KR20200040049A - Analytical method for diagnosing premature ovarian failure and kit therefor - Google Patents

Abstract

The present invention provides an analysis method comprising a step of measuring, in blood of a subject, the overexpression of a gene encoding one or more proteins selected from the group consisting of complement component 3, fibrinogen α, fibrinogen β, fibrinogen γ, ceruloplasmin, and sex hormone-binding globulin, in order to provide information about the diagnosis of premature menopause. Also, the present invention provides a kit for diagnosing premature menopause, comprising a molecule capable of measuring the overexpression of a gene encoding the proteins.

Description

Analytical method for diagnosing premature ovarian failure and kit therefor}

The present invention relates to an analytical method and kit for diagnosing early menopause to provide information necessary for early menopause diagnosis.

Women will experience menopause after their 50s. However, premature menopause (POF) is a pathological condition in which menopause occurs before the forties. Early menopause means that the follicle is completely depleted. The causes of premenopause are known as infection, surgery, chemotherapy or radiation therapy, ovarian damage, autoimmune diseases, and genetic diseases, but the exact cause is still unknown (Jankowska, K. (2017) .Premature ovarian failure. Prz Menopauzalny , 16 (2), 51-56. doi: 10.5114 / pm.2017.68592).

If you have no menstruation for more than 6 months before the age of 40 and your blood follicle stimulating hormone (FSH) is 40 IU / liter or more, it is usually diagnosed as early menopause. However, the diagnosis of early menopause is not only dependent on the level of follicle stimulating hormone (FSH), but various factors should be considered (K. Jankowska, Premature ovarian failure, Prz Menopauzalny, 16 (2017) 51-56; MB Bhongade, et. al., Effect of psychological stress on fertility hormones and seminal quality in male partners of infertile couples, Andrologia, 47 (2015) 336-342). For example, reduced estradiol (E2) triggers a feedback mechanism to stimulate the anterior pituitary gland, resulting in increased follicle stimulating hormone (FSH). In addition, anti-Mullerian hormone (AMH) levels are known to be very low in premenopausal patients and are therefore used as diagnostic markers for premenopause (K. Jankowska, Premature ovarian failure, Prz Menopauzalny, 16 ( 2017) 51-56; A. Kruszynska, et al., Anti-Mullerian hormone (AMH) as a good predictor of time of menopause, Prz Menopauzalny, 16 (2017) 47-50; Y. Tokura, et al. The significance of serum anti-Mullerian hormone (AMH) levels in patients over age 40 in first IVF treatment, J Assist Reprod Genet, 30 (2013) 821-825). AMH is produced by prefollicular follicles and follicle follicles, and is utilized as a blood biomarker for early menopause diagnosis.

Proteomics can be used to identify biomarkers of disease. The proteomics method is used to discover biomarkers through two-dimensional electrophoresis (2-DE) and liquid chromatography-mass spectrometry (LC-MS / MS). Methods have been used to identify biomarkers of many reproductive diseases (YS Kim, et al., Proteomic analysis of recurrent spontaneous abortion: Identification of an inadequately expressed set of proteins in human follicular fluid, Proteomics, 6 (2006) 3445-3454; MS Kim, et al., ITI-H4, as a biomarker in the serum of recurrent pregnancy loss (RPL) patients, Mol Biosyst, 7 (2011) 1430-1440; S. Angelucci, et al., Proteome analysis of human follicular fluid, Biochim Biophys Acta, 1764 (2006) 1775-1785), so far no specific biomarker has been identified for early menopause.Identification of biomarkers is required in the art.

The present inventors performed proteomic analysis through 2-DE-MS / MS in order to identify biomarkers capable of diagnosing premenopause, particularly biomarkers capable of diagnosing premenopause using a small amount of blood as a sample. Did. As a result, the present inventors have found that six specific proteins previously unknown in relation to early menopause are overexpressed in the blood of early menopausal patients. Therefore, the overexpression detection of these proteins can be usefully used to diagnose early menopause, and these proteins can be used as biomarkers for early menopause diagnosis.

Accordingly, an object of the present invention is to provide an analysis method using the specific protein in order to provide information necessary for early menopause diagnosis.

In addition, an object of the present invention is to provide a kit for diagnosing early menopause, which includes a molecule capable of measuring the expression level of a gene encoding the specific protein.

According to an aspect of the present invention, in order to provide information necessary for diagnosing premenopause, Complement component 3, Fibrinogen α, Fibrinogen α in a subject's blood Overexpression of genes encoding proteins selected from one or more of the group consisting of Fibrinogen β, Fibrinogen γ, Celluloplasmin, and Sex hormone-binding globulin An analysis method is provided that includes measuring.

In the analysis method of the present invention, the gene encoding the protein may be a gene encoding one or more proteins selected from proteins consisting of the amino acid sequence of SEQ ID NOs: 1 to 15, for example, of SEQ ID NOs: 16 to 30 One or more kinds may be selected from genes consisting of nucleotide sequences. In one embodiment, the assay method of the invention is from the group consisting of Complete Component 3, Fibrinogen α, Fibrinogen β, Fibrinogen γ, Celluloplasmin, and Sex Hormone-binding Globulin. It can be performed by measuring the over-expression of a gene encoding two or more selected proteins.

Measurement of the overexpression of the gene can be performed by measuring the amount of mRNA or protein. In one embodiment, the measurement of the amount of protein can be performed by Western blotting. In other embodiments, the measurement of the amount of mRNA may be performed through RT-PCR or real-time PCR.

According to another aspect of the invention, at least one member from the group consisting of completion component 3, fibrinogen α, fibrinogen β, fibrinogen γ, cellulose plasmin, and sex hormone-binding globulin A kit for diagnosing early menopause comprising a molecule capable of measuring the overexpression of a gene encoding a selected protein, the antibody, substrate, ligand, or cofactor that the molecule specifically binds to the protein; Alternatively, a kit for diagnosing premenopause, which is a primer having a complementary sequence specific for a gene encoding the protein, is provided.

In the kit for diagnosing early menopause of the present invention, the gene encoding the protein may be a gene encoding one or more proteins selected from proteins consisting of the amino acid sequences of SEQ ID NOs: 1 to 15, for example, SEQ ID NOs: 16 to 30 It may be selected from one or more genes consisting of the base sequence of.

In one embodiment, the kit for diagnosing premenopause of the present invention comprises Complete Component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and sex hormone-binding globulin It may include a molecule capable of measuring the overexpression of a gene encoding a protein selected from two or more groups.

In the kit for diagnosing premenopause of the present invention, the molecule may be labeled with a detectable label. In addition, the primer may be in the form of a microarray immobilized on a substrate.

Certain proteins, such as Complete Component 3, Fibrinogen α, Fibrinogen β, Fibrinogen γ, Celluloplasmin, and sex hormone-binding globulin, are overexpressed in the blood of premenopausal patients It was revealed by the present invention. Therefore, the analysis methods and kits according to the present invention using these proteins as biomarkers can be usefully used to diagnose premenopause.

1 shows the results obtained by performing a 2-DE analysis on plasma samples of a normal control group (A) and three early menopausal patients (BD). In FIG. 1, green indicates protein spots expressed in both control and early menopause patients, and red indicates proteins expressed only in control or early menopause patients.
FIG. 2 shows the results of Western blotting analysis on 31 control samples, FIG. 3 shows the results of Western blotting on 23 risk group (POF risk group) samples, and FIG. 4 shows the results of Western blotting on 12 patient groups 5 shows the results obtained by calculating the relative expression ratio of each protein based on the results of FIGS. 2 to 4.

The present inventors performed 2-DE-LC-MS / MS (two-dimensional electrophoresis-liquid chromatography-mass spectrometry) analysis by separating plasma from the blood of premenopausal patients, and proteins expressing the difference in expression in premenopausal patients and controls Were analyzed. The expression pattern of the protein specifically expressed in the analyzed early menopausal patient is re-verified through Western blot technique, and six proteins, namely, Complement component 3, and fibrinogen α (Fibrinogen α), Fibrinogen β, Fibrinogen γ, Celluloplasmin, and Sex hormone-binding globulin were identified. . These six proteins can be used as biomarkers for diagnosing premenopause using a small amount of blood, and are expected to be useful in the study of molecular biology mechanisms of premenopause.

The present invention, in order to provide information necessary for the diagnosis of early menopause, Complement component 3 (Fibrinogen α), Fibrinogen β (Fibrinogen β), blood in the subject's blood Measuring the overexpression of a gene encoding one or more selected proteins from the group consisting of fibrinogen γ, celluloplasmin, and sex hormone-binding globulin It provides an analysis method that includes.

In the present specification, the term "overexpression" refers to a gene encoding at least about 1.5 times the gene encoding the protein in premenopausal patients compared to normal persons. Accordingly, in the analysis method of the present invention, the coding for the gene encoding the complement component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and sex hormone-binding globulin If the gene to be expressed is about 1.5 times or more compared to the normal person, it can be diagnosed as an early menopausal patient.

The protein used as a biomarker in the analysis method of the present invention and the gene encoding the same are all known, and thus, a known protein and gene sequence can be used in the analysis method of the present invention. The protein sequence and gene sequence of Complement component 3 are as shown in SEQ ID NOs: 1 and 16, respectively. Fibrinogen α is known to have two isoforms, and the protein sequence is the same as SEQ ID NOs: 2 and 3, respectively, and its gene sequence is the same as SEQ ID NOs: 17 and 18, respectively. Two isoforms of Fibrinogen β are also known, and the protein sequences are the same as SEQ ID NOs: 4 and 5, respectively, and their gene sequences are the same as SEQ ID NOs: 19 and 20, respectively. Fibrinogen γ also has two isoforms, the protein sequence is the same as SEQ ID NOs: 6 and 7, respectively, and the gene sequence thereof is the same as SEQ ID NOs: 21 and 22, respectively. Celluloplasmin (Ceruloplasmin) protein sequences and gene sequences are as shown in SEQ ID NOs: 8 and 23, respectively. Sex hormone-binding globulin (Sex hormone-binding globulin) is known to have 7 isoforms, the protein sequence is the same as SEQ ID NO: 9 to 15, respectively, and its gene sequence is the same as SEQ ID NO: 24 to 30. In summary, it is shown in Table 1 below.

protein gene COMPLETE COMPONENT 3 Complement component 3 SEQ ID NO: 1 SEQ ID NO: 16 Fibrinogen α fibrinogen alpha chain isoform alpha-E preproprotein SEQ ID NO: 2 SEQ ID NO: 17 fibrinogen alpha chain isoform alpha precursor SEQ ID NO: 3 SEQ ID NO: 18 Fibrinogen β fibrinogen beta chain isoform 2 preproprotein SEQ ID NO: 4 SEQ ID NO: 19 fibrinogen beta chain isoform 1 preproprotein SEQ ID NO: 5 SEQ ID NO: 20 Fibrinogen γ fibrinogen gamma chain isoform gamma-A precursor SEQ ID NO: 6 SEQ ID NO: 21 fibrinogen gamma chain isoform gamma-B precursor SEQ ID NO: 7 SEQ ID NO: 22 Cellulose plasmin Ceruloplasmin SEQ ID NO: 8 SEQ ID NO: 23 Sex hormone-binding globulin Sex hormone-binding globulin isoform 1 precursor SEQ ID NO: 9 SEQ ID NO: 24 Sex hormone-binding globulin isoform 2 precursor SEQ ID NO: 10 SEQ ID NO: 25 Sex hormone-binding globulin isoform 3 precursor SEQ ID NO: 11 SEQ ID NO: 26 Sex hormone-binding globulin isoform 4 precursor SEQ ID NO: 12 SEQ ID NO: 27 Sex hormone-binding globulin isoform 5 precursor SEQ ID NO: 13 SEQ.ID No. 28 Sex hormone-binding globulin isoform 6 precursor SEQ ID NO: 14 SEQ ID NO: 29 Sex hormone-binding globulin isoform 7 precursor SEQ ID NO: 15 SEQ ID NO: 30

Accordingly, in the analysis method of the present invention, the gene encoding the protein may be a gene encoding a protein selected from one or more types of proteins consisting of the amino acid sequence of SEQ ID NOs: 1 to 15, for example, SEQ ID NOs: 16 to One or more genes may be selected from genes consisting of 30 nucleotide sequences. In addition, the analysis method of the present invention can further increase the diagnostic efficiency of early menopause by using a combination of two or more of the six biomarkers. That is, in one embodiment, the analytical method of the present invention consists of Complete Component 3, Fibrinogen α, Fibrinogen β, Fibrinogen γ, Celluloplasmin, and Sex Hormone-binding Globulin It may be performed by measuring the overexpression of a gene encoding two or more proteins selected from the group, preferably six proteins.

Measurement of the overexpression of the gene may be performed by measuring the level of mRNA or protein of the gene (ie, a protein selected from the group consisting of proteins of SEQ ID NOs: 1 to 15) according to a method commonly used in the field of biotechnology. You can. The protein amount can be measured by Western blotting or the like. When the amount of protein is measured by the Western blotting method, it can be determined as an early menopausal risk patient when the measured protein expression level is 1.5 times or 2 times higher than the protein expression level of a normal person. In addition, the measurement of the amount of mRNA of the gene encoding the protein (for example, a gene selected from the group consisting of the nucleotide sequence of SEQ ID NOs: 16 to 30) is reverse transcription-PCR (Reverse Transcription PCR) or real-time PCR (Real Time PCR). ) And the like.

The present invention also encodes a protein selected from one or more of the group consisting of Complement Component 3, Fibrinogen α, Fibrinogen β, Fibrinogen γ, Celluloplasmin, and sex hormone-binding globulin. A kit for diagnosing early menopause comprising a molecule capable of measuring the overexpression of a gene, an antibody, substrate, ligand, or cofactor to which the molecule specifically binds to the protein; Alternatively, a kit for diagnosing early menopause, which is a primer having a complementary sequence specific for a gene encoding the protein, is provided.

Complement component 3, a molecule capable of measuring the expression level of a gene encoding fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and / or sex hormone-binding globulin As, an antibody, substrate, ligand, or cofactor specifically binding to the protein; Or it may be a primer having a complementary sequence specific for the gene encoding the protein. For example, in the kit for diagnosing premenopause in the present invention, the gene encoding the protein may be a gene encoding a protein selected from one or more types of proteins consisting of the amino acid sequence of SEQ ID NOs: 1 to 15, for example, a sequence. One or more genes may be selected from genes consisting of nucleotide sequences of numbers 16 to 30. In addition, the kit for diagnosing early menopause of the present invention is 2 from the group consisting of complete component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and sex hormone-binding globulin. It may include a molecule capable of measuring the overexpression of a gene encoding a protein selected from more than one species, preferably six kinds of proteins.

Complement component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and / or sex hormone-binding globulins are poly according to methods commonly used in the field of biotechnology. A clone antibody or a monoclonal antibody can be prepared, and a diagnostic kit containing the antibody can be prepared. In addition, Complement Component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and / or sex hormone-binding globulin have a known function, and thus substrate, ligand Alternatively, the kit of the present invention may be manufactured to include an auxiliary factor. In addition, complementary sequences specific for genes encoding complement component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and / or sex hormone-binding globulin The primers can be prepared according to a method commonly used in the field of biotechnology, and a diagnostic kit including the primers can be prepared. In addition, the molecule can be labeled with a detectable label (eg, chromophore, etc.). In addition, the diagnostic kit of the present invention may be in the form of a chip such as a DNA chip or a protein chip by having a microarray form in which the primer is immobilized on a substrate.

Hereinafter, the present invention will be described in more detail through examples. However, the following examples are intended to illustrate the invention, but the invention is not limited by these examples.

Example

1. Test method

(1) patient recruitment

All blood samples (12 early menopausal patients, 23 at risk, and 136 controls) were provided from Korea University Anam Hospital in Seoul, Korea from October 2016 to December 2017. Early menopausal patients were diagnosed based on hormone tests of AMH, FSH, and estrogen. All samples were selected based on AMH levels below 0.01 ng / ml. 2 ml of blood sample was taken from each premenopausal patient. The collected blood samples were centrifuged at 1,500 X g for 15 minutes to separate into plasma and blood cells. Plasma was stored at -80 ° C for testing.

(2) Two-dimensional electrophoresis (2-DE) analysis

A 2-DE analysis was performed using plasma from 3 premenopausal patients. For comparison, three normal samples were randomly mixed and used as a super control. Plasma samples were filtered using a Multiple Affinity Removal Column (MARC) (Agilent, Wilmington, DE, USA) to remove 12 proteins that are highly expressed in plasma. Isoelectric focusing (IEF) was performed with a 3-10 Nonlinear Immobilized pH Gradient (NLIPG) at 80,000 V / hr and visualized using a 9-17% gradient slab gel.

(3) LC-MS / MS for Q-TOF peptide analysis

Nano LC-MS / MS analysis was performed using a nano HPLC system (Agilent, Wilmington, DE, USA). For peptide separation, a nano chip column (150 mm × 0.075 mm, Agilent, Wilmington, DE, USA) was used. Mobile phase A for LC separation was a 0.1% formic acid solution in deionized water, and mobile phase B was a 0.1% formic acid solution in acetonitrile. The chromatography gradient was designed to increase linearly from 3% B to 45% B for 70 minutes, 45% B to 95% B for 1 minute, 95% B for 9 minutes, and 3% B for 10 minutes. The flow rate was maintained at 300 nL / min. The ion spectrum of the product was obtained in an information-dependent acquisition (IDA) mode, one full scan TOF MS (TOF MS) from 300-2000 m / z (1.0 sec) and 150-2000 m / z (1.5 sec) Each product was analyzed with an Agilent 6530 Accurate-Mass Q-TOF using a continuous cycle of three product ion scans. Using the selection quadrupole resolution of 3 Da, the precursor m / z value was selected starting from the strongest ion. A rolling collision energy feature was used to determine the impulse energy based on the precursor value and the state of charge. The dynamic exclusion time for the precursor ion m / z value was 60 seconds.

(4) Database search

The Mascot algorithm (http://www.matrixscience.com, Matrixscience, Boston, MA, USA) was used to identify peptide sequences in the protein sequence database. The criteria for the search are: 1. taxonomy, 2. mykiss fixed modification, 3. carboxyamidomethylated at cysteine residues, 4. variable transformation modification, 5. oxidation at methionine residues, 6. maximum allowed missed cleavage: 7. MS tolerance: 100 ppm, 8. MS / MS tolerance: 0.1 Da. Only proteins caused by digestion with trypsin were considered.

(5) Western blotting

Plasma was separated by centrifugation at 1,500 X g for 15 minutes. After diluting the diluted plasma protein with a 2X SDS protein loading buffer for 10 minutes, the sample was loaded onto an SDS-PAGE gel and polyvinylidene fluoride (PVDF) microporous membrane (Millipore, Billerica, MA, USA). The primary antibody was incubated with the membrane at 4 ° C. overnight, then washed, the secondary antibody was added and incubated for 1 hour at room temperature. Blots were detected using ECL reagent solution (Young In Frontier, Seoul, Korea).

