thr Leu Gly Ser Glu Tyr Gln Ser Thr Ile Leu Gly Met 1700 1705 1710Asp Asn Lys His Val Leu Asn Phe Arg Ile Asn Lys Glu Gly Leu 1715 1720 1725Lys Phe Ser Asn Asn Leu Gln Gly Ser Leu Lys Glu Ile Lys Leu 1730 1735 1740Glu Tyr Thr Asn Asp Leu Asn Ile Pro Gly Leu Ser Leu Thr Phe 1745 1750 1755Val Ser Lys Leu Asp Asn Ser Phe Ser Phe Asp Lys Phe His Lys 1760 1765 1770His Val Phe Asp Leu Gln Leu Gln Pro Arg Ser Leu Thr Ala Lys 1775 1780 1785Leu Asn Asn Asn Ile Lys Tyr Thr Lys Thr Glu Val Ser Asn Lys 1790 1795 1800Ala Glu Leu Leu Leu Glu Pro Leu Lys Leu Asn Leu Gly Gly Asn 1805 1810 1815Val Arg Ala Ala Tyr Gly Thr Asp Glu Val Arg His Thr Tyr Ala 1820 1825 1830Ile Thr Tyr Ala Asp Leu Thr Ala Asn Phe Lys Thr Asp Thr Val 1835 1840 1845Ala Asn Val Gln Gly Ala Ala Val Ser His Arg Val Asn Leu Asn 1850 1855 1860Val Ala Gly Leu Ala Ser Ser Ile Thr Met Asn Thr Asn Cys Asp 1865 1870 1875Ser Lys Ser Leu Arg Phe Ser Asn Ala Leu Arg Ser Thr Met Ala 1880 1885 1890Pro Phe Thr Ile Thr Ala Asp Val His Thr Asn Gly Asn Gly Lys 1895 1900 1905Leu Ile Ala Leu Gly Glu His Thr Gly Asp Leu Tyr Ser Lys Ile 1910 1915 1920Leu Phe Lys Ala Glu Pro Leu Ala Phe Thr Phe Ser His Asp Tyr 1925 1930 1935Arg Gly Ser Thr Ser His Ser Phe Lys Ser Met Arg Arg Tyr Ser 1940 1945 1950Thr Gln Leu Asp Asn Lys Phe His Met Leu Phe Thr Pro Ser Glu 1955 1960 1965Gln Ser Ser Ala Trp Lys Leu Lys Ser Gln Leu Asn Asn Asn Ile 1970 1975 1980Tyr Ser Gln Asp Ile Asn Ala Tyr Asn Asp Ala Glu Lys Ile Gly 1985 1990 1995Val Glu Leu Ser Gly Arg Ala Leu Ala Asp Leu Ser Val Val Asp 2000 2005 2010Thr Ala Ile Arg Leu Pro Phe Met Ser Glu Glu Val Asn Val Ile 2015 2020 2025Asp Val Leu Gly Leu Arg Asp Ser Val Ser Glu Pro Gln Glu Phe 2030 2035 2040Ser Ile Ser Gly Ser Val Lys Tyr Asp Lys Asn Lys Asp Met His 2045 2050 2055Val Ile Asn Leu Pro Phe Leu Glu His Phe Pro Val Tyr Phe Glu 2060 2065 2070Gln Ile Arg Gly Ala Ile Leu Ser Thr Leu Gln Ala Val Gln Asn 2075 2080 2085Tyr Leu Lys Asn Ile Asp Val Asp Gln Tyr Met Lys Lys Tyr Lys 2090 2095 2100Ala Thr Leu Asp Glu Phe Pro Gln His Leu Asn Asp Tyr Met Asp 2105 2110 2115Lys Leu Asp Leu Lys Gly Arg Ala Ser Thr Ile Lys Thr Asn Leu 2120 2125 2130Ile Ala Phe Thr Lys Asp Tyr Arg Ile Thr Ser Asp Asp Leu Glu 2135 2140 2145Ile Ile Leu Glu Lys Ala Leu Asp Asn Leu Gln Glu Ile Leu Leu 2150 2155 2160Gln Leu Gln Val Tyr Leu Val Gln Ile Glu Gln Tyr Ile Lys Glu 2165 2170 2175Asn Tyr Asp Gln Phe Asp Ile Asn Ala Leu Ile Ala Gln Leu Leu 2180 2185 2190Asp Lys Ile Val Glu Lys Met Thr Ala Leu Asp Glu Lys Tyr Lys 2195 2200 2205Ile Arg Val Thr Val Val Asp Thr Ile Gln Lys Leu Gln Phe Phe 2210 2215 2220Leu Asn Gln Tyr Tyr Pro Ser Asn Ile Gly Ser Asn Thr Met Thr 2225 2230 2235Trp Ile Lys Asn Ile Asp Asp Glu Tyr Arg Ile Thr Gly Arg Ile 2240 2245 2250Lys Glu Asn Leu Glu Gln Leu Lys Ile Gln Ile Gln Asn Ile Asp 2255 2260 2265Ile Arg Ser Phe Ala Glu Asn Leu Lys Arg Lys Ile Lys Ile Ile 2270 2275 2280Asp Val Lys Gln Leu Leu Glu Lys Leu Lys Arg Ser Leu Pro Ile 2285 2290 2295Lys Lys Met Lys Glu Val Leu Glu Gln Ile Lys Asp Phe Ile Leu 2300 2305 2310Ser Trp Met Glu Glu Tyr Glu Val Ser Glu Lys Ile Ser Ala Phe 2315 2320 2325Arg Gly His Met His Lys Leu Ile Val Lys Tyr Glu Ile Asp Lys 2330 2335 2340His Val Tyr Phe Leu Leu Asp Arg Met Ile Glu Leu Leu Asn Gln 2345 2350 2355Tyr Arg Ile Arg Glu Thr Val Arg Lys Met Thr Thr Tyr Leu Arg 2360 2365 2370Lys Ile Asp Val Lys Thr Cys Phe Asp Lys Ile Val Ser Leu Ile 2375 2380 2385Asp Asp Ala Val Lys Lys Val Gln Thr Phe Asp Tyr Glu Met Met 2390 2395 2400Ile Lys Lys Leu Asn Lys Phe Leu Asp Met Ile Ile Lys Lys Leu 2405 2410 2415Lys Ser Phe Asp Tyr Asn Gln Phe Val Asp Asp Thr Asn Asn Lys 2420 2425 2430Ile Gln Glu Ile Ile Gln Lys Ile Asn Glu Glu Leu Arg Asn Leu 2435 2440 2445Glu Leu Pro Gln Lys Ala Glu Ala Leu Lys Gln Tyr Met Arg Asp 2450 2455 2460Phe Asn Ala Val Val Ser Lys Tyr Val Glu Gln Leu Arg Asp Thr 2465 2470 2475Lys Leu Val Ala Ile Ile Asn Trp Leu Lys Glu Leu Ile Asp Ser 2480 2485 2490Thr Thr Phe Thr Asn Leu Lys Ala Lys Val Asn Glu His Leu Glu 2495 2500 2505Gly Leu Arg Glu Arg Ile Ser Asp Met Asp Ile Ala Lys Glu Phe 2510 2515 2520Glu Trp Tyr Leu Gln Lys Ile Ser Gln Phe Tyr Asn Ser Val Val 2525 2530 2535Ile Tyr Ile Ser Glu Gln Trp Asn Ile Ala Phe Lys Lys Ile Val 2540 2545 2550Thr Leu Ala Glu Lys Tyr Asp Leu Lys Asn Trp Ala Glu Asn Leu 2555 2560 2565Asn Gln Phe Ile Glu Thr Gly Phe Lys Val Pro Glu Ile Arg Thr 2570 2575 2580Val Ile Val Thr Ile Pro Ala Phe Glu Phe Ser Leu Arg Ser Leu 2585 2590 2595Arg Glu Ala Thr Phe Arg Thr Pro Asp Phe Ile Val Pro Leu Thr 2600 2605 2610Asp Leu Lys Ile Pro Ser Tyr Glu Ile Asn Ile Arg 2615 2620 26251539PRTGallus gallus 153Ala Ala Tyr Gly Thr Asp Glu Val Arg1 515415PRTGallus gallus 154Ala Glu Leu Glu Trp Asn Ser Gly Ala Thr Ala Ala Val Gly Arg1 5 10 151559PRTGallus gallus 155Ala Glu Leu Leu Leu Glu Pro Leu Lys1 51568PRTGallus gallus 156Ala Glu Pro Leu Ala Phe Thr Phe1 515712PRTGallus gallus 157Ala Ile Thr Tyr Ala Asp Leu Thr Ala Asn Phe Lys1 5 1015813PRTGallus gallus 158Ala Leu Ala Asp Leu Ser Val Val Asp Thr Ala Ile Arg1 5 1015911PRTGallus gallus 159Ala Leu Ser Gly Ile Val Thr Pro Gly Ala Lys1 5 1016012PRTGallus gallus 160Ala Ser Phe Tyr Gly Leu Ser His Ala Val Thr Lys1 5 101618PRTGallus gallus 161Ala