(6) Antibodies

Mouse anti-C3 (C-4) monoclonal antibody (sc-25298) and anti-fibrinogen γ (sc-133157), rabbit anti-celluloplasmin (H-60) polyclonal antibody (sc-20957) ), Goat anti-fibrinogen α (sc-18026), and anti-fibrinogen β (sc-18029) antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Rabbit anti-SHBG polyclonal antibody (CSB-PA12289A0Rb) was purchased from CUSABIO (Wuhan, China).

(7) Statistical analysis

Densitometric analysis was performed with Image J (National Institutes of Health, Bethesda, MD, USA), and t-test was performed with GraphPad Prism version 5 (GraphPad Software, La Jolla, CA, USA). ANOVA was performed by one-way analysis to show significant differences.

2. Test results

(1) Classification of blood samples

To investigate proteins related to early menopause using proteomics analysis, patients suspected of early menopause were screened and hormone tests were performed. Menopause was diagnosed by measuring the level of hormones in the blood and is biochemically characterized by high levels of FSH and low levels of AMH. Based on the AMH level, a person who is at least the median of the subject's age group is the control group, a value that is 10% or more greater than the median age group of the subject is the POF risk group, and a value of 10% or less of the age group of the subject is the patient group Was made. A total of 136 controls, 23 risk groups, and 12 patient groups were recruited. Blood was collected and centrifuged at 1,500 X g for 15 minutes to separate into plasma and blood cells.

(2) Spot analysis showing the difference in expression through 2-DE-LC-MS / MS

In order to identify proteins that show differences in expression in premenopausal patients, 2-DE analysis was performed using plasma of premenopausal patients. To compare the protein expression levels of normal (control) and early menopausal patients, plasma samples from 3 early menopausal patients and 1 normal plasma sample (super control obtained by randomly mixing and mixing 3 control samples) were used. MARC was used to remove 12 proteins that are highly expressed in plasma. As a result of performing 2-DE separation, spots of 301 (A) and 340 (B), 375 (C), and 339 (D) in the early menopausal patient sample were detected in the control sample (FIG. 1). . In FIG. 1, green indicates protein spots expressed in both control and early menopause patients, and red indicates proteins expressed only in control or early menopause patients.

Through comparison with the control spot, spots that were increased or decreased by 2 times or more were separated. As a result of analysis using the MALD-TOF-MS / MS analysis, 5 proteins increased expression more than 2 times in control or early menopause, and 30 spots increased expression more than 2 times in normal or early menopause patients, or Decreased. Of these, a total of 11 proteins were found to have significance, of which 5 proteins were expressed more than 2 times in premenopausal patients compared to the control group, and 5 proteins were expressed more than 2 times in premenopausal patients compared to the control group. This decreased, and one protein was specifically expressed in premenopausal patients (Table 2).

From the results of the 2-DE-LC-MS / MS analysis, compared to the control group, the protein whose expression increased more than 2 times in premenopausal patients is Complement component 3, Fibrinogen α, And Fibrinogen β, and the protein whose expression was reduced more than 2 times in premenopausal patients compared to the control group was Celluloplasmin. In addition, the protein specifically expressed in premenopausal patients was sex hormone-binding globulin.

(3) Protein assay in premenopausal patients

In order to assay the protein obtained through 2-DE-LC-MS / MS analysis, Western blotting was performed. For comparison of the control group and the patient group, FIG. 2 shows the results of Western blotting on 31 control samples, FIG. 3 shows the results of Western blotting on 23 risk group (POF risk group) samples, and FIG. 4 shows 12 patient groups. This is the result of Western Blotting. 3 and 4, "C" is a result of Western blotting performed after mixing a control sample. 5 is a result obtained by calculating the relative expression ratio of each protein based on the results of FIGS. 2 to 4.

As can be seen from the results of FIGS. 2 to 5, celluloplasmin was expressed higher in the patient group than in the control group. Other proteins, complete component 3, fibrinogen α, fibrinogen β, and fibrinogen γ were each expressed higher in the patient group than in the control group, which is 2-DE-LC-MS / It is consistent with the results of MS analysis. In addition, it was confirmed that sex hormone-binding globulin (SHBG), a protein specifically expressed in the patient group, is expressed in all patient group samples. Therefore, celluloplasmin, completion component 3, fibrinogen α, fibrinogen β, fibrinogen γ, and sex hormone-binding globulin are expressed higher in the patient group than in the control group, so these proteins It is possible to use them as biomarkers for early menopause diagnosis.

3. Discussion

The present inventors analyzed celluloplasmin, complete component 3, fibrinogen α, fibrinogen β, and fibrinogen γ in blood of premenopausal patients through 2-DE-LC-MS / MS analysis. And sex hormone-binding globulin was specifically expressed, and Western blot analysis confirmed the specific expression of these proteins in premenopausal patients. As of yet, the results of studies on the direct association of these proteins with early menopause are unknown, but the results of this study confirm that these proteins have the potential to be used as serum biomarkers to diagnose early menopause.