Thr Leu Asp Glu Phe Pro Gln1 51628PRTGallus gallus 162Ala Val Ile Leu Asn Leu Glu Lys1 516311PRTGallus gallus 163Ala Tyr Thr Phe Val Ile Asp Phe Asn Asn Lys1 5 1016410PRTGallus gallus 164Asp Glu Pro Leu Asn Val Leu Asn Leu Lys1 5 101658PRTGallus gallus 165Asp Phe Asn Ala Val Val Ser Lys1 51667PRTGallus gallus 166Asp Leu Gln Leu Gln Pro Arg1 516716PRTGallus gallus 167Asp Ser Val Ser Glu Pro Gln Glu Phe Ser Ile Ser Gly Ser Val Lys1 5 10 1516811PRTGallus gallus 168Asp Val Pro Tyr Ala Gln Thr Leu Gln Ala Lys1 5 1016910PRTGallus gallus 169Asp Tyr Val Ser Pro Val Ala Ile Val Lys1 5 1017011PRTGallus gallus 170Glu Phe Gln Glu Gly Asp Ala Pro Thr Asp Lys1 5 1017110PRTGallus gallus 171Glu Gly Thr Asp Leu Val Asp Thr Leu Lys1 5 1017214PRTGallus gallus 172Glu Leu Glu Trp Asn Ser Gly Ala Thr Ala Ala Val Gly Arg1 5 101739PRTGallus gallus 173Glu Thr Phe Gly Val Asp Ser Glu Arg1 517412PRTGallus gallus 174Glu Tyr Ser Ala Ser Ala Asn Tyr Asp Leu Gln Arg1 5 1017512PRTGallus gallus 175Phe Ala Leu Ser Gly Ile Val Thr Pro Gly Ala Lys1 5 101769PRTGallus gallus 176Phe Ala Val Gln Ala Glu Gly Val Lys1 517712PRTGallus gallus 177Phe Glu Val Glu Ile Val Ser Thr Gly Glu Val Lys1 5 1017810PRTGallus gallus 178Phe Ser Asn Asn Leu Gln Gly Ser Leu Lys1 5 101799PRTGallus gallus 179Phe Ser Gln Asn Tyr Gln Val Ser Lys1 518013PRTGallus gallus 180Gly Phe Glu Pro Thr Leu Glu Ala Leu Phe Gly Glu Lys1 5 101819PRTGallus gallus 181Gly Phe Phe Pro Asp Thr Ala Ser Lys1 518217PRTGallus gallus 182Gly Ile Ile Ser Ala Leu Leu Ala Pro Thr Glu Thr Glu Glu Asn Ile1 5 10 15Lys18310PRTGallus gallus 183Gly Leu Ala Leu Glu Ser Thr Asp Ala Lys1 5 1018411PRTGallus gallus 184Gly Ser Val Ala Glu Asp Ile Ser Ile Asn Arg1 5 1018513PRTGallus gallus 185Ile Glu Gly Gln Leu Glu Val Ala Ser Val Phe Ala Arg1 5 101868PRTGallus gallus 186Ile Gly Val Glu Leu Ser Gly Arg1 518715PRTGallus gallus 187Ile Lys Leu Pro Val Ile Thr Ile Pro Glu Glu Leu Phe Leu Lys1 5 10 151887PRTGallus gallus 188Ile Leu Gln Glu Leu Gln Lys1 518920PRTGallus gallus 189Ile Leu Thr Ser Asp Val Ser Ile Pro Asp Val Asp Val Asp Phe Gly1 5 10 15Thr Asn Phe Arg 2019011PRTGallus gallus 190Ile Pro Glu Ile Ile Ala Gln Ala Ile Ser Lys1 5 101919PRTGallus gallus 191Ile Pro Ser Tyr Glu Ile Asn Ile Arg1 519211PRTGallus gallus 192Ile Ser Glu Val Thr Leu Thr Gly Gln Ile Arg1 5 101939PRTGallus gallus 193Ile Thr Asp Glu Ser Val Ser Gly Lys1 519410PRTGallus gallus 194Lys Phe Ser Gln Asn Tyr Gln Val Ser Lys1 5 1019512PRTGallus gallus 195Lys Ile Ser Glu Val Thr Leu Thr Gly Gln Ile Arg1 5 1019611PRTGallus gallus 196Leu Ala Pro Thr Glu Thr Glu Glu Asn Ile Lys1 5

101979PRTGallus gallus 197Leu Asp Asn Ser Phe Ser Phe Asp Lys1 519815PRTGallus gallus 198Leu Asp Ser Ser Tyr Leu Gln Ala Thr Asn His Leu Ser Gly Arg1 5 10 1519915PRTGallus gallus 199Leu Asp Thr Ser Gly Gly Ser Val Ser Leu Ser Ser Ser Gly Arg1 5 10 1520019PRTGallus gallus 200Leu Glu Tyr Thr Asn Asp Leu Asn Ile Pro Gly Leu Ser Leu Thr Phe1 5 10 15Val Ser Lys2017PRTGallus gallus 201Leu Leu Thr Ser Asp Phe Lys1 52028PRTGallus gallus 202Leu Asn Leu Gly Gly Asn Val Arg1 520313PRTGallus gallus 203Leu Pro Val Ile Thr Ile Pro Glu Glu Leu Phe Leu Lys1 5 1020411PRTGallus gallus 204Leu Ser Phe Ser Ser Asp Val Val Ser Glu Lys1 5 1020511PRTGallus gallus 205Leu Ser Gly Leu Gln Glu Leu Asn Ile Gln Lys1 5 1020617PRTGallus gallus 206Leu Tyr Gly Phe Gly Pro Ser Asp Ile Phe Glu Leu Gly Leu Asp Gly1 5 10 15Lys20715PRTGallus gallus 207Leu Tyr Pro Glu Lys Asp Glu Pro Leu Asn Val Leu Asn Leu Lys1 5 10 152087PRTGallus gallus 208Asn Ile Asp Asp Glu Tyr Arg1 520910PRTGallus gallus 209Asn Pro Asp Gly Asp Glu Leu Glu Glu Lys1 5 102109PRTGallus gallus 210Asn Pro Ser Pro Ala Asp Leu Ala Lys1 521110PRTGallus gallus 211Asn Gln Ala Ala Ser Leu Ser Val Gln Lys1 5 1021214PRTGallus gallus 212Asn Ser Phe Leu Ile Asn Ile Pro Leu Pro Phe Gly Gly Arg1 5 102139PRTGallus gallus 213Gln Val Asp Phe Ser Asp Tyr Ser Lys1 521412PRTGallus gallus 214Arg Gly Ser Val Ala Glu Asp Ile Ser Ile Asn Arg1 5 1021513PRTGallus gallus 215Arg Val Ser Val Pro Gly Leu Asn Pro Ile Ser Ala Lys1 5 1021610PRTGallus gallus 216Ser Ala Ser Ala Asn Tyr Asp Leu Gln Arg1 5 102178PRTGallus gallus 217Ser Glu Tyr Gln Ala Thr Tyr Lys1 52189PRTGallus gallus 218Ser Phe Val Ala Ser His Ile Ala Asn1 52199PRTGallus gallus 219Ser Gly Ile Val Thr Pro Gly Ala Lys1 522012PRTGallus gallus 220Ser Gln Asp Ile Asn Ala Tyr Asn Asp Ala Glu Lys1 5 1022120PRTGallus gallus 221Ser Gln Leu Asn Asn Asn Ile Tyr Ser Gln Asp Ile Asn Ala Tyr Asn1 5 10 15Asp Ala Glu Lys 2022215PRTGallus gallus 222Thr Asp Thr Val Ala Asn Val Gln Gly Ala Ala Val Ser His Arg1 5 10 1522311PRTGallus gallus 223Thr Glu Ala Leu Val Asn Tyr Ser Pro Thr Lys1 5 1022411PRTGallus gallus 224Thr Glu Glu Ile Pro Pro Leu Ile Glu Asn Arg1 5 1022514PRTGallus gallus 225Thr Gly Asn Val Asn Pro Leu Val Val Asp Leu Val Thr Tyr1 5 1022625PRTGallus gallus 226Thr Gly Asn Val Asn Pro Leu Val Val Asp Leu Val Thr Tyr Thr Leu1 5 10 15Gly Leu Leu Pro Ser Pro Thr Pro Lys 20 2522712PRTGallus gallus 227Thr Pro Asp Phe Ile Val Pro Leu Thr Asp Leu Lys1 5 1022821PRTGallus gallus 228Thr Thr Leu Asn Leu Tyr Gly Phe Gly Pro Ser Asp Ile Phe Glu Leu1 5 10 15Gly Leu Asp Gly Lys 2022915PRTGallus gallus 229Val Glu Gly Asn Val Ile Phe Asp Pro Ser Ser Tyr Val Pro Lys1 5 10 152309PRTGallus gallus 230Val Phe Asp Leu Gln Leu Gln Pro Arg1 523110PRTGallus gallus 231Val Asn Leu Asn Val Ala Gly Leu Ala Ser1 5 1023212PRTGallus gallus 232Val Ser Val Pro Gly Leu Asn Pro Ile Ser Ala Lys1 5 102339PRTGallus gallus 233Val Thr Val Val Asp Thr Ile Gln Lys1 52348PRTGallus gallus 234Tyr Ala Asn Glu Leu Leu Asp Arg1 52358PRTGallus gallus 235Tyr Ser Thr Gln Leu Asp Asn Lys1 5236927DNAGallus gallus 236atgggccctg tgcggctctt gctgctcttg ctgctgctca gcagtggtgt tctcacacag 60gaaggaacac ctgaaaatgg aaacccagga tgttcaaaag atgcggcccg