<110> CHA University Industry-Academic Cooperation Foundation          Korea University Research and Business Foundation <120> Analytical method for diagnosing premature ovarian failure and          kit therefor <130> PN0866 <160> 30 <170> KoPatentIn 3.0 <210> 1 <211> 1663 <212> PRT <213> Homo sapiens <400> 1 Met Gly Pro Thr Ser Gly Pro Ser Leu Leu Leu Leu Leu Leu Thr His   1 5 10 15 Leu Pro Leu Ala Leu Gly Ser Pro Met Tyr Ser Ile Ile Thr Pro Asn              20 25 30 Ile Leu Arg Leu Glu Ser Glu Glu Thr Met Val Leu Glu Ala His Asp          35 40 45 Ala Gln Gly Asp Val Pro Val Thr Val Thr Val His Asp Phe Pro Gly      50 55 60 Lys Lys Leu Val Leu Ser Ser Glu Lys Thr Val Leu Thr Pro Ala Thr  65 70 75 80 Asn His Met Gly Asn Val Thr Phe Thr Ile Pro Ala Asn Arg Glu Phe                  85 90 95 Lys Ser Glu Lys Gly Arg Asn Lys Phe Val Thr Val Gln Ala Thr Phe             100 105 110 Gly Thr Gln Val Val Glu Lys Val Val Leu Val Ser Leu Gln Ser Gly         115 120 125 Tyr Leu Phe Ile Gln Thr Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr     130 135 140 Val Leu Tyr Arg Ile Phe Thr Val Asn His Lys Leu Leu Pro Val Gly 145 150 155 160 Arg Thr Val Met Val Asn Ile Glu Asn Pro Glu Gly Ile Pro Val Lys                 165 170 175 Gln Asp Ser Leu Ser Ser Gln Asn Gln Leu Gly Val Leu Pro Leu Ser             180 185 190 Trp Asp Ile Pro Glu Leu Val Asn Met Gly Gln Trp Lys Ile Arg Ala         195 200 205 Tyr Tyr Glu Asn Ser Pro Gln Gln Val Phe Ser Thr Glu Phe Glu Val     210 215 220 Lys Glu Tyr Val Leu Pro Ser Phe Glu Val Ile Val Glu Pro Thr Glu 225 230 235 240 Lys Phe Tyr Tyr Ile Tyr Asn Glu Lys Gly Leu Glu Val Thr Ile Thr                 245 250 255 Ala Arg Phe Leu Tyr Gly Lys Lys Val Glu Gly Thr Ala Phe Val Ile             260 265 270 Phe Gly Ile Gln Asp Gly Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu         275 280 285 Lys Arg Ile Pro Ile Glu Asp Gly Ser Gly Glu Val Val Leu Ser Arg     290 295 300 Lys Val Leu Leu Asp Gly Val Gln Asn Pro Arg Ala Glu Asp Leu Val 305 310 315 320 Gly Lys Ser Leu Tyr Val Ser Ala Thr Val Ile Leu His Ser Gly Ser                 325 330 335 Asp Met Val Gln Ala Glu Arg Ser Gly Ile Pro Ile Val Thr Ser Pro             340 345 350 Tyr Gln Ile His Phe Thr Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met         355 360 365 Pro Phe Asp Leu Met Val Phe Val Thr Asn Pro Asp Gly Ser Pro Ala     370 375 380 Tyr Arg Val Pro Val Ala Val Gln Gly Glu Asp Thr Val Gln Ser Leu 385 390 395 400 Thr Gln Gly Asp Gly Val Ala Lys Leu Ser Ile Asn Thr His Pro Ser                 405 410 415 Gln Lys Pro Leu Ser Ile Thr Val Arg Thr Lys Lys Gln Glu Leu Ser             420 425 430 Glu Ala Glu Gln Ala Thr Arg Thr Met Gln Ala Leu Pro Tyr Ser Thr         435 440 445 Val Gly Asn Ser Asn Asn Tyr Leu His Leu Ser Val Leu Arg Thr Glu     450 455 460 Leu Arg Pro Gly Glu Thr Leu Asn Val Asn Phe Leu Leu Arg Met Asp 465 470 475 480 Arg Ala His Glu Ala Lys Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn                 485 490 495 Lys Gly Arg Leu Leu Lys Ala Gly Arg Gln Val Arg Glu Pro Gly Gln             500 505 510 Asp Leu Val Val Leu Pro Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser         515 520 525 Phe Arg Leu Val Ala Tyr Tyr Thr Leu Ile Gly Ala Ser Gly Gln Arg     530 535 540 Glu Val Val Ala Asp Ser Val Trp Val Asp Val Lys Asp Ser Cys Val 545 550 555 560 Gly Ser Leu Val Val Lys Ser Gly Gln Ser Glu Asp Arg Gln Pro Val                 565 570 575 Pro Gly Gln Gln Met Thr Leu Lys Ile Glu Gly Asp His Gly Ala Arg             580 585 590 Val Val Leu Val Ala Val Asp Lys Gly Val Phe Val Leu Asn Lys Lys         595 600 605 Asn Lys Leu Thr Gln Ser Lys Ile Trp Asp Val Val Glu Lys Ala Asp     610 615 620 Ile Gly Cys Thr Pro Gly Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser 625 630 635 640 Asp Ala Gly Leu Thr Phe Thr Ser Ser Ser Gly Gln Gln Thr Ala Gln                 645 650 655 Arg Ala Glu Leu Gln Cys Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser             660 665 670 Val Gln Leu Thr Glu Lys Arg Met Asp Lys Val Gly Lys Tyr Pro Lys         675 680 685 Glu Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Glu Asn Pro Met Arg     690 695 700 Phe Ser Cys Gln Arg Arg Thr Arg Phe Ile Ser Leu Gly Glu Ala Cys 705 710 715 720 Lys Lys Val Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg                 725 730 735 Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg Ser Asn Leu Asp             740 745 750 Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg Ser Glu Phe Pro         755 760 765 Glu Ser Trp Leu Trp Asn Val Glu Asp Leu Lys Glu Pro Pro Lys Asn     770 775 780 Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys Asp Ser Ile Thr 785 790 795 800 Thr Trp Glu Ile Leu Ala Val Ser Met Ser Asp Lys Lys Gly Ile Cys                 805 810 815 Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp Phe Phe Ile Asp             820 825 830 Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile Arg         835 840 845 Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu Lys Val Arg Val     850 855 860 Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala Thr Thr Lys Arg 865 870 875 880 Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser Ser Leu Ser Val                 885 890 895 Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Leu Gln Glu Val Glu Val             900 905 910 Lys Ala Ala Val Tyr His His Phe Ile Ser Asp Gly Val Arg Lys Ser         915 920 925 Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys Thr Val Ala Val     930 935 940 Arg Thr Leu Asp Pro Glu Arg Leu Gly Arg Glu Gly Val Gln Lys Glu 945 950 955 960 Asp Ile Pro Pro Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Glu Ser                 965 970 975 Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Thr Glu             980 985 990 Asp Ala Val Asp Ala Glu Arg Leu Lys His Leu Ile Val Thr Pro Ser         995 1000 1005 Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro Thr Val Ile Ala    1010 1015 1020 Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys Phe Gly Leu Glu 1025 1030 1035 1040 Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly Tyr Thr Gln Gln                1045 1050 1055 Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala Phe Val Lys Arg            1060 1065 1070 Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val Lys Val Phe Ser Leu        1075 1080 1085 Ala Val Asn Leu Ile Ala Ile Asp Ser Gln Val Leu Cys Gly Ala Val    1090 1095 1100 Lys Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly Val Phe Gln Glu 1105 1110 1115 1120 Asp Ala Pro Val Ile His Gln Glu Met Ile Gly Gly Leu Arg Asn Asn                1125 1130 1135 Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu Ile Ser Leu Gln            1140 1145 1150 Glu Ala Lys Asp Ile Cys Glu Glu Gln Val Asn Ser Leu Pro Gly Ser        1155 1160 1165 Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr Met Asn Leu Gln    1170 1175 1180 Arg Ser Tyr Thr Val Ala Ile Ala Gly Tyr Ala Leu Ala Gln Met Gly 1185 1190 1195 1200 Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe Leu Thr Thr Ala Lys Asp                1205 1210 1215 Lys Asn Arg Trp Glu Asp Pro Gly Lys Gln Leu Tyr Asn Val Glu Ala            1220 1225 1230 Thr Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys Asp Phe Asp Phe        1235 1240 1245 Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg Tyr Tyr Gly Gly    1250 1255 1260 Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala Leu Ala 1265 1270 1275 1280 Gln Tyr Gln Lys Asp Ala Pro Asp His Gln Glu Leu Asn Leu Asp Val                1285 1290 1295 Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Thr His Arg Ile His            1300 1305 1310 Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu Thr Lys Glu Asn Glu        1315 1320 1325 Gly Phe Thr Val Thr Ala Glu Gly Lys Gly Gln Gly Thr Leu Ser Val    1330 1335 1340 Val Thr Met Tyr His Ala Lys Ala Lys Asp Gln Leu Thr Cys Asn Lys 1345 1350 1355 1360 Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu Thr Glu Lys Arg                1365 1370 1375 Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile Cys Thr Arg Tyr            1380 1385 1390 Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp Ile Ser Met Met        1395 1400 1405 Thr Gly Phe Ala Pro Asp Thr Asp Asp Leu Lys Gln Leu Ala Asn Gly    1410 1415 1420 Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp Lys Ala Phe Ser Asp 1425 1430 1435 1440 Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys Val Ser His Ser Glu Asp                1445 1450 1455 Asp Cys Leu Ala Phe Lys Val His Gln Tyr Phe Asn Val Glu Leu Ile            1460 1465 1470 Gln Pro Gly Ala Val Lys Val Tyr Ala Tyr Tyr Asn Leu Glu Glu Ser        1475 1480 1485 Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly Lys Leu Asn Lys    1490 1495 1500 Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu Asn Cys Phe Ile 1505 1510 1515 1520 Gln Lys Ser Asp Asp Lys Val Thr Leu Glu Glu Arg Leu Asp Lys Ala                1525 1530 1535 Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg Leu Val Lys Val            1540 1545 1550 Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met Ala Ile Glu Gln Thr        1555 1560 1565 Ile Lys Ser Gly Ser Asp Glu Val Gln Val Gly Gln Gln Arg Thr Phe    1570 1575 1580 Ile Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu Glu Glu Lys Lys 1585 1590 1595 1600 His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp Gly Glu Lys Pro                1605 1610 1615 Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val Glu His Trp Pro            1620 1625 1630 Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys Gln Cys Gln Asp        1635 1640 1645 Leu Gly Ala Phe Thr Glu Ser Met Val Val Phe Gly Cys Pro Asn    1650 1655 1660 <210> 2 <211> 866 <212> PRT <213> Homo sapiens <400> 2 Met Phe Ser Met Arg Ile Val Cys Leu Val Leu Ser Val Val Gly Thr   1 5 10 15 Ala Trp Thr Ala Asp Ser Gly Glu Gly Asp Phe Leu Ala Glu Gly Gly              20 25 30 Gly Val Arg Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys Lys          35 40 45 Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys Cys      50 55 60 Pro Ser Gly Cys Arg Met Lys Gly Leu Ile Asp Glu Val Asn Gln Asp  65 70 75 80 Phe Thr Asn Arg Ile Asn Lys Leu Lys Asn Ser Leu Phe Glu Tyr Gln                  85 90 95 Lys Asn Asn Lys Asp Ser His Ser Leu Thr Thr Asn Ile Met Glu Ile             100 105 110 Leu Arg Gly Asp Phe Ser Ser Ala Asn Asn Arg Asp Asn Thr Tyr Asn         115 120 125 Arg Val Ser Glu Asp Leu Arg Ser Arg Ile Glu Val Leu Lys Arg Lys     130 135 140 Val Ile Glu Lys Val Gln His Ile Gln Leu Leu Gln Lys Asn Val Arg 145 150 155 160 Ala Gln Leu Val Asp Met Lys Arg Leu Glu Val Asp Ile Asp Ile Lys                 165 170 175 Ile Arg Ser Cys Arg Gly Ser Cys Ser Arg Ala Leu Ala Arg Glu Val             180 185 190 Asp Leu Lys Asp Tyr Glu Asp Gln Gln Lys Gln Leu Glu Gln Val Ile         195 200 205 Ala Lys Asp Leu Leu Pro Ser Arg Asp Arg Gln His Leu Pro Leu Ile     210 215 220 Lys Met Lys Pro Val Pro Asp Leu Val Pro Gly Asn Phe Lys Ser Gln 225 230 235 240 Leu Gln Lys Val Pro Pro Glu Trp Lys Ala Leu Thr Asp Met Pro Gln                 245 250 255 Met Arg Met Glu Leu Glu Arg Pro Gly Gly Asn Glu Ile Thr Arg Gly             260 265 270 Gly Ser Thr Ser Tyr Gly Thr Gly Ser Glu Thr Glu Ser Pro Arg Asn         275 280 285 Pro Ser Ser Ala Gly Ser Trp Asn Ser Gly Ser Ser Gly Pro Gly Ser     290 295 300 Thr Gly Asn Arg Asn Pro Gly Ser Ser Gly Thr Gly Gly Thr Ala Thr 305 310 315 320 Trp Lys Pro Gly Ser Ser Gly Pro Gly Ser Thr Gly Ser Trp Asn Ser                 325 330 335 Gly Ser Ser Gly Thr Gly Ser Thr Gly Asn Gln Asn Pro Gly Ser Pro             340 345 350 Arg Pro Gly Ser Thr Gly Thr Trp Asn Pro Gly Ser Ser Glu Arg Gly         355 360 365 Ser Ala Gly His Trp Thr Ser Glu Ser Ser Val Ser Gly Ser Thr Gly     370 375 380 Gln Trp His Ser Glu Ser Gly Ser Phe Arg Pro Asp Ser Pro Gly Ser 385 390 395 400 Gly Asn Ala Arg Pro Asn Asn Pro Asp Trp Gly Thr Phe Glu Glu Val                 405 410 415 Ser Gly Asn Val Ser Pro Gly Thr Arg Arg Glu Tyr His Thr Glu Lys             420 425 430 Leu Val Thr Ser Lys Gly Asp Lys Glu Leu Arg Thr Gly Lys Glu Lys         435 440 445 Val Thr Ser Gly Ser Thr Thr Thr Thr Arg Arg Ser Cys Ser Lys Thr     450 455 460 Val Thr Lys Thr Val Ile Gly Pro Asp Gly His Lys Glu Val Thr Lys 465 470 475 480 Glu Val Val Thr Ser Glu Asp Gly Ser Asp Cys Pro Glu Ala Met Asp                 485 490 495 Leu Gly Thr Leu Ser Gly Ile Gly Thr Leu Asp Gly Phe Arg His Arg             500 505 510 His Pro Asp Glu Ala Ala Phe Phe Asp Thr Ala Ser Thr Gly Lys Thr         515 520 525 Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu Thr     530 535 540 Glu Ser Arg Gly Ser Glu Ser Gly Ile Phe Thr Asn Thr Lys Glu Ser 545 550 555 560 Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg Gly Lys Ser                 565 570 575 Ser Ser Tyr Ser Lys Gln Phe Thr Ser Ser Thr Ser Tyr Asn Arg Gly             580 585 590 Asp Ser Thr Phe Glu Ser Lys Ser Tyr Lys Met Ala Asp Glu Ala Gly         595 600 605 Ser Glu Ala Asp His Glu Gly Thr His Ser Thr Lys Arg Gly His Ala     610 615 620 Lys Ser Arg Pro Val Arg Asp Cys Asp Asp Val Leu Gln Thr His Pro 625 630 635 640 Ser Gly Thr Gln Ser Gly Ile Phe Asn Ile Lys Leu Pro Gly Ser Ser                 645 650 655 Lys Ile Phe Ser Val Tyr Cys Asp Gln Glu Thr Ser Leu Gly Gly Trp             660 665 670 Leu Leu Ile Gln Gln Arg Met Asp Gly Ser Leu Asn Phe Asn Arg Thr         675 680 685 Trp Gln Asp Tyr Lys Arg Gly Phe Gly Ser Leu Asn Asp Glu Gly Glu     690 695 700 Gly Glu Phe Trp Leu Gly Asn Asp Tyr Leu His Leu Leu Thr Gln Arg 705 710 715 720 Gly Ser Val Leu Arg Val Glu Leu Glu Asp Trp Ala Gly Asn Glu Ala                 725 730 735 Tyr Ala Glu Tyr His Phe Arg Val Gly Ser Glu Ala Glu Gly Tyr Ala             740 745 750 Leu Gln Val Ser Ser Tyr Glu Gly Thr Ala Gly Asp Ala Leu Ile Glu         755 760 765 Gly Ser Val Glu Glu Gly Ala Glu Tyr Thr Ser His Asn Asn Met Gln     770 775 780 Phe Ser Thr Phe Asp Arg Asp Ala Asp Gln Trp Glu Glu Asn Cys Ala 785 790 795 800 Glu Val Tyr Gly Gly Gly Trp Trp Tyr Asn Asn Cys Gln Ala Ala Asn                 805 810 815 Leu Asn Gly Ile Tyr Tyr Pro Gly Gly Ser Tyr Asp Pro Arg Asn Asn             820 825 830 Ser Pro Tyr Glu Ile Glu Asn Gly Val Val Trp Val Ser Phe Arg Gly         835 840 845 Ala Asp Tyr Ser Leu Arg Ala Val Arg Met Lys Ile Arg Pro Leu