atttaaaagc 120cttagaaaat atgtttactt atatgaagca gaaacatcaa gtgggatcac gggaacagca 180gattctcgaa gcggttcaaa gatcacctgt aaagttgagt tggaggtacc acagctgtgc 240cagttcatcc tgaggacaat gcattgctcc ctaagggaga catttggtgt tgacagtgag 300agaagagcca tgctgaggaa gtcaaagaac tctgatgact ttgcaaatgc catgtccaaa 360catgagctaa gattcagcac tcaggatgga acaaaagtta aactatatcc agagaaggat 420gaacctctga atgtcctcaa tctcaagaga ggaattatct cagctctcct tgcaccaaca 480gaaacagagg aaaacataaa aacaatttcc atggatactg tatatggaaa gtgtgacagt 540gaggttgagt tcaaatccag aagaggaagt gttgcagaag atatttcaat taacaggaac 600ctgaaagcct gtgacaactt cagtccaatc agagattatg tcagccctgt tgccattgta 660aaaggactaa acatcccact atctaccctt ctgagtagca ctcaatcctg tcactacagt 720attgatgcaa agaaaaagca tatcagagat gttgtctgca gtgaaaaaca cctgtttctg 780ccttcctcat acaaaaatca gtatggtatg atgacagaag tcaaccagac actgaagctt 840gaagataatc agaggatgaa taacagaaat cctgatggag atgaactgga agagaaagga 900cttgcactgg aaagcacaga tgctaaa 927237309PRTGallus gallus 237Met Gly Pro Val Arg Leu Leu Leu Leu Leu Leu Leu Leu Ser Ser Gly1 5 10 15Val Leu Thr Gln Glu Gly Thr Pro Glu Asn Gly Asn Pro Gly Cys Ser 20 25 30Lys Asp Ala Ala Arg Phe Lys Ser Leu Arg Lys Tyr Val Tyr Leu Tyr 35 40 45Glu Ala Glu Thr Ser Ser Gly Ile Thr Gly Thr Ala Asp Ser Arg Ser 50 55 60Gly Ser Lys Ile Thr Cys Lys Val Glu Leu Glu Val Pro Gln Leu Cys65 70 75 80Gln Phe Ile Leu Arg Thr Met His Cys Ser Leu Arg Glu Thr Phe Gly 85 90 95Val Asp Ser Glu Arg Arg Ala Met Leu Arg Lys Ser Lys Asn Ser Asp 100 105 110Asp Phe Ala Asn Ala Met Ser Lys His Glu Leu Arg Phe Ser Thr Gln 115 120 125Asp Gly Thr Lys Val Lys Leu Tyr Pro Glu Lys Asp Glu Pro Leu Asn 130 135 140Val Leu Asn Leu Lys Arg Gly Ile Ile Ser Ala Leu Leu Ala Pro Thr145 150 155 160Glu Thr Glu Glu Asn Ile Lys Thr Ile Ser Met Asp Thr Val Tyr Gly 165 170 175Lys Cys Asp Ser Glu Val Glu Phe Lys Ser Arg Arg Gly Ser Val Ala 180 185 190Glu Asp Ile Ser Ile Asn Arg Asn Leu Lys Ala Cys Asp Asn Phe Ser 195 200 205Pro Ile Arg Asp Tyr Val Ser Pro Val Ala Ile Val Lys Gly Leu Asn 210 215 220Ile Pro Leu Ser Thr Leu Leu Ser Ser Thr Gln Ser Cys His Tyr Ser225 230 235 240Ile Asp Ala Lys Lys Lys His Ile Arg Asp Val Val Cys Ser Glu Lys 245 250 255His Leu Phe Leu Pro Ser Ser Tyr Lys Asn Gln Tyr Gly Met Met Thr 260 265 270Glu Val Asn Gln Thr Leu Lys Leu Glu Asp Asn Gln Arg Met Asn Asn 275 280 285Arg Asn Pro Asp Gly Asp Glu Leu Glu Glu Lys Gly Leu Ala Leu Glu 290 295 300Ser Thr Asp Ala Lys30523813PRTGallus gallus 238Ala Leu Leu Ala Pro Thr Glu Thr Glu Glu Asn Ile Lys1 5 1023910PRTGallus gallus 239Asp Tyr Val Ser Pro Val Ala Ile Val Lys1 5 102409PRTGallus gallus 240Glu Thr Phe Gly Val Asp Ser Glu Arg1 524117PRTGallus gallus 241Gly Ile Ile Ser Ala Leu Leu Ala Pro Thr Glu Thr Glu Glu Asn Ile1 5 10 15Lys24211PRTGallus gallus 242Gly Ser Val Ala Glu Asp Ile Ser Ile Asn Arg1 5 102439PRTGallus gallus 243His Leu Phe Leu Pro Ser Ser Tyr Lys1 524411PRTGallus gallus 244Leu Ala Pro Thr Glu Thr Glu Glu Asn Ile Lys1 5 102458PRTGallus gallus 245Leu Phe Leu Pro Ser Ser Tyr Lys1 524612PRTGallus gallus 246Leu Leu Ala Pro Thr Glu Thr Glu Glu Asn Ile Lys1 5 1024715PRTGallus gallus 247Leu Tyr Pro Glu Lys Asp Glu Pro Leu Asn Val Leu Asn Leu Lys1 5 10 1524818PRTGallus gallus 248Arg Gly Ile Ile Ser Ala Leu Leu Ala Pro Thr Glu Thr Glu Glu Asn1 5 10 15Ile Lys24910PRTGallus gallus 249Ser Val Ala Glu Asp Ile Ser Ile Asn Arg1 5 102501041DNAGallus gallus 250ctggatggct caaccagttt gacaagaaaa agaggactga agctggccac agcactgtct 60ctgaataata acaaatttct aggaggaagt catgacaaca gtattagtct cacaaagaag 120aacctggaag cttcaatgat aacaaatgca aaaatcaaca caccagtttt taaaatgaat 180ttcagccaag agctttctgg aaatactaaa tctaaaccca ctatttcttc agggctaaaa 240gtaacatatg actttactac tcctaagcat ggcatcagtg ctaagggagg agttgctcac 300aaacttgctt tagagactct tacatcttac ctgtcagtag aaacatcaac aaaggggaat 360atcgatggag caatttacac tggaaattca ttttctggag ctctagacca tgaagcaaac 420acctatctgc atgctaatgg agttcggtca tctctcaagc ttgaggccaa ctccaaagta 480gatggactct ggaacagtga aatgaaagaa atacttgcag ttgaagcatc taccagtcgt 540gtttatgcag tctgggagca caatgggaaa aactttgcac gatacacacc tctcttcaca 600acgacaggat ctcagaaatg caaagcaacc ttcgagctgg ctccttggac agtgtcagca 660gatcttcaga ttcaggtcac tcagccaaat tccttcctgg acacagcatc agttaatcaa 720gttgtcttaa tgaaagtcag tcctacagac cagaaagttg gctggaaggg tgaaggccaa 780attcagtcat tatctctgag acatgacatg caattatcaa atgaaaaatc aaatgcaaag 840tttgatattt ctggatcttt ggaagggtac atggacttcc tgaaaagaat taattgtgct 900atttctaaga agagcttgtg ggatatcttg aagttggatg tcactactgt tgctgacaga 960aagcactact taaatgcttc agcatccttc atatacagga agagtgatga tggttacttt 1020ttccctatgc ctgtgattag g 1041251347PRTGallus gallus 251Leu Asp Gly Ser Thr Ser Leu Thr Arg Lys Arg Gly Leu Lys Leu Ala1 5 10 15Thr Ala Leu Ser Leu Asn Asn Asn Lys Phe Leu Gly Gly Ser His Asp 20 25 30Asn Ser Ile Ser Leu Thr Lys Lys Asn Leu Glu Ala Ser Met Ile Thr 35 40 45Asn Ala Lys Ile Asn Thr Pro Val Phe Lys Met Asn Phe Ser Gln Glu 50 55 60Leu Ser Gly Asn Thr Lys Ser Lys Pro Thr Ile Ser Ser Gly Leu Lys65 70 75 80Val Thr Tyr Asp Phe Thr Thr Pro Lys His Gly Ile Ser Ala Lys Gly 85 90 95Gly Val Ala His Lys Leu Ala Leu Glu Thr Leu Thr Ser Tyr Leu Ser 100 105 110Val Glu Thr Ser Thr Lys Gly Asn Ile Asp Gly Ala Ile Tyr Thr Gly 115 120 125Asn Ser Phe Ser Gly Ala Leu Asp His Glu Ala Asn Thr Tyr Leu His 130 135 140Ala Asn Gly Val Arg Ser Ser Leu Lys Leu Glu Ala Asn Ser Lys Val145 150 155 160Asp Gly Leu Trp Asn Ser Glu Met Lys Glu Ile Leu Ala Val Glu Ala 165 170 175Ser Thr Ser Arg Val Tyr Ala Val Trp Glu His Asn Gly Lys Asn Phe 180 185 190Ala Arg Tyr Thr Pro Leu Phe Thr Thr Thr Gly Ser Gln Lys Cys Lys 195 200 205Ala Thr Phe Glu Leu Ala Pro Trp Thr Val Ser Ala Asp Leu Gln Ile 210 215 220Gln Val Thr Gln Pro Asn Ser Phe Leu Asp Thr Ala Ser Val Asn Gln225 230 235 240Val Val Leu Met Lys Val Ser Pro Thr Asp Gln Lys Val Gly Trp Lys 245 250 255Gly Glu Gly Gln Ile Gln Ser Leu Ser Leu Arg His Asp Met Gln Leu 260 265 270Ser Asn Glu Lys Ser Asn Ala Lys Phe Asp Ile Ser Gly Ser Leu Glu 275 280 285Gly Tyr Met Asp Phe Leu Lys Arg Ile Asn Cys Ala Ile Ser Lys Lys 290 295 300Ser Leu Trp Asp Ile Leu Lys Leu Asp Val Thr Thr Val Ala Asp Arg305 310 315 320Lys His Tyr Leu Asn Ala Ser Ala Ser Phe Ile Tyr Arg Lys Ser Asp 325 330 335Asp Gly Tyr Phe Phe Pro Met Pro Val Ile Arg 340 34525211PRTGallus gallus 252Glu Ile Leu Ala Val Glu Ala Ser Thr Ser Arg1 5 1025314PRTGallus gallus 253Phe Leu Gly Gly Ser His Asp Asn Ser Ile Ser Leu Thr Lys1 5 1025411PRTGallus gallus 