Val     850 855 860 Thr Gln 865 <210> 3 <211> 644 <212> PRT <213> Homo sapiens <400> 3 Met Phe Ser Met Arg Ile Val Cys Leu Val Leu Ser Val Val Gly Thr   1 5 10 15 Ala Trp Thr Ala Asp Ser Gly Glu Gly Asp Phe Leu Ala Glu Gly Gly              20 25 30 Gly Val Arg Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys Lys          35 40 45 Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys Cys      50 55 60 Pro Ser Gly Cys Arg Met Lys Gly Leu Ile Asp Glu Val Asn Gln Asp  65 70 75 80 Phe Thr Asn Arg Ile Asn Lys Leu Lys Asn Ser Leu Phe Glu Tyr Gln                  85 90 95 Lys Asn Asn Lys Asp Ser His Ser Leu Thr Thr Asn Ile Met Glu Ile             100 105 110 Leu Arg Gly Asp Phe Ser Ser Ala Asn Asn Arg Asp Asn Thr Tyr Asn         115 120 125 Arg Val Ser Glu Asp Leu Arg Ser Arg Ile Glu Val Leu Lys Arg Lys     130 135 140 Val Ile Glu Lys Val Gln His Ile Gln Leu Leu Gln Lys Asn Val Arg 145 150 155 160 Ala Gln Leu Val Asp Met Lys Arg Leu Glu Val Asp Ile Asp Ile Lys                 165 170 175 Ile Arg Ser Cys Arg Gly Ser Cys Ser Arg Ala Leu Ala Arg Glu Val             180 185 190 Asp Leu Lys Asp Tyr Glu Asp Gln Gln Lys Gln Leu Glu Gln Val Ile         195 200 205 Ala Lys Asp Leu Leu Pro Ser Arg Asp Arg Gln His Leu Pro Leu Ile     210 215 220 Lys Met Lys Pro Val Pro Asp Leu Val Pro Gly Asn Phe Lys Ser Gln 225 230 235 240 Leu Gln Lys Val Pro Pro Glu Trp Lys Ala Leu Thr Asp Met Pro Gln                 245 250 255 Met Arg Met Glu Leu Glu Arg Pro Gly Gly Asn Glu Ile Thr Arg Gly             260 265 270 Gly Ser Thr Ser Tyr Gly Thr Gly Ser Glu Thr Glu Ser Pro Arg Asn         275 280 285 Pro Ser Ser Ala Gly Ser Trp Asn Ser Gly Ser Ser Gly Pro Gly Ser     290 295 300 Thr Gly Asn Arg Asn Pro Gly Ser Ser Gly Thr Gly Gly Thr Ala Thr 305 310 315 320 Trp Lys Pro Gly Ser Ser Gly Pro Gly Ser Thr Gly Ser Trp Asn Ser                 325 330 335 Gly Ser Ser Gly Thr Gly Ser Thr Gly Asn Gln Asn Pro Gly Ser Pro             340 345 350 Arg Pro Gly Ser Thr Gly Thr Trp Asn Pro Gly Ser Ser Glu Arg Gly         355 360 365 Ser Ala Gly His Trp Thr Ser Glu Ser Ser Val Ser Gly Ser Thr Gly     370 375 380 Gln Trp His Ser Glu Ser Gly Ser Phe Arg Pro Asp Ser Pro Gly Ser 385 390 395 400 Gly Asn Ala Arg Pro Asn Asn Pro Asp Trp Gly Thr Phe Glu Glu Val                 405 410 415 Ser Gly Asn Val Ser Pro Gly Thr Arg Arg Glu Tyr His Thr Glu Lys             420 425 430 Leu Val Thr Ser Lys Gly Asp Lys Glu Leu Arg Thr Gly Lys Glu Lys         435 440 445 Val Thr Ser Gly Ser Thr Thr Thr Thr Arg Arg Ser Cys Ser Lys Thr     450 455 460 Val Thr Lys Thr Val Ile Gly Pro Asp Gly His Lys Glu Val Thr Lys 465 470 475 480 Glu Val Val Thr Ser Glu Asp Gly Ser Asp Cys Pro Glu Ala Met Asp                 485 490 495 Leu Gly Thr Leu Ser Gly Ile Gly Thr Leu Asp Gly Phe Arg His Arg             500 505 510 His Pro Asp Glu Ala Ala Phe Phe Asp Thr Ala Ser Thr Gly Lys Thr         515 520 525 Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu Thr     530 535 540 Glu Ser Arg Gly Ser Glu Ser Gly Ile Phe Thr Asn Thr Lys Glu Ser 545 550 555 560 Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg Gly Lys Ser                 565 570 575 Ser Ser Tyr Ser Lys Gln Phe Thr Ser Ser Thr Ser Tyr Asn Arg Gly             580 585 590 Asp Ser Thr Phe Glu Ser Lys Ser Tyr Lys Met Ala Asp Glu Ala Gly         595 600 605 Ser Glu Ala Asp His Glu Gly Thr His Ser Thr Lys Arg Gly His Ala     610 615 620 Lys Ser Arg Pro Val Arg Gly Ile His Thr Ser Pro Leu Gly Lys Pro 625 630 635 640 Ser Leu Ser Pro                 <210> 4 <211> 432 <212> PRT <213> Homo sapiens <400> 4 Met Lys Arg Met Val Ser Trp Ser Phe His Lys Leu Lys Thr Met Lys   1 5 10 15 His Leu Leu Leu Leu Leu Leu Cys Val Phe Leu Val Lys Ser Gln Gly              20 25 30 Val Asn Asp Asn Glu Glu Gly Phe Phe Ser Ala Arg Gly His Arg Pro          35 40 45 Leu Asp Lys Lys Arg Glu Glu Ala Leu Leu Gln Gln Glu Arg Pro Ile      50 55 60 Arg Asn Ser Val Asp Glu Leu Asn Asn Asn Val Glu Ala Val Ser Gln  65 70 75 80 Thr Ser Ser Ser Ser Phe Gln Tyr Met Tyr Leu Leu Lys Asp Leu Trp                  85 90 95 Gln Lys Arg Gln Lys Gln Val Lys Asp Asn Glu Asn Val Val Asn Glu             100 105 110 Tyr Ser Ser Glu Leu Glu Lys His Gln Leu Tyr Ile Asp Glu Thr Val         115 120 125 Asn Ser Asn Ile Pro Thr Asn Leu Arg Val Leu Arg Ser Ile Leu Glu     130 135 140 Asn Leu Arg Ser Lys Ile Gln Lys Leu Glu Ser Asp Val Ser Ala Gln 145 150 155 160 Met Glu Tyr Cys Arg Thr Pro Cys Thr Val Ser Cys Asn Ile Pro Val                 165 170 175 Val Ser Gly Lys Glu Cys Glu Glu Ile Ile Arg Lys Gly Gly Glu Thr             180 185 190 Ser Glu Met Tyr Leu Ile Gln Pro Asp Ser Ser Val Lys Pro Tyr Arg         195 200 205 Val Tyr Cys Asp Met Asn Thr Glu Asn Gly Gly Trp Thr Val Ile Gln     210 215 220 Asn Arg Gln Asp Gly Ser Val Asp Phe Gly Arg Lys Trp Asp Pro Tyr 225 230 235 240 Lys Gln Gly Phe Gly Asn Val Ala Thr Asn Thr Asp Gly Lys Asn Tyr                 245 250 255 Cys Gly Leu Pro Gly Glu Tyr Trp Leu Gly Asn Asp Lys Ile Ser Gln             260 265 270 Leu Thr Arg Met Gly Pro Thr Glu Leu Leu Ile Glu Met Glu Asp Trp         275 280 285 Lys Gly Asp Lys Val Lys Ala His Tyr Gly Gly Phe Thr Val Gln Asn     290 295 300 Glu Ala Asn Lys Tyr Gln Ile Ser Val Asn Lys Tyr Arg Gly Thr Ala 305 310 315 320 Gly Asn Ala Leu Met Asp Gly Ala Ser Gln Leu Met Gly Glu Asn Arg                 325 330 335 Thr Met Thr Ile His Asn Gly Met Phe Phe Ser Thr Tyr Asp Arg Asp             340 345 350 Asn Asp Gly Trp Leu Thr Ser Asp Pro Arg Lys Gln Cys Ser Lys Glu         355 360 365 Asp Gly Gly Gly Trp Trp Tyr Asn Arg Cys His Ala Ala Asn Pro Asn     370 375 380 Gly Arg Tyr Tyr Trp Gly Gly Gln Tyr Thr Trp Asp Met Ala Lys His 385 390 395 400 Gly Thr Asp Asp Gly Val Val Trp Met Asn Trp Lys Gly Ser Trp Tyr                 405 410 415 Ser Met Arg Lys Met Ser Met Lys Ile Arg Pro Phe Phe Pro Gln Gln             420 425 430 <210> 5 <211> 491 <212> PRT <213> Homo sapiens <400> 5 Met Lys Arg Met Val Ser Trp Ser Phe His Lys Leu Lys Thr Met Lys   1 5 10 15 His Leu Leu Leu Leu Leu Leu Cys Val Phe Leu Val Lys Ser Gln Gly              20 25 30 Val Asn Asp Asn Glu Glu Gly Phe Phe Ser Ala Arg Gly His Arg Pro          35 40 45 Leu Asp Lys Lys Arg Glu Glu Ala Pro Ser Leu Arg Pro Ala Pro Pro      50 55 60 Pro Ile Ser Gly Gly Gly Tyr Arg Ala Arg Pro Ala Lys Ala Ala Ala  65 70 75 80 Thr Gln Lys Lys Val Glu Arg Lys Ala Pro Asp Ala Gly Gly Cys Leu                  85 90 95 His Ala Asp Pro Asp Leu Gly Val Leu Cys Pro Thr Gly Cys Gln Leu             100 105 110 Gln Glu Ala Leu Leu Gln Gln Glu Arg Pro Ile Arg Asn Ser Val Asp         115 120 125 Glu Leu Asn Asn Asn Val Glu Ala Val Ser Gln Thr Ser Ser Ser Ser     130 135 140 Phe Gln Tyr Met Tyr Leu Leu Lys Asp Leu Trp Gln Lys Arg Gln Lys 145 150 155 160 Gln Val Lys Asp Asn Glu Asn Val Val Asn Glu Tyr Ser Ser Glu Leu                 165 170 175 Glu Lys His Gln Leu Tyr Ile Asp Glu Thr Val Asn Ser Asn Ile Pro             180 185 190 Thr Asn Leu Arg Val Leu Arg Ser Ile Leu Glu Asn Leu Arg Ser Lys         195 200 205 Ile Gln Lys Leu Glu Ser Asp Val Ser Ala Gln Met Glu Tyr Cys Arg     210 215 220 Thr Pro Cys Thr Val Ser Cys Asn Ile Pro Val Val Ser Gly Lys Glu 225 230 235 240 Cys Glu Glu Ile Ile Arg Lys Gly Gly Glu Thr Ser Glu Met Tyr Leu                 245 250 255 Ile Gln Pro Asp Ser Ser Val Lys Pro Tyr Arg Val Tyr Cys Asp Met             260 265 270 Asn Thr Glu Asn Gly Gly Trp Thr Val Ile Gln Asn Arg Gln Asp Gly         275 280 285 Ser Val Asp Phe Gly Arg Lys Trp Asp Pro Tyr Lys Gln Gly Phe Gly     290 295 300 Asn Val Ala Thr Asn Thr Asp Gly Lys Asn Tyr Cys Gly Leu Pro Gly 305 310 315 320 Glu Tyr Trp Leu Gly Asn Asp Lys Ile Ser Gln Leu Thr Arg Met Gly                 325 330 335 Pro Thr Glu Leu Leu Ile Glu Met Glu Asp Trp Lys Gly Asp Lys Val             340 345 350 Lys Ala His Tyr Gly Gly Phe Thr Val Gln Asn Glu Ala Asn Lys Tyr         355 360 365 Gln Ile Ser Val Asn Lys Tyr Arg Gly Thr Ala Gly Asn Ala Leu Met     370 375 380 Asp Gly Ala Ser Gln Leu Met Gly Glu Asn Arg Thr Met Thr Ile His 385 390 395 400 Asn Gly Met Phe Phe Ser Thr Tyr Asp Arg Asp Asn Asp Gly Trp Leu                 405 410 415 Thr Ser Asp Pro Arg Lys Gln Cys Ser Lys Glu Asp Gly Gly Gly Trp             420 425 430 Trp Tyr Asn Arg Cys His Ala Ala Asn Pro Asn Gly Arg Tyr Tyr Trp         435 440 445 Gly Gly Gln Tyr Thr Trp Asp Met Ala Lys His Gly Thr Asp Asp Gly     450 455 460 Val Val Trp Met Asn Trp Lys Gly Ser Trp Tyr Ser Met Arg Lys Met 465 470 475 480 Ser Met Lys Ile Arg Pro Phe Phe Pro Gln Gln                 485 490 <210> 6 <211> 437 <212> PRT <213> Homo sapiens <400> 6 Met Ser Trp Ser Leu His Pro Arg Asn Leu Ile Leu Tyr Phe Tyr Ala   1 5 10 15 Leu Leu Phe Leu Ser Ser Thr Cys Val Ala Tyr Val Ala Thr Arg Asp              20 25 30 Asn Cys Cys Ile Leu Asp Glu Arg Phe Gly Ser Tyr Cys Pro Thr Thr          35 40 45 Cys Gly Ile Ala Asp Phe Leu Ser Thr Tyr Gln Thr Lys Val Asp Lys      50 55 60 Asp Leu Gln Ser Leu Glu Asp Ile Leu His Gln Val Glu Asn Lys Thr  65 70 75 80 Ser Glu Val Lys Gln Leu Ile Lys Ala Ile Gln Leu Thr Tyr Asn Pro                  85 90 95 Asp Glu Ser Ser Lys Pro Asn Met Ile Asp Ala Ala Thr Leu Lys Ser             100 105 110 Arg Lys Met Leu Glu Glu Ile Met Lys Tyr Glu Ala Ser Ile Leu Thr         115 120 125 His Asp Ser Ser Ile Arg Tyr Leu Gln Glu Ile Tyr Asn Ser Asn Asn     130 135 140 Gln Lys Ile Val Asn Leu Lys Glu Lys Val Ala Gln Leu Glu Ala Gln 145 150 155 160 Cys Gln Glu Pro Cys Lys Asp Thr Val Gln Ile His Asp Ile Thr Gly                 165 170 175 Lys Asp Cys Gln Asp Ile Ala Asn Lys Gly Ala Lys Gln Ser Gly Leu             180 185 190 Tyr Phe Ile Lys Pro Leu Lys Ala Asn Gln Gln Phe Leu Val Tyr Cys         195 200 205 Glu Ile Asp Gly Ser Gly Asn Gly Trp Thr Val Phe Gln Lys Arg Leu     210 215 220 Asp Gly Ser Val Asp Phe Lys Lys Asn Trp Ile Gln Tyr Lys Glu Gly 225 230 235 240 Phe Gly His Leu Ser Pro Thr Gly Thr Thr Glu Phe Trp Leu Gly Asn                 245 250 255 Glu Lys Ile His Leu Ile Ser Thr Gln Ser Ala Ile Pro Tyr Ala Leu             260 265 270 Arg Val Glu Leu Glu Asp Trp Asn Gly Arg Thr Ser Thr Ala Asp Tyr         275 280 285 Ala Met Phe Lys Val Gly Pro Glu Ala Asp Lys Tyr Arg Leu Thr Tyr     290 295 300 Ala Tyr Phe Ala Gly Gly Asp Ala Gly Asp Ala Phe Asp Gly Phe Asp 305 310 315 320 Phe Gly Asp Asp Pro Ser Asp Lys Phe Phe Thr Ser His Asn Gly Met                 325 330 335 Gln Phe Ser Thr Trp Asp Asn Asp Asn Asp Lys Phe Glu Gly Asn Cys             340 345 350 Ala Glu Gln Asp Gly Ser Gly Trp Trp Met Asn Lys Cys His Ala Gly         355 360 365 His Leu Asn Gly Val Tyr Tyr Gln Gly Gly Thr Tyr Ser Lys Ala Ser     370 375 380 Thr Pro Asn Gly Tyr Asp Asn Gly Ile Ile Trp Ala Thr Trp Lys Thr 385 390 395 400 Arg Trp Tyr Ser Met Lys Lys Thr Thr Met Lys Ile Ile Pro Phe Asn                 405 410 415 Arg Leu Thr Ile Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys             420 425 430 Gln Ala Gly Asp Val         435 <210> 7 <211> 453 <212> PRT <213> Homo sapiens <400> 7 Met Ser Trp Ser Leu His Pro Arg Asn Leu Ile Leu Tyr Phe Tyr Ala   1 5 10 15 Leu Leu Phe Leu Ser Ser Thr Cys Val Ala Tyr Val Ala Thr Arg Asp              20 25 30 Asn Cys Cys Ile Leu Asp Glu Arg Phe Gly Ser Tyr Cys Pro Thr Thr          35 40 45 Cys Gly Ile Ala Asp Phe Leu Ser Thr Tyr Gln Thr Lys Val Asp Lys      50 55 60 Asp Leu Gln Ser Leu Glu Asp Ile Leu His Gln Val Glu Asn Lys Thr  65 70 75 80 Ser Glu Val Lys Gln Leu Ile Lys Ala Ile Gln Leu Thr Tyr Asn Pro                  85 90 95 Asp Glu Ser Ser Lys Pro Asn Met Ile Asp Ala Ala Thr Leu Lys Ser             100 105 110 Arg Lys Met Leu Glu Glu Ile Met Lys Tyr Glu Ala Ser Ile Leu Thr         115 120 125 His Asp Ser Ser Ile Arg Tyr Leu Gln Glu Ile Tyr Asn Ser Asn Asn     130 135 140 Gln Lys Ile Val Asn Leu Lys Glu Lys Val Ala Gln Leu Glu Ala Gln 145 150 155 160 Cys Gln Glu Pro Cys Lys Asp Thr Val Gln Ile His Asp Ile Thr Gly                 165 170 175 Lys Asp Cys Gln Asp Ile Ala Asn Lys Gly Ala Lys Gln Ser Gly Leu             180 185 190 Tyr Phe Ile Lys Pro Leu Lys Ala Asn Gln Gln Phe Leu Val Tyr Cys         195 200 205 Glu Ile Asp Gly Ser Gly Asn Gly Trp Thr Val Phe Gln Lys Arg Leu     210 215 220 Asp Gly Ser Val Asp Phe Lys Lys Asn Trp Ile Gln Tyr Lys Glu Gly 225 230 235 240 Phe Gly His Leu Ser Pro Thr Gly Thr Thr Glu Phe Trp Leu Gly Asn                 245 250 255 Glu Lys Ile His Leu Ile Ser Thr Gln Ser Ala Ile Pro Tyr Ala Leu             260 265 270 Arg Val Glu Leu Glu Asp Trp Asn Gly Arg Thr Ser Thr Ala Asp Tyr         275 280 285 Ala Met Phe Lys Val Gly Pro Glu Ala Asp Lys Tyr Arg Leu Thr Tyr     290 295 300 Ala Tyr Phe Ala Gly Gly Asp Ala Gly Asp Ala Phe Asp Gly Phe Asp 305 310 315 320 Phe Gly Asp Asp Pro Ser Asp Lys Phe Phe Thr Ser His Asn Gly Met                 325 330 335 Gln Phe Ser Thr Trp Asp Asn Asp Asn Asp Lys Phe Glu Gly Asn Cys             340 345 350 Ala Glu Gln Asp Gly Ser Gly Trp Trp Met Asn Lys Cys His Ala Gly         355 360 365 His Leu Asn Gly Val Tyr Tyr Gln Gly Gly Thr Tyr Ser Lys Ala Ser     370 375 380 Thr Pro Asn Gly Tyr Asp Asn Gly Ile Ile Trp Ala Thr Trp Lys Thr 385 390 395 400 Arg Trp Tyr Ser Met Lys Lys Thr Thr Met Lys Ile Ile Pro Phe Asn                 405 410 415 Arg Leu Thr Ile Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys             420 425 430 Gln Val Arg Pro Glu His Pro Ala Glu Thr Glu Tyr Asp Ser Leu Tyr         435 440 445 Pro Glu Asp Asp Leu     450 <210> 8 <211> 1065 <212> PRT <213> Homo sapiens <400> 8 Met Lys Ile Leu Ile Leu Gly Ile Phe Leu Phe Leu Cys Ser Thr Pro   1 5 10 15 Ala Trp Ala Lys Glu Lys His Tyr Tyr Ile Gly Ile Ile Glu Thr Thr              20 25 30 Trp Asp Tyr Ala Ser Asp His Gly Glu Lys Lys Leu Ile Ser Val Asp          35 40 45 Thr Glu His Ser Asn Ile Tyr Leu Gln Asn Gly Pro Asp Arg Ile Gly      50 55 60 Arg Leu Tyr Lys Lys Ala Leu Tyr Leu Gln Tyr Thr Asp Glu Thr Phe  65 70 75 80 Arg Thr Thr Ile Glu Lys Pro Val Trp Leu Gly Phe Leu Gly Pro Ile                  85 90 95 Ile Lys Ala Glu Thr Gly Asp Lys Val Tyr Val His Leu Lys Asn Leu             100 105 110 Ala Ser Arg Pro Tyr Thr Phe His Ser His Gly Ile Thr Tyr Tyr Lys         115 120 125 Glu His Glu Gly Ala Ile Tyr Pro Asp Asn Thr Thr Asp Phe Gln Arg     130 135 140 Ala Asp Asp Lys Val Tyr Pro Gly Glu Gln Tyr Thr Tyr Met Leu Leu 145 150 155 160 Ala Thr Glu Glu Gln Ser Pro Gly Glu Gly Asp Gly Asn Cys Val Thr                 165 170 175 Arg Ile