254Gly Glu Gly Gln Ile Gln Ser Leu Ser Leu Arg1 5 102557PRTGallus gallus 255Ile Asn Thr Pro Val Phe Lys1 525617PRTGallus gallus 256Leu Ala Leu Glu Thr Leu Thr Ser Tyr Leu Ser Val Glu Thr Ser Thr1 5 10 15Lys25711PRTGallus gallus 257Leu Ala Thr Ala Leu Ser Leu Asn Asn Asn Lys1 5 102589PRTGallus gallus 258Leu Asp Gly Ser Thr Ser Leu Thr Arg1 52598PRTGallus gallus 259Pro Thr Ile Ser Ser Gly Leu Lys1 526012PRTGallus gallus 260Tyr Thr Pro Leu Phe Thr Thr Thr Gly Ser Gln Lys1 5 10261741DNAGallus gallus 261accccagtgt tagctgcttt tctccatggc attagtaaca ataagaagac aggaggcctc 60cagcttgtgg tatatgctga taccgactcg gtcaggccgc gggtgcaggt atttgtgaca 120aacctcacag attcgagcaa gtggaagctc tgcgcagatg cttcggtccg caatgctcac 180aaggcagtgg cctacgtgaa atggggctgg gactgccggg actacaaggt ttctactgag 240ctggtaactg ggcggtttgc tgggcaccct gctgcacaag tgaagctgga gtggcccaag 300gttccttcga atgtcagatc agtggttgaa tggttttacg agtttgtccc tggggctgca 360tttatgctgg gtttctctga gagaatggac aagaatcctt ctcgacaagc caggatggtt 420gtggctctaa cttctccgag gacatgtgat gttgttgtca agctgcctga tataatcctc 480tatcaaaaag ccgtgaggct tcctctatca ctccctgtgg gtccaaggat cccagcttca 540gagctgcagc ctccaatctg gaacgtcttt gctgaagccc cctctgccgt gctcgagaat 600ttgaaagctc gctgctcagt ttcgtacaac aagatcaaaa cctttaatga agtcaagttc 660aactactcga tgcccgcaaa ctgctatcac atcttggttc aggattgcag ctctgaactt 720aagttcctgg tgatgatgaa a 741262247PRTGallus gallus 262Thr Pro Val Leu Ala Ala Phe Leu His Gly Ile Ser Asn Asn Lys Lys1 5 10 15Thr Gly Gly Leu Gln Leu Val Val Tyr Ala Asp Thr Asp Ser Val Arg 20 25 30Pro Arg Val Gln Val Phe Val Thr Asn Leu Thr Asp Ser Ser Lys Trp 35 40 45Lys Leu Cys Ala Asp Ala Ser Val Arg Asn Ala His Lys Ala Val Ala 50 55 60Tyr Val Lys Trp Gly Trp Asp Cys Arg Asp Tyr Lys Val Ser Thr Glu65 70 75 80Leu Val Thr Gly Arg Phe Ala Gly His Pro Ala Ala Gln Val Lys Leu 85 90 95Glu Trp Pro Lys Val Pro Ser Asn Val Arg Ser Val Val Glu Trp Phe 100 105 110Tyr Glu Phe Val Pro Gly Ala Ala Phe Met Leu Gly Phe Ser Glu Arg 115 120 125Met Asp Lys Asn Pro Ser Arg Gln Ala Arg Met Val Val Ala Leu Thr 130 135 140Ser Pro Arg Thr Cys Asp Val Val Val Lys Leu Pro Asp Ile Ile Leu145 150 155 160Tyr Gln Lys Ala Val Arg Leu Pro Leu Ser Leu Pro Val Gly Pro Arg 165 170 175Ile Pro Ala Ser Glu Leu Gln Pro Pro Ile Trp Asn Val Phe Ala Glu 180 185 190Ala Pro Ser Ala Val Leu Glu Asn Leu Lys Ala Arg Cys Ser Val Ser 195 200 205Tyr Asn Lys Ile Lys Thr Phe Asn Glu Val Lys Phe Asn Tyr Ser Met 210 215 220Pro Ala Asn Cys Tyr His Ile Leu Val Gln Asp Cys Ser Ser Glu Leu225 230 235 240Lys Phe Leu Val Met Met Lys 24526310PRTGallus gallus 263Phe Ala Gly His Pro Ala Ala Gln Val Lys1 5 1026419PRTGallus gallus 264Lys Thr Gly Gly Leu Gln Leu Val Val Tyr Ala Asp Thr Asp Ser Val1 5 10 15Arg Pro Arg26510PRTGallus gallus 265Leu Pro Leu Ser Leu Pro Val Gly Pro Arg1 5 102669PRTGallus gallus 266Thr Gly Gly Leu Gln Leu Val Val Tyr1 52679PRTGallus gallus 267Ala Asp Thr Asp Ser Val Arg Pro Arg1 526815PRTGallus gallus 268Thr Pro Val Leu Ala Ala Phe Leu His Gly Ile Ser Asn Asn Lys1 5 10 1526913PRTGallus gallus 269Val Gln Val Phe Val Thr Asn Leu Thr Asp Ser Ser Lys1 5 102709PRTGallus gallus 270Val Ser Thr Glu Leu Val Thr Gly Arg1 52718PRTGallus gallus 271Val Val Ala Leu Thr Ser Pro Arg1 5