Tyr His Ser His Ile Asp Ala Pro Lys Asp Ile Ala Ser Gly             180 185 190 Leu Ile Gly Pro Leu Ile Ile Cys Lys Lys Asp Ser Leu Asp Lys Glu         195 200 205 Lys Glu Lys His Ile Asp Arg Glu Phe Val Val Met Phe Ser Val Val     210 215 220 Asp Glu Asn Phe Ser Trp Tyr Leu Glu Asp Asn Ile Lys Thr Tyr Cys 225 230 235 240 Ser Glu Pro Glu Lys Val Asp Lys Asp Asn Glu Asp Phe Gln Glu Ser                 245 250 255 Asn Arg Met Tyr Ser Val Asn Gly Tyr Thr Phe Gly Ser Leu Pro Gly             260 265 270 Leu Ser Met Cys Ala Glu Asp Arg Val Lys Trp Tyr Leu Phe Gly Met         275 280 285 Gly Asn Glu Val Asp Val His Ala Ala Phe Phe His Gly Gln Ala Leu     290 295 300 Thr Asn Lys Asn Tyr Arg Ile Asp Thr Ile Asn Leu Phe Pro Ala Thr 305 310 315 320 Leu Phe Asp Ala Tyr Met Val Ala Gln Asn Pro Gly Glu Trp Met Leu                 325 330 335 Ser Cys Gln Asn Leu Asn His Leu Lys Ala Gly Leu Gln Ala Phe Phe             340 345 350 Gln Val Gln Glu Cys Asn Lys Ser Ser Ser Lys Asp Asn Ile Arg Gly         355 360 365 Lys His Val Arg His Tyr Tyr Ile Ala Ala Glu Glu Ile Ile Trp Asn     370 375 380 Tyr Ala Pro Ser Gly Ile Asp Ile Phe Thr Lys Glu Asn Leu Thr Ala 385 390 395 400 Pro Gly Ser Asp Ser Ala Val Phe Phe Glu Gln Gly Thr Thr Arg Ile                 405 410 415 Gly Gly Ser Tyr Lys Lys Leu Val Tyr Arg Glu Tyr Thr Asp Ala Ser             420 425 430 Phe Thr Asn Arg Lys Glu Arg Gly Pro Glu Glu Glu His Leu Gly Ile         435 440 445 Leu Gly Pro Val Ile Trp Ala Glu Val Gly Asp Thr Ile Arg Val Thr     450 455 460 Phe His Asn Lys Gly Ala Tyr Pro Leu Ser Ile Glu Pro Ile Gly Val 465 470 475 480 Arg Phe Asn Lys Asn Asn Glu Gly Thr Tyr Tyr Ser Pro Asn Tyr Asn                 485 490 495 Pro Gln Ser Arg Ser Val Pro Pro Ser Ala Ser His Val Ala Pro Thr             500 505 510 Glu Thr Phe Thr Tyr Glu Trp Thr Val Pro Lys Glu Val Gly Pro Thr         515 520 525 Asn Ala Asp Pro Val Cys Leu Ala Lys Met Tyr Tyr Ser Ala Val Asp     530 535 540 Pro Thr Lys Asp Ile Phe Thr Gly Leu Ile Gly Pro Met Lys Ile Cys 545 550 555 560 Lys Lys Gly Ser Leu His Ala Asn Gly Arg Gln Lys Asp Val Asp Lys                 565 570 575 Glu Phe Tyr Leu Phe Pro Thr Val Phe Asp Glu Asn Glu Ser Leu Leu             580 585 590 Leu Glu Asp Asn Ile Arg Met Phe Thr Thr Ala Pro Asp Gln Val Asp         595 600 605 Lys Glu Asp Glu Asp Phe Gln Glu Ser Asn Lys Met His Ser Met Asn     610 615 620 Gly Phe Met Tyr Gly Asn Gln Pro Gly Leu Thr Met Cys Lys Gly Asp 625 630 635 640 Ser Val Val Trp Tyr Leu Phe Ser Ala Gly Asn Glu Ala Asp Val His                 645 650 655 Gly Ile Tyr Phe Ser Gly Asn Thr Tyr Leu Trp Arg Gly Glu Arg Arg             660 665 670 Asp Thr Ala Asn Leu Phe Pro Gln Thr Ser Leu Thr Leu His Met Trp         675 680 685 Pro Asp Thr Glu Gly Thr Phe Asn Val Glu Cys Leu Thr Thr Asp His     690 695 700 Tyr Thr Gly Gly Met Lys Gln Lys Tyr Thr Val Asn Gln Cys Arg Arg 705 710 715 720 Gln Ser Glu Asp Ser Thr Phe Tyr Leu Gly Glu Arg Thr Tyr Tyr Ile                 725 730 735 Ala Ala Val Glu Val Glu Trp Asp Tyr Ser Pro Gln Arg Glu Trp Glu             740 745 750 Lys Glu Leu His His Leu Gln Glu Gln Asn Val Ser Asn Ala Phe Leu         755 760 765 Asp Lys Gly Glu Phe Tyr Ile Gly Ser Lys Tyr Lys Lys Val Val Tyr     770 775 780 Arg Gln Tyr Thr Asp Ser Thr Phe Arg Val Pro Val Glu Arg Lys Ala 785 790 795 800 Glu Glu Glu His Leu Gly Ile Leu Gly Pro Gln Leu His Ala Asp Val                 805 810 815 Gly Asp Lys Val Lys Ile Ile Phe Lys Asn Met Ala Thr Arg Pro Tyr             820 825 830 Ser Ile His Ala His Gly Val Gln Thr Glu Ser Ser Thr Val Thr Pro         835 840 845 Thr Leu Pro Gly Glu Thr Leu Thr Tyr Val Trp Lys Ile Pro Glu Arg     850 855 860 Ser Gly Ala Gly Thr Glu Asp Ser Ala Cys Ile Pro Trp Ala Tyr Tyr 865 870 875 880 Ser Thr Val Asp Gln Val Lys Asp Leu Tyr Ser Gly Leu Ile Gly Pro                 885 890 895 Leu Ile Val Cys Arg Arg Pro Tyr Leu Lys Val Phe Asn Pro Arg Arg             900 905 910 Lys Leu Glu Phe Ala Leu Leu Phe Leu Val Phe Asp Glu Asn Glu Ser         915 920 925 Trp Tyr Leu Asp Asp Asn Ile Lys Thr Tyr Ser Asp His Pro Glu Lys     930 935 940 Val Asn Lys Asp Asp Glu Glu Phe Ile Glu Ser Asn Lys Met His Ala 945 950 955 960 Ile Asn Gly Arg Met Phe Gly Asn Leu Gln Gly Leu Thr Met His Val                 965 970 975 Gly Asp Glu Val Asn Trp Tyr Leu Met Gly Met Gly Asn Glu Ile Asp             980 985 990 Leu His Thr Val His Phe His Gly His Ser Phe Gln Tyr Lys His Arg         995 1000 1005 Gly Val Tyr Ser Ser Asp Val Phe Asp Ile Phe Pro Gly Thr Tyr Gln    1010 1015 1020 Thr Leu Glu Met Phe Pro Arg Thr Pro Gly Ile Trp Leu Leu His Cys 1025 1030 1035 1040 His Val Thr Asp His Ile His Ala Gly Met Glu Thr Thr Tyr Thr Val                1045 1050 1055 Leu Gln Asn Glu Asp Thr Lys Ser Gly            1060 1065 <210> 9 <211> 402 <212> PRT <213> Homo sapiens <400> 9 Met Glu Ser Arg Gly Pro Leu Ala Thr Ser Arg Leu Leu Leu Leu Leu   1 5 10 15 Leu Leu Leu Leu Leu Arg His Thr Arg Gln Gly Trp Ala Leu Arg Pro              20 25 30 Val Leu Pro Thr Gln Ser Ala His Asp Pro Pro Ala Val His Leu Ser          35 40 45 Asn Gly Pro Gly Gln Glu Pro Ile Ala Val Met Thr Phe Asp Leu Thr      50 55 60 Lys Ile Thr Lys Thr Ser Ser Ser Phe Glu Val Arg Thr Trp Asp Pro  65 70 75 80 Glu Gly Val Ile Phe Tyr Gly Asp Thr Asn Pro Lys Asp Asp Trp Phe                  85 90 95 Met Leu Gly Leu Arg Asp Gly Arg Pro Glu Ile Gln Leu His Asn His             100 105 110 Trp Ala Gln Leu Thr Val Gly Ala Gly Pro Arg Leu Asp Asp Gly Arg         115 120 125 Trp His Gln Val Glu Val Lys Met Glu Gly Asp Ser Val Leu Leu Glu     130 135 140 Val Asp Gly Glu Glu Val Leu Arg Leu Arg Gln Val Ser Gly Pro Leu 145 150 155 160 Thr Ser Lys Arg His Pro Ile Met Arg Ile Ala Leu Gly Gly Leu Leu                 165 170 175 Phe Pro Ala Ser Asn Leu Arg Leu Pro Leu Val Pro Ala Leu Asp Gly             180 185 190 Cys Leu Arg Arg Asp Ser Trp Leu Asp Lys Gln Ala Glu Ile Ser Ala         195 200 205 Ser Ala Pro Thr Ser Leu Arg Ser Cys Asp Val Glu Ser Asn Pro Gly     210 215 220 Ile Phe Leu Pro Pro Gly Thr Gln Ala Glu Phe Asn Leu Arg Asp Ile 225 230 235 240 Pro Gln Pro His Ala Glu Pro Trp Ala Phe Ser Leu Asp Leu Gly Leu                 245 250 255 Lys Gln Ala Ala Gly Ser Gly His Leu Leu Ala Leu Gly Thr Pro Glu             260 265 270 Asn Pro Ser Trp Leu Ser Leu His Leu Gln Asp Gln Lys Val Val Leu         275 280 285 Ser Ser Gly Ser Gly Pro Gly Leu Asp Leu Pro Leu Val Leu Gly Leu     290 295 300 Pro Leu Gln Leu Lys Leu Ser Met Ser Arg Val Val Leu Ser Gln Gly 305 310 315 320 Ser Lys Met Lys Ala Leu Ala Leu Pro Pro Leu Gly Leu Ala Pro Leu                 325 330 335 Leu Asn Leu Trp Ala Lys Pro Gln Gly Arg Leu Phe Leu Gly Ala Leu             340 345 350 Pro Gly Glu Asp Ser Ser Thr Ser Phe Cys Leu Asn Gly Leu Trp Ala         355 360 365 Gln Gly Gln Arg Leu Asp Val Asp Gln Ala Leu Asn Arg Ser His Glu     370 375 380 Ile Trp Thr His Ser Cys Pro Gln Ser Pro Gly Asn Gly Thr Asp Ala 385 390 395 400 Ser His         <210> 10 <211> 384 <212> PRT <213> Homo sapiens <400> 10 Met Glu Ser Arg Gly Pro Leu Ala Thr Ser Arg Leu Leu Leu Leu Leu   1 5 10 15 Leu Leu Leu Leu Leu Arg His Thr Arg Gln Gly Trp Ala Leu Arg Pro              20 25 30 Val Leu Pro Thr Gln Ser Ala His Asp Pro Pro Ala Val His Leu Ser          35 40 45 Asn Gly Pro Gly Gln Glu Pro Ile Ala Val Met Thr Phe Asp Leu Thr      50 55 60 Lys Ile Thr Lys Thr Ser Ser Ser Phe Glu Val Arg Thr Trp Asp Pro  65 70 75 80 Glu Gly Val Ile Phe Tyr Gly Asp Thr Asn Pro Lys Asp Asp Trp Phe                  85 90 95 Met Leu Gly Leu Arg Asp Gly Arg Pro Glu Ile Gln Leu His Asn His             100 105 110 Trp Ala Gln Leu Thr Val Gly Ala Gly Pro Arg Leu Asp Asp Gly Arg         115 120 125 Trp His Gln Val Glu Val Lys Met Glu Gly Asp Ser Val Leu Leu Glu     130 135 140 Val Asp Gly Glu Glu Val Leu Arg Leu Arg Gln Val Ser Gly Pro Leu 145 150 155 160 Thr Ser Lys Arg His Pro Ile Met Arg Ile Ala Leu Gly Gly Leu Leu                 165 170 175 Phe Pro Ala Ser Asn Leu Arg Leu Pro Ala Glu Ile Ser Ala Ser Ala             180 185 190 Pro Thr Ser Leu Arg Ser Cys Asp Val Glu Ser Asn Pro Gly Ile Phe         195 200 205 Leu Pro Pro Gly Thr Gln Ala Glu Phe Asn Leu Arg Asp Ile Pro Gln     210 215 220 Pro His Ala Glu Pro Trp Ala Phe Ser Leu Asp Leu Gly Leu Lys Gln 225 230 235 240 Ala Ala Gly Ser Gly His Leu Leu Ala Leu Gly Thr Pro Glu Asn Pro                 245 250 255 Ser Trp Leu Ser Leu His Leu Gln Asp Gln Lys Val Val Leu Ser Ser             260 265 270 Gly Ser Gly Pro Gly Leu Asp Leu Pro Leu Val Leu Gly Leu Pro Leu         275 280 285 Gln Leu Lys Leu Ser Met Ser Arg Val Val Leu Ser Gln Gly Ser Lys     290 295 300 Met Lys Ala Leu Ala Leu Pro Pro Leu Gly Leu Ala Pro Leu Leu Asn 305 310 315 320 Leu Trp Ala Lys Pro Gln Gly Arg Leu Phe Leu Gly Ala Leu Pro Gly                 325 330 335 Glu Asp Ser Ser Thr Ser Phe Cys Leu Asn Gly Leu Trp Ala Gln Gly             340 345 350 Gln Arg Leu Asp Val Asp Gln Ala Leu Asn Arg Ser His Glu Ile Trp         355 360 365 Thr His Ser Cys Pro Gln Ser Pro Gly Asn Gly Thr Asp Ala Ser His     370 375 380 <210> 11 <211> 293 <212> PRT <213> Homo sapiens <400> 11 Met Glu Ser Arg Gly Pro Leu Ala Thr Ser Arg Leu Leu Leu Leu Leu   1 5 10 15 Leu Leu Leu Leu Leu Arg His Thr Arg Gln Gly Trp Ala Leu Arg Pro              20 25 30 Val Leu Pro Thr Gln Ser Ala His Asp Pro Pro Ala Val His Leu Ser          35 40 45 Asn Gly Pro Gly Gln Glu Pro Ile Ala Val Met Thr Phe Asp Leu Thr      50 55 60 Lys Ile Thr Lys Thr Ser Ser Ser Phe Glu Val Arg Thr Trp Asp Pro  65 70 75 80 Glu Gly Val Ile Phe Tyr Gly Asp Thr Asn Pro Lys Asp Asp Trp Phe                  85 90 95 Met Leu Gly Leu Arg Asp Gly Arg Pro Glu Ile Gln Leu His Asn His             100 105 110 Trp Ala Gln Leu Thr Val Gly Ala Gly Pro Arg Leu Asp Asp Gly Arg         115 120 125 Trp His Gln Val Glu Val Lys Met Glu Gly Asp Ser Val Leu Leu Glu     130 135 140 Val Asp Gly Glu Glu Val Leu Arg Leu Arg Gln Val Ser Gly Pro Leu 145 150 155 160 Thr Ser Lys Arg His Pro Ile Met Arg Ile Ala Leu Gly Gly Leu Leu                 165 170 175 Phe Pro Ala Ser Asn Leu Arg Leu Pro Leu Val Pro Ala Leu Asp Gly             180 185 190 Cys Leu Arg Arg Asp Ser Trp Leu Asp Lys Gln Ala Glu Ile Ser Ala         195 200 205 Ser Ala Pro Thr Ser Leu Arg Ser Cys Asp Val Glu Ser Asn Pro Gly     210 215 220 Ile Phe Leu Pro Pro Gly Thr Gln Ala Glu Phe Asn Leu Arg Asp Ile 225 230 235 240 Pro Gln Pro His Ala Glu Pro Trp Ala Phe Ser Leu Asp Leu Gly Leu                 245 250 255 Lys Gln Ala Ala Gly Ser Gly His Leu Leu Ala Leu Gly Thr Pro Glu             260 265 270 Asn Pro Ser Trp Leu Ser Leu His Leu Gln Asp Gln Glu Lys Thr Leu         275 280 285 Pro Pro Leu Phe Ala     290 <210> 12 <211> 287 <212> PRT <213> Homo sapiens <400> 12 Met Glu Ser Arg Gly Pro Leu Ala Thr Ser Arg Leu Leu Leu Leu Leu   1 5 10 15 Leu Leu Leu Leu Leu Arg His Thr Arg Gln Gly Trp Ala Leu Arg Pro              20 25 30 Val Leu Pro Thr Gln Ser Ala His Asp Pro Pro Ala Val His Leu Ser          35 40 45 Asn Gly Pro Gly Gln Glu Pro Ile Ala Val Met Thr Phe Asp Leu Thr      50 55 60 Lys Ile Thr Lys Thr Ser Ser Ser Phe Glu Val Arg Thr Trp Asp Pro  65 70 75 80 Glu Gly Val Ile Phe Tyr Gly Asp Thr Asn Pro Lys Asp Asp Trp Phe                  85 90 95 Met Leu Gly Leu Arg Asp Gly Arg Pro Glu Ile Gln Leu His Asn His             100 105 110 Trp Ala Gln Leu Thr Val Gly Ala Gly Pro Arg Leu Asp Asp Gly Arg         115 120 125 Trp His Gln Val Glu Val Lys Met Glu Gly Asp Ser Val Leu Leu Glu     130 135 140 Val Asp Gly Glu Glu Val Leu Arg Leu Arg Gln Val Ser Gly Pro Leu 145 150 155 160 Thr Ser Lys Arg His Pro Ile Met Arg Ile Ala Leu Gly Gly Leu Leu                 165 170 175 Phe Pro Ala Ser Asn Leu Arg Leu Pro Leu Val Pro Ala Leu Asp Gly             180 185 190 Cys Leu Arg Arg Asp Ser Trp Leu Asp Lys Gln Ala Glu Ile Ser Ala         195 200 205 Ser Ala Pro Thr Ser Leu Arg Ser Cys Asp Val Glu Ser Asn Pro Gly     210 215 220 Ile Phe Leu Pro Pro Gly Thr Gln Ala Glu Phe Asn Leu Arg Gly Glu 225 230 235 240 Asp Ser Ser Thr Ser Phe Cys Leu Asn Gly Leu Trp Ala Gln Gly Gln                 245 250 255 Arg Leu Asp Val Asp Gln Ala Leu Asn Arg Ser His Glu Ile Trp Thr             260 265 270 His Ser Cys Pro Gln Ser Pro Gly Asn Gly Thr Asp Ala Ser His         275 280 285 <210> 13 <211> 344 <212> PRT <213> Homo sapiens <400> 13 Met Thr Phe Asp Leu Thr Lys Ile Thr Lys Thr Ser Ser Ser Phe Glu   1 5 10 15 Val Arg Thr Trp Asp Pro Glu Gly Val Ile Phe Tyr Gly Asp Thr Asn              20 25 30 Pro Lys Asp Asp Trp Phe Met Leu Gly Leu Arg Asp Gly Arg Pro Glu          35 40 45 Ile Gln Leu His Asn His Trp Ala Gln Leu Thr Val Gly Ala Gly Pro      50 55 60 Arg Leu Asp Asp Gly Arg Trp His Gln Val Glu Val Lys Met Glu Gly  65 70 75 80 Asp Ser Val Leu Leu Glu Val Asp Gly Glu Glu Val Leu Arg Leu Arg                  85 90 95 Gln Val Ser Gly Pro Leu Thr Ser Lys Arg His Pro Ile Met Arg Ile             100 105 110 Ala Leu Gly Gly Leu Leu Phe Pro Ala Ser Asn Leu Arg Leu Pro Leu         115 120 125 Val Pro Ala Leu Asp Gly Cys Leu Arg Arg Asp Ser Trp Leu Asp Lys     130 135 140 Gln Ala Glu Ile Ser Ala Ser Ala Pro Thr Ser Leu Arg Ser Cys Asp 145 150 155 160 Val Glu Ser Asn Pro Gly Ile Phe Leu Pro Pro Gly Thr Gln Ala Glu                 165 170 175 Phe Asn Leu Arg Asp Ile Pro Gln Pro His Ala Glu Pro Trp Ala Phe             180 185 190 Ser Leu Asp Leu Gly Leu Lys Gln Ala Ala Gly Ser Gly His Leu Leu         195 200 205 Ala Leu Gly Thr Pro Glu Asn Pro Ser Trp Leu Ser Leu His Leu Gln     210 215 220 Asp Gln Lys Val Val Leu Ser Ser Gly Ser Gly Pro Gly Leu Asp Leu 225 230 235 240 Pro Leu Val Leu Gly Leu Pro Leu Gln Leu Lys Leu Ser Met Ser Arg                 245 250 255 Val Val Leu Ser Gln Gly Ser Lys Met Lys Ala Leu Ala Leu Pro Pro             260 265 270 Leu Gly Leu Ala Pro Leu Leu Asn Leu Trp Ala Lys Pro Gln Gly Arg         275 280 285 Leu Phe Leu Gly Ala Leu Pro Gly Glu Asp Ser Ser Thr Ser Phe Cys     290 295 300 Leu Asn Gly Leu Trp Ala Gln Gly Gln Arg Leu Asp Val Asp Gln Ala 305 310 315 320 Leu Asn Arg Ser His Glu Ile Trp Thr His Ser Cys Pro Gln Ser Pro                 325 330 335 Gly Asn Gly Thr Asp Ala Ser His             340 <210> 14 <211> 235 <212> PRT <213> Homo sapiens <400> 14 Met Thr Phe Asp Leu Thr Lys Ile Thr Lys Thr Ser Ser Ser Phe Glu   1 5 10 15 Val Arg Thr Trp Asp Pro Glu Gly Val Ile Phe Tyr Gly Asp Thr Asn              20 25 30 Pro Lys Asp Asp Trp Phe Met Leu Gly Leu Arg Asp Gly Arg Pro Glu          35 40 45 Ile Gln Leu His Asn His Trp Ala Gln Leu Thr Val Gly Ala Gly Pro      50 55 60 Arg Leu Asp Asp Gly Arg Trp His Gln Val Glu Val Lys Met Glu Gly  65 70 75 80 Asp Ser Val Leu Leu Glu Val Asp Gly Glu Glu Val Leu Arg Leu Arg                  85 90 95 Gln Val Ser Gly Pro Leu Thr Ser Lys Arg His Pro Ile Met Arg Ile             100 105 110 Ala Leu Gly Gly Leu Leu Phe Pro Ala Ser Asn Leu Arg Leu Pro Leu         115 120 125 Val Pro Ala Leu Asp Gly Cys Leu Arg Arg Asp Ser Trp Leu Asp Lys     130 135 140 Gln Ala Glu Ile Ser Ala Ser Ala Pro Thr Ser Leu Arg Ser Cys Asp 145 150 155 160 Val Glu Ser Asn Pro Gly Ile Phe Leu Pro Pro Gly Thr Gln Ala Glu                 165 170 175 Phe Asn Leu Arg Asp Ile Pro Gln Pro His Ala Glu Pro Trp Ala Phe             180 185 190 Ser Leu Asp Leu Gly Leu Lys Gln Ala Ala Gly Ser Gly His Leu Leu         195 200 205 Ala Leu Gly Thr Pro Glu Asn Pro Ser Trp Leu Ser Leu His Leu Gln     210 215 220 Asp Gln Glu Lys Thr Leu Pro Pro Leu Phe Ala 225 230 235 <210> 15 <211> 286 <212> PRT <213> Homo sapiens <400> 15 Met Gly Ile Pro Thr Leu Arg Met Thr Gly Leu Cys Trp Asp Phe Glu   1 5 10 15 Thr Ala Gly Leu Arg Ser Asn Cys Thr Ile Thr Gly Pro Ser Leu Arg              20 25 30 Trp Val Leu Arg Leu Arg Gln Val Ser Gly Pro Leu Thr Ser Lys Arg          35 40 45 His Pro Ile Met Arg Ile Ala Leu Gly Gly Leu Leu Phe Pro Ala Ser      50 55 60 Asn Leu Arg Leu Pro Leu Val Pro Ala Leu Asp Gly Cys Leu Arg Arg  65 70 75 80 Asp Ser Trp Leu Asp Lys Gln Ala Glu Ile Ser Ala Ser Ala Pro Thr                  85 90 95 Ser Leu Arg Ser Cys Asp Val Glu Ser Asn Pro Gly Ile Phe Leu Pro             100 105 110 Pro Gly Thr Gln Ala Glu Phe Asn Leu Arg Asp Ile Pro Gln Pro His         115 120 125 Ala Glu Pro Trp Ala Phe Ser Leu Asp Leu Gly Leu Lys Gln Ala Ala     130 135 140 Gly Ser Gly His Leu Leu Ala Leu Gly Thr Pro Glu Asn Pro Ser Trp 145 150 155 160 Leu Ser Leu His Leu Gln Asp Gln Lys Val Val Leu Ser Ser Gly Ser                 165 170 175 Gly Pro Gly Leu Asp Leu Pro Leu Val Leu Gly Leu Pro Leu Gln Leu             180 185 190 Lys Leu Ser Met Ser Arg Val Val Leu Ser Gln Gly Ser Lys Met Lys         195 200 205 Ala Leu Ala Leu Pro Pro Leu Gly Leu Ala Pro Leu Leu Asn Leu Trp     210 215 220 Ala Lys Pro Gln Gly Arg Leu Phe Leu Gly Ala Leu Pro Gly Glu Asp 225 230 235 240 Ser Ser Thr Ser Phe Cys Leu Asn Gly Leu Trp Ala Gln Gly Gln Arg                 245 250 255 Leu Asp Val Asp Gln Ala Leu Asn Arg Ser His Glu Ile Trp Thr His             260 265 270 Ser Cys Pro Gln Ser Pro Gly Asn Gly Thr Asp Ala Ser His         275 280 285 <210> 16 <211> 5148 <212> DNA <213> Homo sapiens <400> 16 agataaaaag ccagctccag caggcgctgc tcactcctcc ccatcctctc cctctgtccc 60 tctgtccctc tgaccctgca ctgtcccagc accatgggac ccacctcagg tcccagcctg 120 ctgctcctgc tactaaccca cctccccctg gctctgggga gtcccatgta ctctatcatc 180 acccccaaca tcttgcggct ggagagcgag gagaccatgg tgctggaggc ccacgacgcg 240 caaggggatg ttccagtcac tgttactgtc cacgacttcc caggcaaaaa actagtgctg 300 tccagtgaga agactgtgct gacccctgcc accaaccaca tgggcaacgt caccttcacg 360 atcccagcca acagggagtt caagtcagaa aaggggcgca acaagttcgt gaccgtgcag 420 gccaccttcg ggacccaagt ggtggagaag gtggtgctgg tcagcctgca gagcgggtac 480 ctcttcatcc agacagacaa gaccatctac acccctggct ccacagttct ctatcggatc 540 ttcaccgtca accacaagct gctacccgtg ggccggacgg tcatggtcaa cattgagaac 600 ccggaaggca tcccggtcaa gcaggactcc ttgtcttctc agaaccagct tggcgtcttg 660 cccttgtctt gggacattcc ggaactcgtc aacatgggcc agtggaagat ccgagcctac 720 tatgaaaact caccacagca ggtcttctcc actgagtttg aggtgaagga gtacgtgctg 780 cccagtttcg aggtcatagt ggagcctaca gagaaattct actacatcta taacgagaag 840 ggcctggagg tcaccatcac cgccaggttc ctctacggga agaaagtgga gggaactgcc 900 tttgtcatct tcgggatcca ggatggcgaa cagaggattt ccctgcctga atccctcaag 960 cgcattccga ttgaggatgg ctcgggggag gttgtgctga gccggaaggt actgctggac 1020 ggggtgcaga acccccgagc agaagacctg gtggggaagt ctttgtacgt gtctgccacc 1080 gtcatcttgc actcaggcag tgacatggtg caggcagagc gcagcgggat ccccatcgtg 1140 acctctccct accagatcca cttcaccaag acacccaagt acttcaaacc aggaatgccc 1200 tttgacctca tggtgttcgt gacgaaccct gatggctctc cagcctaccg agtccccgtg 1260 gcagtccagg gcgaggacac tgtgcagtct ctaacccagg gagatggcgt ggccaaactc 1320 agcatcaaca cacaccccag ccagaagccc ttgagcatca cggtgcgcac gaagaagcag 1380 gagctctcgg aggcagagca ggctaccagg accatgcagg ctctgcccta cagcaccgtg 1440 ggcaactcca acaattacct gcatctctca gtgctacgta cagagctcag acccggggag 1500 accctcaacg tcaacttcct cctgcgaatg gaccgcgccc acgaggccaa gatccgctac 1560 tacacctacc tgatcatgaa caagggcagg ctgttgaagg cgggacgcca ggtgcgagag 1620 cccggccagg acctggtggt gctgcccctg tccatcacca ccgacttcat cccttccttc 1680 cgcctggtgg cgtactacac gctgatcggt gccagcggcc agagggaggt ggtggccgac 1740 tccgtgtggg tggacgtcaa ggactcctgc gtgggctcgc tggtggtaaa aagcggccag 1800 tcagaagacc ggcagcctgt acctgggcag cagatgaccc tgaagataga gggtgaccac 1860 ggggcccggg tggtactggt ggccgtggac aagggcgtgt tcgtgctgaa taagaagaac 1920 aaactgacgc agagtaagat ctgggacgtg gtggagaagg cagacatcgg ctgcaccccg 1980 ggcagtggga aggattacgc cggtgtcttc tccgacgcag ggctgacctt cacgagcagc 2040 agtggccagc agaccgccca gagggcagaa cttcagtgcc cgcagccagc cgcccgccga 2100 cgccgttccg tgcagctcac ggagaagcga atggacaaag tcggcaagta ccccaaggag 2160 ctgcgcaagt gctgcgagga cggcatgcgg gagaacccca tgaggttctc gtgccagcgc 2220 cggacccgtt tcatctccct gggcgaggcg tgcaagaagg tcttcctgga ctgctgcaac 2280 tacatcacag agctgcggcg gcagcacgcg cgggccagcc acctgggcct ggccaggagt 2340 aacctggatg aggacatcat tgcagaagag aacatcgttt cccgaagtga gttcccagag 2400 agctggctgt ggaacgttga ggacttgaaa gagccaccga aaaatggaat ctctacgaag 2460 ctcatgaata tatttttgaa agactccatc accacgtggg agattctggc tgtgagcatg 2520 tcggacaaga aagggatctg tgtggcagac cccttcgagg tcacagtaat gcaggacttc 2580 ttcatcgacc tgcggctacc ctactctgtt gttcgaaacg agcaggtgga aatccgagcc 2640 gttctctaca attaccggca gaaccaagag ctcaaggtga gggtggaact actccacaat 2700 ccagccttct gcagcctggc caccaccaag aggcgtcacc agcagaccgt aaccatcccc 2760 cccaagtcct cgttgtccgt tccatatgtc atcgtgccgc taaagaccgg cctgcaggaa 2820 gtggaagtca aggctgctgt ctaccatcat ttcatcagtg acggtgtcag gaagtccctg 2880 aaggtcgtgc cggaaggaat cagaatgaac aaaactgtgg ctgttcgcac cctggatcca 2940 gaacgcctgg gccgtgaagg agtgcagaaa gaggacatcc cacctgcaga cctcagtgac 3000 caagtcccgg acaccgagtc tgagaccaga attctcctgc aagggacccc agtggcccag 3060 atgacagagg atgccgtcga cgcggaacgg ctgaagcacc tcattgtgac cccctcgggc 3120 tgcggggaac agaacatgat cggcatgacg cccacggtca tcgctgtgca ttacctggat 3180 gaaacggagc agtgggagaa gttcggccta gagaagcggc agggggcctt ggagctcatc 3240 aagaaggggt acacccagca gctggccttc agacaaccca gctctgcctt tgcggccttc 3300 gtgaaacggg cacccagcac ctggctgacc gcctacgtgg tcaaggtctt ctctctggct 3360 gtcaacctca tcgccatcga ctcccaagtc ctctgcgggg ctgttaaatg gctgatcctg 3420 gagaagcaga agcccgacgg ggtcttccag gaggatgcgc ccgtgataca ccaagaaatg 3480 attggtggat tacggaacaa caacgagaaa gacatggccc tcacggcctt tgttctcatc 3540 tcgctgcagg aggctaaaga tatttgcgag gagcaggtca acagcctgcc aggcagcatc 3600 actaaagcag gagacttcct tgaagccaac tacatgaacc tacagagatc ctacactgtg 3660 gccattgctg gctatgctct ggcccagatg ggcaggctga aggggcctct tcttaacaaa 3720 tttctgacca cagccaaaga taagaaccgc tgggaggacc ctggtaagca gctctacaac 3780 gtggaggcca catcctatgc cctcttggcc ctactgcagc taaaagactt tgactttgtg 3840 cctcccgtcg tgcgttggct caatgaacag agatactacg gtggtggcta tggctctacc 3900 caggccacct tcatggtgtt ccaagccttg gctcaatacc aaaaggacgc ccctgaccac 3960 caggaactga accttgatgt gtccctccaa ctgcccagcc gcagctccaa gatcacccac 4020 cgtatccact gggaatctgc cagcctcctg cgatcagaag agaccaagga aaatgagggt 4080 ttcacagtca cagctgaagg aaaaggccaa ggcaccttgt cggtggtgac aatgtaccat 4140 gctaaggcca aagatcaact cacctgtaat aaattcgacc tcaaggtcac cataaaacca 4200 gcaccggaaa cagaaaagag gcctcaggat gccaagaaca ctatgatcct tgagatctgt 4260 accaggtacc ggggagacca ggatgccact atgtctatat tggacatatc catgatgact 4320 ggctttgctc cagacacaga tgacctgaag cagctggcca atggtgttga cagatacatc 4380 tccaagtatg agctggacaa agccttctcc gataggaaca ccctcatcat ctacctggac 4440 aaggtctcac actctgagga tgactgtcta gctttcaaag ttcaccaata ctttaatgta 4500 gagcttatcc agcctggagc agtcaaggtc tacgcctatt acaacctgga ggaaagctgt 4560 acccggttct accatccgga aaaggaggat ggaaagctga acaagctctg ccgtgatgaa 4620 ctgtgccgct gtgctgagga gaattgcttc atacaaaagt cggatgacaa ggtcaccctg 4680 gaagaacggc tggacaaggc ctgtgagcca ggagtggact atgtgtacaa gacccgactg 4740 gtcaaggttc agctgtccaa tgactttgac gagtacatca tggccattga gcagaccatc 4800 aagtcaggct cggatgaggt gcaggttgga cagcagcgca cgttcatcag ccccatcaag 4860 tgcagagaag ccctgaagct ggaggagaag aaacactacc tcatgtgggg tctctcctcc 4920 gatttctggg gagagaagcc caacctcagc tacatcatcg ggaaggacac ttgggtggag 4980 cactggcccg aggaggacga atgccaagac gaagagaacc agaaacaatg ccaggacctc 5040 ggcgccttca ccgagagcat ggttgtcttt gggtgcccca actgaccaca cccccattcc 5100 cccactccag ataaagcttc agttatatct caaaaaaaaa aaaaaaaa 5148 <210> 17 <211> 3692 <212> DNA <213> Homo sapiens <400> 17 aggatgggaa ctaggagtgg cagcaatcct ttctttcagc tggagtgctc ctcaggagcc 60 agccccaccc ttagaaaaga tgttttccat gaggatcgtc tgcctggtcc taagtgtggt 120 gggcacagca tggactgcag atagtggtga aggtgacttt ctagctgaag gaggaggcgt 180 gcgtggccca agggttgtgg aaagacatca atctgcctgc aaagattcag actggccctt 240 ctgctctgat gaagactgga actacaaatg cccttctggc tgcaggatga aagggttgat 300 tgatgaagtc aatcaagatt ttacaaacag aataaataag ctcaaaaatt cactatttga 360 atatcagaag aacaataagg attctcattc gttgaccact aatataatgg aaattttgag 420 aggcgatttt tcctcagcca ataaccgtga taatacctac aaccgagtgt cagaggatct 480 gagaagcaga attgaagtcc tgaagcgcaa agtcatagaa aaagtacagc atatccagct 540 tctgcagaaa aatgttagag ctcagttggt tgatatgaaa cgactggagg tggacattga 600 tattaagatc cgatcttgtc gagggtcatg cagtagggct ttagctcgtg aagtagatct 660 gaaggactat gaagatcagc agaagcaact tgaacaggtc attgccaaag acttacttcc 720 ctctagagat aggcaacact taccactgat aaaaatgaaa ccagttccag acttggttcc 780 cggaaatttt aagagccagc ttcagaaggt acccccagag tggaaggcat taacagacat 840 gccgcagatg agaatggagt tagagagacc tggtggaaat gagattactc gaggaggctc 900 cacctcttat ggaaccggat cagagacgga aagccccagg aaccctagca gtgctggaag 960 ctggaactct gggagctctg gacctggaag tactggaaac cgaaaccctg ggagctctgg 1020 gactggaggg actgcaacct ggaaacctgg gagctctgga cctggaagta ctggaagctg 1080 gaactctggg agctctggaa ctggaagtac tggaaaccaa aaccctggga gccctagacc 1140 tggtagtacc ggaacctgga atcctggcag ctctgaacgc ggaagtgctg ggcactggac 1200 ctctgagagc tctgtatctg gtagtactgg acaatggcac tctgaatctg gaagttttag 1260 gccagatagc ccaggctctg ggaacgcgag gcctaacaac ccagactggg gcacatttga 1320 agaggtgtca ggaaatgtaa gtccagggac aaggagagag taccacacag aaaaactggt 1380 cacttctaaa ggagataaag agctcaggac tggtaaagag aaggtcacct ctggtagcac 1440 aaccaccacg cgtcgttcat gctctaaaac cgttactaag actgttattg gtcctgatgg 1500 tcacaaagaa gttaccaaag aagtggtgac ctccgaagat ggttctgact gtcccgaggc 1560 aatggattta ggcacattgt ctggcatagg tactctggat gggttccgcc ataggcaccc 1620 tgatgaagct gccttcttcg acactgcctc aactggaaaa acattcccag gtttcttctc 1680 acctatgtta ggagagtttg tcagtgagac tgagtctagg ggctcagaat ctggcatctt 1740 cacaaataca aaggaatcca gttctcatca ccctgggata gctgaattcc cttcccgtgg 1800 taaatcttca agttacagca aacaatttac tagtagcacg agttacaaca gaggagactc 1860 cacatttgaa agcaagagct ataaaatggc agatgaggcc ggaagtgaag ccgatcatga 1920 aggaacacat agcaccaaga gaggccatgc taaatctcgc cctgtcagag actgtgatga 1980 tgtcctccaa acacatcctt caggtaccca aagtggcatt ttcaatatca agctaccggg 2040 atccagtaag attttttctg tttattgcga tcaagagacc agtttgggag gatggctttt 2100 gatccagcaa agaatggatg gatcactgaa ttttaaccgg acctggcaag actacaagag 2160 aggtttcggc agcctgaatg acgaggggga aggagaattc tggctaggca atgactacct 2220 ccacttacta acccaaaggg gctctgttct tagggttgaa ttagaggact gggctgggaa 2280 tgaagcttat gcagaatatc acttccgggt aggctctgag gctgaaggct atgccctcca 2340 agtctcctcc tatgaaggca ctgcgggtga tgctctgatt gagggttccg tagaggaagg 2400 ggcagagtac acctctcaca acaacatgca gttcagcacc tttgacaggg atgcagacca 2460 gtgggaagag aactgtgcag aagtctatgg gggaggctgg tggtataata actgccaagc 2520 agccaatctc aatggaatct actaccctgg gggctcctat gacccaagga ataacagtcc 2580 ttatgagatt gagaatggag tggtctgggt ttcctttaga ggggcagatt attccctcag 2640 ggctgttcgc atgaaaatta ggccccttgt gacccaatag gctgaagaag tgggaatggg 2700 agcactctgt cttctttgct agagaagtgg agagaaaata caaaaggtaa agcagttgag 2760 attctctaca acctaaaaaa ttcctaggtg ctattttctt atcctttgta ctgtagctaa 2820 atgtacctga gacatattag tctttgaaaa ataaagttat gtaaggtttt ttttatcttt 2880 aaatagctct gtgggtttta acatttttat aaagatatac caagggccat tcagtacatc 2940 aggaaagtgg cagacagaag cttctctctg caaccttgaa gactattggt ttgagaactt 3000 ctcttcccat accacccaaa atcataatgc cattggaaag caaaaagttg ttttatccat 3060 ttgatttgaa ttgttttaag ccaatatttt aaggtaaaac tcactgaatc taaccatagc 3120 tgacctttgt agtagaattt acaacttata attacaatgc acaatttata attacaatat 3180 gtatttatgt cttttgctat ggagcaaatc caggaaggca agagaaacat tctttcctaa 3240 atataaatga aaatctatcc tttaaactct tccactagac gttgtaatgc acacttattt 3300 ttttcccaag gagtaaccaa tttctttcta aaacacattt aaaattttaa aactatttat 3360 gaatattaaa aaaagacata attcacacat taataaacaa tctcccaagt attgatttaa 3420 cttcattttt ctaataatca taaactatat tctgtgacat gctaattatt attaaatgta 3480 agtcgttagt tcgaaagcct ctcactaagt atgatctatg ctatattcaa aattcaaccc 3540 atttactttg gtcaatattt gatctaagtt gcatctttaa tcctggtggt cttgccttct 3600 gatttttaat ttgtatcctt ttctattaag atatatttgt cattttctct tgaatatgta 3660 ttaaaatatc ccaagcaaaa aaaaaaaaaa aa 3692 <210> 18 <211> 2248 <212> DNA <213> Homo sapiens <400> 18 aggatgggaa ctaggagtgg cagcaatcct ttctttcagc tggagtgctc ctcaggagcc 60 agccccaccc ttagaaaaga tgttttccat gaggatcgtc tgcctggtcc taagtgtggt 120 gggcacagca tggactgcag atagtggtga aggtgacttt ctagctgaag gaggaggcgt 180 gcgtggccca agggttgtgg aaagacatca atctgcctgc aaagattcag actggccctt 240 ctgctctgat gaagactgga actacaaatg cccttctggc tgcaggatga aagggttgat 300 tgatgaagtc aatcaagatt ttacaaacag aataaataag ctcaaaaatt cactatttga 360 atatcagaag aacaataagg attctcattc gttgaccact aatataatgg aaattttgag 420 aggcgatttt tcctcagcca ataaccgtga taatacctac aaccgagtgt cagaggatct 480 gagaagcaga attgaagtcc tgaagcgcaa agtcatagaa aaagtacagc atatccagct 540 tctgcagaaa aatgttagag ctcagttggt tgatatgaaa cgactggagg tggacattga 600 tattaagatc cgatcttgtc gagggtcatg cagtagggct ttagctcgtg aagtagatct 660 gaaggactat gaagatcagc agaagcaact tgaacaggtc attgccaaag acttacttcc 720 ctctagagat aggcaacact taccactgat aaaaatgaaa ccagttccag acttggttcc 780 cggaaatttt aagagccagc ttcagaaggt acccccagag tggaaggcat taacagacat 840 gccgcagatg agaatggagt tagagagacc tggtggaaat gagattactc gaggaggctc 900 cacctcttat ggaaccggat