Claims

1. A kit for diagnosing an egg allergy, the kit comprising, as an antigen, at least one protein defined in any one of the following (1) to (3): (1) (1A) a protein comprising a C-terminal portion of Vitellogenin-3 or a variant thereof, which is defined below in any of (1A-a) to (1A-e) which is an antigen for the egg allergy: (1A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 2; (1A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 2; (1A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 1; (1A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 1; or (1A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 1; or (1B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 2-11; (2) (2A) a protein comprising a C-terminal portion of Vitellogenin-3 or a variant thereof, which is defined below in any of (2A-a) to (2A-e) which is an antigen for the egg allergy: (2A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 13; (2A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 13; (2A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 12; (2A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 12; or (2A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 12; or (2B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 9-11, 13, 14, and 16; (3) (3A) A protein comprising a middle portion of Vitellogenin-1 or a C-terminal portion of Lipovitelin-1 or a variant thereof, which is defined below in any of (3A-a) to (3A-e) which is an antigen for the egg allergy: (3A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 18; (3A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 18; (3A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 17; (3A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 17; or (3A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 17; or (3B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 18-45.

2. A kit for diagnosing an egg allergy, the kit comprising, as an antigen, at least one protein defined in any one of the following (4) to (10): (4) (4A) a protein comprising Vitellogenin-3 or a variant thereof, which is defined below in any of (4A-a) to (4A-e) which is an antigen for the egg allergy: (4A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 47; (4A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 47; (4A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 46; (4A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 46; or (4A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 46; or (4B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 47-57, (5) (5A) a protein comprising a Vitellogenin-2 precursor or a variant thereof, which is defined below in any of (5A-a) to (5A-e) which is an antigen for the egg allergy: (5A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 59; (5A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 59; (5A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 58; (5A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 58; or (5A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 58; or (5B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 59-104; (6) (6A) a Vitellogenin-2 precursor or a variant thereof, which is defined below in any of (6A-a) to (6A-e) which is an antigen for the egg allergy: (6A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 106; (6A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 106; (6A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 105; (6A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 105; or (6A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 105; or (6B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 106-150; (7) (7A) an Apolipoprotein B precursor or a variant thereof, which is defined below in any of (7A-a) to (7A-e) which is an antigen for the egg allergy: (7A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 152; (7A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 152; (7A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 151; (7A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 151; or (7A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 151; or (7B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 152-235; (8) (8A) an Apolipoprotein B precursor or a variant thereof, which is defined below in any of (8A-a) to (8A-e) which is an antigen for the egg allergy: (8A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 237; (8A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 237; (8A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 236; (8A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 236; or (8A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 236; or (8B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 237-249; (9) (9A) an Apolipoprotein B precursor or a variant thereof, which is defined below in any of (9A-a) to (9A-e) which is an antigen for the egg allergy: (9A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 251; (9A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 251; (9A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 250; (9A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 250; or (9A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 250; or (9B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 251-260; (10) (10A) a Vitellogenin-2 precursor or a variant thereof, which is defined below in any of (10A-a) to (10A-e) which is an antigen for the egg allergy: (10A-a) a protein comprising an amino acid sequence with deletion, substitution, insertion or addition of one or several amino acids in SEQ ID NO: 262; (10A-b) a protein comprising an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 262; (10A-c) a protein comprising an amino acid sequence encoded by a nucleotide sequence with deletion, substitution, insertion or addition of one or several nucleotides in SEQ ID NO: 261; (10A-d) a protein comprising an amino acid sequence encoded by a nucleotide sequence having at least 70% identity to the nucleotide sequence of SEQ ID NO: 261; or (10A-e) a protein comprising an amino acid sequence encoded by a nucleic acid that hybridizes under stringent conditions with a nucleic acid having a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO: 261; or (10B) a protein comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 262-271.

3. A composition for diagnosing an egg allergy, the composition comprising, as an antigen, at least one of proteins as defined in any of (1) to (3) of claim 1.

4. A method for providing an indicator for diagnosing an egg allergy in a subject, the method comprising the steps of: (i) contacting a sample obtained from the subject with an antigen, wherein the sample is a solution comprising an IgE antibody; (ii) detecting binding between an IgE antibody present in the sample from the subject and the antigen; and (iii) when the binding between the IgE antibody in the subject and the antigen is detected, an indicator of the fact that the subject is allergic to an egg is provided; wherein the antigen is at least one of proteins as defined in any of (1) to (3) of claim 1.

5. A pharmaceutical composition comprising at least one of the proteins as defined in (1) to (3) of claim 1.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is intended for the treatment of an egg allergy.

7. An egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which an antigen is eliminated or reduced, wherein the antigen is at least one of the proteins as defined in (1) to (3) of claim 1.

8. A tester for determining the presence or absence of an egg antigen in an object of interest, comprising an antibody which binds to at least one of the proteins as defined in (1) to (3) of claim 1.

9. A tester for determining the presence or absence of an antigen for an egg allergy in an object of interest, comprising a primer having a nucleotide sequence complementary to at least one of the nucleotide sequences set forth in SEQ ID NO: 1, 12, 17, 46, 58, 105, 151, 236, 250, or 261.

10. A method for producing a processed product of an egg in which an antigen is eliminated or reduced, comprising the step of confirming that the antigen is eliminated or reduced in the process of producing the processed product, wherein the antigen is at least one of the proteins as defined in any of (1) to (3) of claim 1.

11. An antigen derived from an egg, wherein the antigen is at least one of the proteins as defined in any of (1) to (3) of claim 1 and causative of an egg allergy.

12. A composition for diagnosing an egg allergy, the composition comprising, as an antigen, at least one of proteins as defined in any of (4) to (10) of claim 2.

13. A method for providing an indicator for diagnosing an egg allergy in a subject, the method comprising the steps of: (i) contacting a sample obtained from the subject with an antigen, wherein the sample is a solution comprising an IgE antibody; (ii) detecting binding between an IgE antibody present in the sample from the subject and the antigen; and (iii) when the binding between the IgE antibody in the subject and the antigen is detected, an indicator of the fact that the subject is allergic to an egg is provided; wherein the antigen is at least one of proteins as defined in any of (4) to (10) of claim 2.

14. A pharmaceutical composition comprising at least one of the proteins as defined in (4) to (10) of claim 2.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is intended for the treatment of an egg allergy.

16. An egg, a processed product of an egg, or a bird which lays or has hatched from the egg in which an antigen is eliminated or reduced, wherein the antigen is at least one of the proteins as defined in (4) to (10) of claim 2.

17. A tester for determining the presence or absence of an egg antigen in an object of interest, comprising an antibody which binds to at least one of the proteins as defined in (4) to (10) of claim 2.

18. A method for producing a processed product of an egg in which an antigen is eliminated or reduced, comprising the step of confirming that the antigen is eliminated or reduced in the process of producing the processed product, wherein the antigen is at least one of the proteins as defined in any of (4) to (10) of claim 2.

19. An antigen derived from an egg, wherein the antigen is at least one of the proteins as defined in any of (4) to (10) of claim 2 and causative of an egg allergy.