cagagacgga aagccccagg aaccctagca gtgctggaag 960 ctggaactct gggagctctg gacctggaag tactggaaac cgaaaccctg ggagctctgg 1020 gactggaggg actgcaacct ggaaacctgg gagctctgga cctggaagta ctggaagctg 1080 gaactctggg agctctggaa ctggaagtac tggaaaccaa aaccctggga gccctagacc 1140 tggtagtacc ggaacctgga atcctggcag ctctgaacgc ggaagtgctg ggcactggac 1200 ctctgagagc tctgtatctg gtagtactgg acaatggcac tctgaatctg gaagttttag 1260 gccagatagc ccaggctctg ggaacgcgag gcctaacaac ccagactggg gcacatttga 1320 agaggtgtca ggaaatgtaa gtccagggac aaggagagag taccacacag aaaaactggt 1380 cacttctaaa ggagataaag agctcaggac tggtaaagag aaggtcacct ctggtagcac 1440 aaccaccacg cgtcgttcat gctctaaaac cgttactaag actgttattg gtcctgatgg 1500 tcacaaagaa gttaccaaag aagtggtgac ctccgaagat ggttctgact gtcccgaggc 1560 aatggattta ggcacattgt ctggcatagg tactctggat gggttccgcc ataggcaccc 1620 tgatgaagct gccttcttcg acactgcctc aactggaaaa acattcccag gtttcttctc 1680 acctatgtta ggagagtttg tcagtgagac tgagtctagg ggctcagaat ctggcatctt 1740 cacaaataca aaggaatcca gttctcatca ccctgggata gctgaattcc cttcccgtgg 1800 taaatcttca agttacagca aacaatttac tagtagcacg agttacaaca gaggagactc 1860 cacatttgaa agcaagagct ataaaatggc agatgaggcc ggaagtgaag ccgatcatga 1920 aggaacacat agcaccaaga gaggccatgc taaatctcgc cctgtcagag gtatccacac 1980 ttctcctttg gggaagcctt ccctgtcccc ctagactaag ttaaatattt ctgcacagtg 2040 ttcccatggc cccttgcatt tccttcttaa ctctctgtta cacgtcattg aaactacact 2100 tttttggtct gtttttgtgc tagactgtaa gttccttggg ggcagggcct ttgtctgtct 2160 catctctgta ttcccaaatg cctaacagta cagagccatg actcaataaa tacatgttaa 2220 atggatgaat gaattcctct gaaactct 2248 <210> 19 <211> 3451 <212> DNA <213> Homo sapiens <400> 19 agatatatat aggattgaag atctctcagt taagtctaca tgaaaaggat ggtttcttgg 60 agcttccaca aacttaaaac catgaaacat ctattattgc tactattgtg tgtttttcta 120 gttaagtccc aaggtgtcaa cgacaatgag gagggtttct tcagtgcccg tggtcatcga 180 ccccttgaca agaagagaga agaggctttg ctacaacagg aaaggccaat cagaaatagt 240 gttgatgagt taaataacaa tgtggaagct gtttcccaga cctcctcttc ttcctttcag 300 tacatgtatt tgctgaaaga cctgtggcaa aagaggcaga agcaagtaaa agataatgaa 360 aatgtagtca atgagtactc ctcagaactg gaaaagcacc aattatatat agatgagact 420 gtgaatagca atatcccaac taaccttcgt gtgcttcgtt caatcctgga aaacctgaga 480 agcaaaatac aaaagttaga atctgatgtc tcagctcaaa tggaatattg tcgcacccca 540 tgcactgtca gttgcaatat tcctgtggtg tctggcaaag aatgtgagga aattatcagg 600 aaaggaggtg aaacatctga aatgtatctc attcaacctg acagttctgt caaaccgtat 660 agagtatact gtgacatgaa tacagaaaat ggaggatgga cagtgattca gaaccgtcaa 720 gacggtagtg ttgactttgg caggaaatgg gatccatata aacagggatt tggaaatgtt 780 gcaaccaaca cagatgggaa gaattactgt ggcctaccag gtgaatattg gcttggaaat 840 gataaaatta gccagcttac caggatggga cccacagaac ttttgataga aatggaggac 900 tggaaaggag acaaagtaaa ggctcactat ggaggattca ctgtacagaa tgaagccaac 960 aaataccaga tctcagtgaa caaatacaga ggaacagccg gtaatgccct catggatgga 1020 gcatctcagc tgatgggaga aaacaggacc atgaccattc acaacggcat gttcttcagc 1080 acgtatgaca gagacaatga cggctggtta acatcagatc ccagaaaaca gtgttctaaa 1140 gaagacggtg gtggatggtg gtataataga tgtcatgcag ccaatccaaa cggcagatac 1200 tactggggtg gacagtacac ctgggacatg gcaaagcatg gcacagatga tggtgtagta 1260 tggatgaatt ggaaggggtc atggtactca atgaggaaga tgagtatgaa gatcaggccc 1320 ttcttcccac agcaatagtc cccaatacgt agatttttgc tcttctgtat gtgacaacat 1380 ttttgtacat tatgttattg gaattttctt tcatacatta tattcctcta aaactctcaa 1440 gcagacgtga gtgtgacttt ttgaaaaaag tataggataa attacattaa aatagcacat 1500 gattttcttt tgttttcttc atttctcttg ctcaccaaga agtaacaaaa gtatagtttt 1560 gacagagttg gtgttcataa tttcagttct agttgattgc gagaattttc aaataaggaa 1620 gaggggtctt ttatccttgt cgtaggaaaa ccatgacgga aaggaaaaac tgatgtttaa 1680 aagtccactt ttaaaactat atttatttat gtaggatctg tcaaagaaaa cttccaaaaa 1740 gatttattaa ttaaaccaga ctctgttgca ataagttaat gttttcttgt tttgtaatcc 1800 acacattcaa tgagttaggc tttgcacttg taaggaagga gaagcgttca caacctcaaa 1860 tagctaataa accggtcttg aatatttgaa gatttaaaat ctgactctag gacgggcacg 1920 gtggctcacg actataatcc caacactttg ggaggctgag gcgggcggtc acaaggtcag 1980 gagttcaaga ccagcctgac caatatggtg aaaccccatc tctactaaaa atacaaaaat 2040 tagccaggcg tggtggcagg tgcctgtagt cccagctacc tgtgaggtgg agattgcatt 2100 gagccaagat ctcaacactg cactccagcc tgggcaacag cgtgagactc cacctcaaaa 2160 aaaaaaaaaa aagaatctga ctatatacca tggaaaagcc accactctgc cacttaaata 2220 aacatcagga tcagagattc caagaggaca atctgcatca agtcttcacc aagtgttttt 2280 taagcgaaat aatgaaatag ggagcagaat atgcctgttg cccatagaaa cgaggtctat 2340 tcttgtcctc aattaggctt ttttttcttc atagttacac cagaactaaa gtaaaagtgg 2400 tttttctgtt ctttctactt ctccccatga aatgggcata tcatctcaac acttcactcc 2460 aagtcgccac gggcaacctt atgaccctag gtcctccacc cctaatgtat catcattgcc 2520 acccattttt atggtactta ttgttcttaa gcttatcctc ttaatctttt catgtaagca 2580 aagctcatta atttctgtct tggaaatgct actactctct ttaattactc accaaatcca 2640 actttaactt ttgacctggt ttctctgcca caagttctgt cccactggag cccatactca 2700 cctaccgctt tgccatcaca tttaacagaa aactcttatc aacttacttc ctgcttaaca 2760 ttagctcctt cctatctata tccaaatttc ttaaattcaa attttttagc tggagtaaaa 2820 atggtcccag taccatttcc tgttcccttc actataacct acatttttgt cacattaagt 2880 ttttccccat tccaggacag gtcaggccct ttaaaaattt caacagcttt attgagatat 2940 aattgatata atttaaaaaa tcctgcacat gtgtcatgct ggagccctat tgattccaac 3000 agggatggcg ccttgtccaa gaagagaccc agagccagtg aatgggacat agggtttatt 3060 taggacttaa atacagatgt ggtccagtgg cagtgggctg gacaggaccg ctactatttg 3120 taaagagtat gtagtttata taacatttct acttagcact ctccacttag caacctccat 3180 ttaacccaaa ataaaaggcc ttggttcctt gcacatcctg agttccaacg gacaggcagg 3240 gagttcaagt gtccttcaca gataagaagt gaatctctct gggttggcca ttcccggatt 3300 ccttagctta gactctgaac acatattctt cttagaccat acagtcattc tcagggtatg 3360 cttgagttaa tgctgtcgga tgcatctgtc atacaaagtg tttaacatat acgatttcat 3420 gattttggaa atatgcatac acccatgata t 3451 <210> 20 <211> 3628 <212> DNA <213> Homo sapiens <400> 20 agatatatat aggattgaag atctctcagt taagtctaca tgaaaaggat ggtttcttgg 60 agcttccaca aacttaaaac catgaaacat ctattattgc tactattgtg tgtttttcta 120 gttaagtccc aaggtgtcaa cgacaatgag gagggtttct tcagtgcccg tggtcatcga 180 ccccttgaca agaagagaga agaggctccc agcctgaggc ctgccccacc gcccatcagt 240 ggaggtggct atcgggctcg tccagccaaa gcagctgcca ctcaaaagaa agtagaaaga 300 aaagcccctg atgctggagg ctgtcttcac gctgacccag acctgggggt gttgtgtcct 360 acaggatgtc agttgcaaga ggctttgcta caacaggaaa ggccaatcag aaatagtgtt 420 gatgagttaa ataacaatgt ggaagctgtt tcccagacct cctcttcttc ctttcagtac 480 atgtatttgc tgaaagacct gtggcaaaag aggcagaagc aagtaaaaga taatgaaaat 540 gtagtcaatg agtactcctc agaactggaa aagcaccaat tatatataga tgagactgtg 600 aatagcaata tcccaactaa ccttcgtgtg cttcgttcaa tcctggaaaa cctgagaagc 660 aaaatacaaa agttagaatc tgatgtctca gctcaaatgg aatattgtcg caccccatgc 720 actgtcagtt gcaatattcc tgtggtgtct ggcaaagaat gtgaggaaat tatcaggaaa 780 ggaggtgaaa catctgaaat gtatctcatt caacctgaca gttctgtcaa accgtataga 840 gtatactgtg acatgaatac agaaaatgga ggatggacag tgattcagaa ccgtcaagac 900 ggtagtgttg actttggcag gaaatgggat ccatataaac agggatttgg aaatgttgca 960 accaacacag atgggaagaa ttactgtggc ctaccaggtg aatattggct tggaaatgat 1020 aaaattagcc agcttaccag gatgggaccc acagaacttt tgatagaaat ggaggactgg 1080 aaaggagaca aagtaaaggc tcactatgga ggattcactg tacagaatga agccaacaaa 1140 taccagatct cagtgaacaa atacagagga acagccggta atgccctcat ggatggagca 1200 tctcagctga tgggagaaaa caggaccatg accattcaca acggcatgtt cttcagcacg 1260 tatgacagag acaatgacgg ctggttaaca tcagatccca gaaaacagtg ttctaaagaa 1320 gacggtggtg gatggtggta taatagatgt catgcagcca atccaaacgg cagatactac 1380 tggggtggac agtacacctg ggacatggca aagcatggca cagatgatgg tgtagtatgg 1440 atgaattgga aggggtcatg gtactcaatg aggaagatga gtatgaagat caggcccttc 1500 ttcccacagc aatagtcccc aatacgtaga tttttgctct tctgtatgtg acaacatttt 1560 tgtacattat gttattggaa ttttctttca tacattatat tcctctaaaa ctctcaagca 1620 gacgtgagtg tgactttttg aaaaaagtat aggataaatt acattaaaat agcacatgat 1680 tttcttttgt tttcttcatt tctcttgctc accaagaagt aacaaaagta tagttttgac 1740 agagttggtg ttcataattt cagttctagt tgattgcgag aattttcaaa taaggaagag 1800 gggtctttta tccttgtcgt aggaaaacca tgacggaaag gaaaaactga tgtttaaaag 1860 tccactttta aaactatatt tatttatgta ggatctgtca aagaaaactt ccaaaaagat 1920 ttattaatta aaccagactc tgttgcaata agttaatgtt ttcttgtttt gtaatccaca 1980 cattcaatga gttaggcttt gcacttgtaa ggaaggagaa gcgttcacaa cctcaaatag 2040 ctaataaacc ggtcttgaat atttgaagat ttaaaatctg actctaggac gggcacggtg 2100 gctcacgact ataatcccaa cactttggga ggctgaggcg ggcggtcaca aggtcaggag 2160 ttcaagacca gcctgaccaa tatggtgaaa ccccatctct actaaaaata caaaaattag 2220 ccaggcgtgg tggcaggtgc ctgtagtccc agctacctgt gaggtggaga ttgcattgag 2280 ccaagatctc aacactgcac tccagcctgg gcaacagcgt gagactccac ctcaaaaaaa 2340 aaaaaaaaag aatctgacta tataccatgg aaaagccacc actctgccac ttaaataaac 2400 atcaggatca gagattccaa gaggacaatc tgcatcaagt cttcaccaag tgttttttaa 2460 gcgaaataat gaaataggga gcagaatatg cctgttgccc atagaaacga ggtctattct 2520 tgtcctcaat taggcttttt tttcttcata gttacaccag aactaaagta aaagtggttt 2580 ttctgttctt tctacttctc cccatgaaat gggcatatca tctcaacact tcactccaag 2640 tcgccacggg caaccttatg accctaggtc ctccacccct aatgtatcat cattgccacc 2700 catttttatg gtacttattg ttcttaagct tatcctctta atcttttcat gtaagcaaag 2760 ctcattaatt tctgtcttgg aaatgctact actctcttta attactcacc aaatccaact 2820 ttaacttttg acctggtttc tctgccacaa gttctgtccc actggagccc atactcacct 2880 accgctttgc catcacattt aacagaaaac tcttatcaac ttacttcctg cttaacatta 2940 gctccttcct atctatatcc aaatttctta aattcaaatt ttttagctgg agtaaaaatg 3000 gtcccagtac catttcctgt tcccttcact ataacctaca tttttgtcac attaagtttt 3060 tccccattcc aggacaggtc aggcccttta aaaatttcaa cagctttatt gagatataat 3120 tgatataatt taaaaaatcc tgcacatgtg tcatgctgga gccctattga ttccaacagg 3180 gatggcgcct tgtccaagaa gagacccaga gccagtgaat gggacatagg gtttatttag 3240 gacttaaata cagatgtggt ccagtggcag tgggctggac aggaccgcta ctatttgtaa 3300 agagtatgta gtttatataa catttctact tagcactctc cacttagcaa cctccattta 3360 acccaaaata aaaggccttg gttccttgca catcctgagt tccaacggac aggcagggag 3420 ttcaagtgtc cttcacagat aagaagtgaa tctctctggg ttggccattc ccggattcct 3480 tagcttagac tctgaacaca tattcttctt agaccataca gtcattctca gggtatgctt 3540 gagttaatgc tgtcggatgc atctgtcata caaagtgttt aacatatacg atttcatgat 3600 tttggaaata tgcatacacc catgatat 3628 <210> 21 <211> 1735 <212> DNA <213> Homo sapiens <400> 21 tgacagtata ggttgggggc caggatgagg aaaaaggaac gggaaagacc tgcccaccct 60 tctggtaagg aggccccgtg atcagctcca gccatttgca gtcctggcta tcccaggagc 120 ttacataaag ggacaattgg agcctgagag gtgacagtgc tgacactaca aggctcggag 180 ctccgggcac tcagacatca tgagttggtc cttgcacccc cggaatttaa ttctctactt 240 ctatgctctt ttatttctct cttcaacatg tgtagcatat gttgctacca gagacaactg 300 ctgcatctta gatgaaagat tcggtagtta ttgtccaact acctgtggca ttgcagattt 360 cctgtctact tatcaaacca aagtagacaa ggatctacag tctttggaag acatcttaca 420 tcaagttgaa aacaaaacat cagaagtcaa acagctgata aaagcaatcc aactcactta 480 taatcctgat gaatcatcaa aaccaaatat gatagacgct gctactttga agtccaggaa 540 aatgttagaa gaaattatga aatatgaagc atcgatttta acacatgact caagtattcg 600 atatttgcag gaaatatata attcaaataa tcaaaagatt gttaacctga aagagaaggt 660 agcccagctt gaagcacagt gccaggaacc ttgcaaagac acggtgcaaa tccatgatat 720 cactgggaaa gattgtcaag acattgccaa taagggagct aaacagagcg ggctttactt 780 tattaaacct ctgaaagcta accagcaatt cttagtctac tgtgaaatcg atgggtctgg 840 aaatggatgg actgtgtttc agaagagact tgatggcagt gtagatttca agaaaaactg 900 gattcaatat aaagaaggat ttggacatct gtctcctact ggcacaacag aattttggct 960 gggaaatgag aagattcatt tgataagcac acagtctgcc atcccatatg cattaagagt 1020 ggaactggaa gactggaatg gcagaaccag tactgcagac tatgccatgt tcaaggtggg 1080 acctgaagct gacaagtacc gcctaacata tgcctacttc gctggtgggg atgctggaga 1140 tgcctttgat ggctttgatt ttggcgatga tcctagtgac aagtttttca catcccataa 1200 tggcatgcag ttcagtacct gggacaatga caatgataag tttgaaggca actgtgctga 1260 acaggatgga tctggttggt ggatgaacaa gtgtcacgct ggccatctca atggagttta 1320 ttaccaaggt ggcacttact caaaagcatc tactcctaat ggttatgata atggcattat 1380 ttgggccact tggaaaaccc ggtggtattc catgaagaaa accactatga agataatccc 1440 attcaacaga ctcacaattg gagaaggaca gcaacaccac ctggggggag ccaaacaggc 1500 tggagacgtt taaaagaccg tttcaaaaga gatttacttt tttaaaggac tttatctgaa 1560 cagagagata taatattttt cctattggac aatggacttg caaagcttca cttcatttta 1620 agagcaaaag accccatgtt gaaaactcca taacagtttt atgctgatga taatttatct 1680 acatgcattt caataaacct tttgtttcct aagactagaa aaaaaaaaaa aaaaa 1735 <210> 22 <211> 1763 <212> DNA <213> Homo sapiens <400> 22 cttctggtaa ggaggccccg tgatcagctc cagccatttg cagtcctggc tatcccagga 60 gcttacataa agggacaatt ggagcctgag aggtgacagt gctgacacta caaggctcgg 120 agctccgggc actcagacat catgagttgg tccttgcacc cccggaattt aattctctac 180 ttctatgctc ttttatttct ctcttcaaca tgtgtagcat atgttgctac cagagacaac 240 tgctgcatct tagatgaaag attcggtagt tattgtccaa ctacctgtgg cattgcagat 300 ttcctgtcta cttatcaaac caaagtagac aaggatctac agtctttgga agacatctta 360 catcaagttg aaaacaaaac atcagaagtc aaacagctga taaaagcaat ccaactcact 420 tataatcctg atgaatcatc aaaaccaaat atgatagacg ctgctacttt gaagtccagg 480 aaaatgttag aagaaattat gaaatatgaa gcatcgattt taacacatga ctcaagtatt 540 cgatatttgc aggaaatata taattcaaat aatcaaaaga ttgttaacct gaaagagaag 600 gtagcccagc ttgaagcaca gtgccaggaa ccttgcaaag acacggtgca aatccatgat 660 atcactggga aagattgtca agacattgcc aataagggag ctaaacagag cgggctttac 720 tttattaaac ctctgaaagc taaccagcaa ttcttagtct actgtgaaat cgatgggtct 780 ggaaatggat ggactgtgtt tcagaagaga cttgatggca gtgtagattt caagaaaaac 840 tggattcaat ataaagaagg atttggacat ctgtctccta ctggcacaac agaattttgg 900 ctgggaaatg agaagattca tttgataagc acacagtctg ccatcccata tgcattaaga 960 gtggaactgg aagactggaa tggcagaacc agtactgcag actatgccat gttcaaggtg 1020 ggacctgaag ctgacaagta ccgcctaaca tatgcctact tcgctggtgg ggatgctgga 1080 gatgcctttg atggctttga ttttggcgat gatcctagtg acaagttttt cacatcccat 1140 aatggcatgc agttcagtac ctgggacaat gacaatgata agtttgaagg caactgtgct 1200 gaacaggatg gatctggttg gtggatgaac aagtgtcacg ctggccatct caatggagtt 1260 tattaccaag gtggcactta ctcaaaagca tctactccta atggttatga taatggcatt 1320 atttgggcca cttggaaaac ccggtggtat tccatgaaga aaaccactat gaagataatc 1380 ccattcaaca gactcacaat tggagaagga cagcaacacc acctgggggg agccaaacag 1440 gtcagaccag agcaccctgc ggaaacagaa tatgactcac tttaccctga ggatgatttg 1500 tagaaaatta actgctaact tctattgacc cacaaagttt cagaaattct ctgaaagttt 1560 cttccttttt tctcttacta tatttattga tttcaagtct tctattaagg acatttagcc 1620 ttcaatggaa attaaaactc atttaggact gtatttccaa attactgata tcagagttat 1680 ttaaaaattg tttatttgag gagataacat ttcaactttg ttcctaaata tataataata 1740 aaatgattga ctttatttgc aaa 1763 <210> 23 <211> 4674 <212> DNA <213> Homo sapiens <400> 23 acaccctaat gcctccaaca ataactgttg actttttatt ttcagtcaga gaagcctggc 60 aaccaagaac tgtttttttg gtggtttacg agaacttaac tgaattggaa aatatttgct 120 ttaatgaaac aatttactct tgtgcaacac taaattgtgt caatcaagca aataaggaag 180 aaagtcttat ttataaaatt gcctgctcct gattttactt catttcttct caggctccaa 240 gaaggggaaa aaaatgaaga ttttgatact tggtattttt ctgtttttat gtagtacccc 300 agcctgggcg aaagaaaagc attattacat tggaattatt gaaacgactt gggattatgc 360 ctctgaccat ggggaaaaga aacttatttc tgttgacacg gaacattcca atatctatct 420 tcaaaatggc ccagatagaa ttgggagact atataagaag gccctttatc ttcagtacac 480 agatgaaacc tttaggacaa ctatagaaaa accggtctgg cttgggtttt taggccctat 540 tatcaaagct gaaactggag ataaagttta tgtacactta aaaaaccttg cctctaggcc 600 ctacaccttt cattcacatg gaataactta ctataaggaa catgaggggg ccatctaccc 660 tgataacacc acagattttc aaagagcaga tgacaaagta tatccaggag agcagtatac 720 atacatgttg cttgccactg aagaacaaag tcctggggaa ggagatggca attgtgtgac 780 taggatttac cattcccaca ttgatgctcc aaaagatatt gcctcaggac tcatcggacc 840 tttaataatc tgtaaaaaag attctctaga taaagaaaaa gaaaaacata ttgaccgaga 900 atttgtggtg atgttttctg tggtggatga aaatttcagc tggtacctag aagacaacat 960 taaaacctac tgctcagaac cagagaaagt tgacaaagac aacgaagact tccaggagag 1020 taacagaatg tattctgtga atggatacac ttttggaagt ctcccaggac tctccatgtg 1080 tgctgaagac agagtaaaat ggtacctttt tggtatgggt aatgaagttg atgtgcacgc 1140 agctttcttt cacgggcaag cactgactaa caagaactac cgtattgaca caatcaacct 1200 ctttcctgct accctgtttg atgcttatat ggtggcccag aaccctggag aatggatgct 1260 cagctgtcag aatctaaacc atctgaaagc cggtttgcaa gcctttttcc aggtccagga 1320 gtgtaacaag tcttcatcaa aggataatat ccgtgggaag catgttagac actactacat 1380 tgccgctgag gaaatcatct ggaactatgc tccctctggt atagacatct tcactaaaga 1440 aaacttaaca gcacctggaa gtgactcagc ggtgtttttt gaacaaggta ccacaagaat 1500 tggaggctct tataaaaagc tggtttatcg tgagtacaca gatgcctcct tcacaaatcg 1560 aaaggagaga ggccctgaag aagagcatct tggcatcctg ggtcctgtca tttgggcaga 1620 ggtgggagac accatcagag taaccttcca taacaaagga gcatatcccc tcagtattga 1680 gccgattggg gtgagattca ataagaacaa cgagggcaca tactattccc caaattacaa 1740 cccccagagc agaagtgtgc ctccttcagc ctcccatgtg gcacccacag aaacattcac 1800 ctatgaatgg actgtcccca aagaagtagg acccactaat gcagatcctg tgtgtctagc 1860 taagatgtat tattctgctg tggatcccac taaagatata ttcactgggc ttattgggcc 1920 aatgaaaata tgcaagaaag gaagtttaca tgcaaatggg agacagaaag atgtagacaa 1980 ggaattctat ttgtttccta cagtatttga tgagaatgag agtttactcc tggaagataa 2040 tattagaatg tttacaactg cacctgatca ggtggataag gaagatgaag actttcagga 2100 atctaataaa atgcactcca tgaatggatt catgtatggg aatcagccgg gtctcactat 2160 gtgcaaagga gattcggtcg tgtggtactt attcagcgcc ggaaatgagg ccgatgtaca 2220 tggaatatac ttttcaggaa acacatatct gtggagagga gaacggagag acacagcaaa 2280 cctcttccct caaacaagtc ttacgctcca catgtggcct gacacagagg ggacttttaa 2340 tgttgaatgc cttacaactg atcattacac aggcggcatg aagcaaaaat atactgtgaa 2400 ccaatgcagg cggcagtctg aggattccac cttctacctg ggagagagga catactatat 2460 cgcagcagtg gaggtggaat gggattattc cccacaaagg gagtgggaaa aggagctgca 2520 tcatttacaa gagcagaatg tttcaaatgc atttttagat aagggagagt tttacatagg 2580 ctcaaagtac aagaaagttg tgtatcggca gtatactgat agcacattcc gtgttccagt 2640 ggagagaaaa gctgaagaag aacatctggg aattctaggt ccacaacttc atgcagatgt 2700 tggagacaaa gtcaaaatta tctttaaaaa catggccaca aggccctact caatacatgc 2760 ccatggggta caaacagaga gttctacagt tactccaaca ttaccaggtg aaactctcac 2820 ttacgtatgg aaaatcccag aaagatctgg agctggaaca gaggattctg cttgtattcc 2880 atgggcttat tattcaactg tggatcaagt taaggacctc tacagtggat taattggccc 2940 cctgattgtt tgtcgaagac cttacttgaa agtattcaat cccagaagga aactggaatt 3000 tgcccttctg tttctagttt ttgatgagaa tgaatcttgg tacttagatg acaacatcaa 3060 aacatactct gatcaccccg agaaagtaaa caaagatgat gaggaattca tagaaagcaa 3120 taaaatgcat gctattaatg gaagaatgtt tggaaaccta caaggcctca caatgcacgt 3180 gggagatgaa gtcaactggt atctgatggg aatgggcaat gaaatagact tacacactgt 3240 acattttcac ggccatagct tccaatacaa gcacagggga gtttatagtt ctgatgtctt 3300 tgacattttc cctggaacat accaaaccct agaaatgttt ccaagaacac ctggaatttg 3360 gttactccac tgccatgtga ccgaccacat tcatgctgga atggaaacca cttacaccgt 3420 tctacaaaat gaagacacca aatctggctg aatgaaataa attggtgata agtggaaaaa 3480 agagaaaaac caatgattca taacaatgta tgtgaaagtg taaaatagaa tgttactttg 3540 gaatgactat aaacattaaa agaagactgg aagcatacaa ctttgtacat ttgtggggga 3600 aaactattaa ttttttgcaa atggaaagat caacagacta tataatgata catgactgac 3660 acttgtacac taggtaataa aactgattca tacagtctaa tgatatcacc gctgttaggg 3720 ttttataaaa ctgcatttaa aaaaagatct atgaccagat attctcctgg gtgctcctca 3780 aaggaacact attaaggttc attgaaatgt tttcaatcat tgccttccca ttgatccttc 3840 taacatgctg ttgacatcac acctaatatt cagagggaat gggcaaggta tgagggaagg 3900 aaataaaaaa taaaataaat aaaatagaat gacacaaatt tgagttttgt gaacccctga 3960 acagatggtc ttaaggacgt tatctggaac tggagaaaag cagagttgag agacaattct 4020 atagattaaa tcctggtaag gacaaacatt gccattagaa gaaaagcttc aaaatagacc 4080 tgtggcagat gtcacatgag tagaatttct gcccagcctt aactgcattc agaggataat 4140 atcaatgaac taaacttgaa ctaaaaattt tttaaacaaa aagttataaa tgaagacaca 4200 tggttgtgaa tacaatgatg tatttcttta ttttcacata cactctagct aaaagagcaa 4260 gagtacacat caacaaaaat ggaaacaagg ctttggctga aaaaaacatg catttgacaa 4320 atcatgttaa tagctagaca agaagaaagt tagctttgta aacttctact tcatttgatt 4380 cagagaaaca gagcatgagt tttcttaaaa gtaacaagaa aaggaacaaa aaaaatgagg 4440 tttgaaatct tttaccatgg caaaacatta acatctttct caaaaacata gagaaatctg 4500 gaaaaatcaa gaagataaaa ttctggacca gttagtgaca ttctttcaag catacttgta 4560 aaatgtttcc ttaaagtgtt cttgggatga aaatgattgt catgtctcca acaacagtga 4620 actgatgttg ttccttggaa taaaagtcaa tccccacctt aaaaaaaaaa aaaa 4674 <210> 24 <211> 1333 <212> DNA <213> Homo sapiens <400> 24 accgcccaca cgcaaggctg cctgcctcta cacattctcc caagagttgt ctgagccgcc 60 gagtggacag tggctgatta tggagagcag aggcccactg gctacctcgc gcctgctgct 120 gttgctgctg ttgctactac tgcgtcacac ccgccaggga tgggccctga gacctgttct 180 ccccacccag agtgcccacg accctccggc tgtccacctc agcaatggcc caggacaaga 240 gcctatcgct gtcatgacct ttgacctcac caagatcaca aaaacctcct cctcctttga 300 ggttcgaacc tgggacccag agggagtgat tttttatggg gataccaacc ctaaggatga 360 ctggtttatg ctgggacttc gagacggcag gcctgagatc caactgcaca atcactgggc 420 ccagcttacg gtgggtgctg gaccacggct ggatgatggg agatggcacc aggtggaagt 480 caagatggag ggggactctg tgctgctgga ggtggatggg gaggaggtgc tgcgcctgag 540 acaggtctct gggcccctga ccagcaaacg ccatcccatc atgaggattg cgcttggggg 600 gctgctcttc cccgcttcca accttcggtt gccgctggtt cctgccctgg atggctgcct 660 gcgccgggat tcctggctgg acaaacaggc cgagatctca gcatctgccc ccactagcct 720 cagaagctgt gatgtagaat caaatcccgg gatatttctc cctccaggga ctcaggcaga 780 attcaatctc cgagacattc cccagcctca tgcagagccc tgggccttct ctttggacct 840 gggactcaag caggcagcag gctcaggcca cctccttgct cttgggacac cagagaaccc 900 atcttggctc agtctccacc tccaagatca aaaggtggtg ttgtcttctg ggtcggggcc 960 agggctggat ctgcccctgg tcttgggact ccctcttcag ctgaagctga gtatgtccag 1020 ggtggtcttg agccaagggt cgaagatgaa ggcccttgcc ctgcctccct taggcctggc 1080 tcccctcctt aacctctggg ccaagcctca agggcgtctc ttcctggggg ctttaccagg 1140 agaagactct tccacctctt tttgcctgaa tggcctttgg gcacaaggtc agaggctgga 1200 tgtggaccag gccctgaaca gaagccatga gatctggact cacagctgcc cccagagccc 1260 aggcaatggc actgacgctt cccattaaag ctccacctaa gaaccccctt tgaaagttaa 1320 aaaaaaaaaa aaa 1333 <210> 25 <211> 1279 <212> DNA <213> Homo sapiens <400> 25 accgcccaca cgcaaggctg cctgcctcta cacattctcc caagagttgt ctgagccgcc 60 gagtggacag tggctgatta tggagagcag aggcccactg gctacctcgc gcctgctgct 120 gttgctgctg ttgctactac tgcgtcacac ccgccaggga tgggccctga gacctgttct 180 ccccacccag agtgcccacg accctccggc tgtccacctc agcaatggcc caggacaaga 240 gcctatcgct gtcatgacct ttgacctcac caagatcaca aaaacctcct cctcctttga 300 ggttcgaacc tgggacccag agggagtgat tttttatggg gataccaacc ctaaggatga 360 ctggtttatg ctgggacttc gagacggcag gcctgagatc caactgcaca atcactgggc 420 ccagcttacg gtgggtgctg gaccacggct ggatgatggg agatggcacc aggtggaagt 480 caagatggag ggggactctg tgctgctgga ggtggatggg gaggaggtgc tgcgcctgag 540 acaggtctct gggcccctga ccagcaaacg ccatcccatc atgaggattg cgcttggggg 600 gctgctcttc cccgcttcca accttcggtt gccggccgag atctcagcat ctgcccccac 660 tagcctcaga agctgtgatg tagaatcaaa tcccgggata tttctccctc cagggactca 720 ggcagaattc aatctccgag acattcccca gcctcatgca gagccctggg ccttctcttt 780 ggacctggga ctcaagcagg cagcaggctc aggccacctc cttgctcttg ggacaccaga 840 gaacccatct tggctcagtc tccacctcca agatcaaaag gtggtgttgt cttctgggtc 900 ggggccaggg ctggatctgc ccctggtctt gggactccct cttcagctga agctgagtat 960 gtccagggtg gtcttgagcc aagggtcgaa gatgaaggcc cttgccctgc ctcccttagg 1020 cctggctccc ctccttaacc tctgggccaa gcctcaaggg cgtctcttcc tgggggcttt 1080 accaggagaa gactcttcca cctctttttg cctgaatggc ctttgggcac aaggtcagag 1140 gctggatgtg gaccaggccc tgaacagaag ccatgagatc tggactcaca gctgccccca 1200 gagcccaggc aatggcactg acgcttccca ttaaagctcc acctaagaac cccctttgaa 1260 agttaaaaaa aaaaaaaaa 1279 <210> 26 <211> 1125 <212> DNA <213> Homo sapiens <400> 26 accgcccaca cgcaaggctg cctgcctcta cacattctcc caagagttgt ctgagccgcc 60 gagtggacag tggctgatta tggagagcag aggcccactg gctacctcgc gcctgctgct 120 gttgctgctg ttgctactac tgcgtcacac ccgccaggga tgggccctga gacctgttct 180 ccccacccag agtgcccacg accctccggc tgtccacctc agcaatggcc caggacaaga 240 gcctatcgct gtcatgacct ttgacctcac caagatcaca aaaacctcct cctcctttga 300 ggttcgaacc tgggacccag agggagtgat tttttatggg gataccaacc ctaaggatga 360 ctggtttatg ctgggacttc gagacggcag gcctgagatc caactgcaca atcactgggc 420 ccagcttacg gtgggtgctg gaccacggct ggatgatggg agatggcacc aggtggaagt 480 caagatggag ggggactctg tgctgctgga ggtggatggg gaggaggtgc tgcgcctgag 540 acaggtctct gggcccctga ccagcaaacg ccatcccatc atgaggattg cgcttggggg 600 gctgctcttc cccgcttcca accttcggtt gccgctggtt cctgccctgg atggctgcct 660 gcgccgggat tcctggctgg acaaacaggc cgagatctca gcatctgccc ccactagcct 720 cagaagctgt gatgtagaat caaatcccgg gatatttctc cctccaggga ctcaggcaga 780 attcaatctc cgagacattc cccagcctca tgcagagccc tgggccttct ctttggacct 840 gggactcaag caggcagcag gctcaggcca cctccttgct cttgggacac cagagaaccc 900 atcttggctc agtctccacc tccaagatca agagaagact cttccacctc tttttgcctg 960 aatggccttt gggcacaagg tcagaggctg gatgtggacc aggccctgaa cagaagccat 1020 gagatctgga ctcacagctg cccccagagc ccaggcaatg gcactgacgc ttcccattaa 1080 agctccacct aagaaccccc tttgaaagtt aaaaaaaaaa aaaaa 1125 <210> 27 <211> 988 <212> DNA <213> Homo sapiens <400> 27 accgcccaca cgcaaggctg cctgcctcta cacattctcc caagagttgt ctgagccgcc 60 gagtggacag tggctgatta tggagagcag aggcccactg gctacctcgc gcctgctgct 120 gttgctgctg ttgctactac tgcgtcacac ccgccaggga tgggccctga gacctgttct 180 ccccacccag agtgcccacg accctccggc tgtccacctc agcaatggcc caggacaaga 240 gcctatcgct gtcatgacct ttgacctcac caagatcaca aaaacctcct cctcctttga 300 ggttcgaacc tgggacccag agggagtgat tttttatggg gataccaacc ctaaggatga 360 ctggtttatg ctgggacttc gagacggcag gcctgagatc caactgcaca atcactgggc 420 ccagcttacg gtgggtgctg gaccacggct ggatgatggg agatggcacc aggtggaagt 480 caagatggag ggggactctg tgctgctgga ggtggatggg gaggaggtgc tgcgcctgag 540 acaggtctct gggcccctga ccagcaaacg ccatcccatc atgaggattg cgcttggggg 600 gctgctcttc cccgcttcca accttcggtt gccgctggtt cctgccctgg atggctgcct 660 gcgccgggat tcctggctgg acaaacaggc cgagatctca gcatctgccc ccactagcct 720 cagaagctgt gatgtagaat caaatcccgg gatatttctc cctccaggga ctcaggcaga 780 attcaatctc cgaggagaag actcttccac ctctttttgc ctgaatggcc tttgggcaca 840 aggtcagagg ctggatgtgg accaggccct gaacagaagc catgagatct ggactcacag 900 ctgcccccag agcccaggca atggcactga cgcttcccat taaagctcca cctaagaacc 960 ccctttgaaa gttaaaaaaa aaaaaaaa 988 <210> 28 <211> 1326 <212> DNA <213> Homo sapiens <400> 28 gtgactgggc tcctgggtag agttcaaggt tggagtgaag cggcttcctt gcggttgtgt 60 gggtgtccca acctgggtcg agataccccg cggttcaaag gctcccccgc agtgcttttt 120 aaattgacat atgcagtgat aacctgcttt agcctcaggc tcactcaccc gcccagaccc 180 tggagtgccc acgaccctcc ggctgtccac ctcagcaatg gcccaggaca agagcctatc 240 gctgtcatga cctttgacct caccaagatc acaaaaacct cctcctcctt tgaggttcga 300 acctgggacc cagagggagt gattttttat ggggatacca accctaagga tgactggttt 360 atgctgggac ttcgagacgg caggcctgag atccaactgc acaatcactg ggcccagctt 420 acggtgggtg ctggaccacg gctggatgat gggagatggc accaggtgga agtcaagatg 480 gagggggact ctgtgctgct ggaggtggat ggggaggagg tgctgcgcct gagacaggtc 540 tctgggcccc tgaccagcaa acgccatccc atcatgagga ttgcgcttgg ggggctgctc 600 ttccccgctt ccaaccttcg gttgccgctg gttcctgccc tggatggctg cctgcgccgg 660 gattcctggc tggacaaaca ggccgagatc tcagcatctg cccccactag cctcagaagc 720 tgtgatgtag aatcaaatcc cgggatattt ctccctccag ggactcaggc agaattcaat 780 ctccgagaca ttccccagcc tcatgcagag ccctgggcct tctctttgga cctgggactc 840 aagcaggcag caggctcagg ccacctcctt gctcttggga caccagagaa cccatcttgg 900 ctcagtctcc acctccaaga tcaaaaggtg gtgttgtctt ctgggtcggg gccagggctg 960 gatctgcccc tggtcttggg actccctctt cagctgaagc tgagtatgtc cagggtggtc 1020 ttgagccaag ggtcgaagat gaaggccctt gccctgcctc ccttaggcct ggctcccctc 1080 cttaacctct gggccaagcc tcaagggcgt ctcttcctgg gggctttacc aggagaagac 1140 tcttccacct ctttttgcct gaatggcctt tgggcacaag gtcagaggct ggatgtggac 1200 caggccctga acagaagcca tgagatctgg actcacagct gcccccagag cccaggcaat 1260 ggcactgacg cttcccatta aagctccacc taagaacccc ctttgaaagt taaaaaaaaa 1320 aaaaaa 1326 <210> 29 <211> 1118 <212> DNA <213> Homo sapiens <400> 29 gtgactgggc tcctgggtag agttcaaggt tggagtgaag cggcttcctt gcggttgtgt 60 gggtgtccca acctgggtcg agataccccg cggttcaaag gctcccccgc agtgcttttt 120 aaattgacat atgcagtgat aacctgcttt agcctcaggc tcactcaccc gcccagaccc 180 tggagtgccc acgaccctcc ggctgtccac ctcagcaatg gcccaggaca agagcctatc 240 gctgtcatga cctttgacct caccaagatc acaaaaacct cctcctcctt tgaggttcga 300 acctgggacc cagagggagt gattttttat ggggatacca accctaagga tgactggttt 360 atgctgggac ttcgagacgg caggcctgag atccaactgc acaatcactg ggcccagctt 420 acggtgggtg ctggaccacg gctggatgat gggagatggc accaggtgga agtcaagatg 480 gagggggact ctgtgctgct ggaggtggat ggggaggagg tgctgcgcct gagacaggtc 540 tctgggcccc tgaccagcaa acgccatccc atcatgagga ttgcgcttgg ggggctgctc 600 ttccccgctt ccaaccttcg gttgccgctg gttcctgccc tggatggctg cctgcgccgg 660 gattcctggc tggacaaaca ggccgagatc tcagcatctg cccccactag cctcagaagc 720 tgtgatgtag aatcaaatcc cgggatattt ctccctccag ggactcaggc agaattcaat 780 ctccgagaca ttccccagcc tcatgcagag ccctgggcct tctctttgga cctgggactc 840 aagcaggcag caggctcagg ccacctcctt gctcttggga caccagagaa cccatcttgg 900 ctcagtctcc acctccaaga tcaagagaag actcttccac ctctttttgc ctgaatggcc 960 tttgggcaca aggtcagagg ctggatgtgg accaggccct gaacagaagc catgagatct 1020 ggactcacag ctgcccccag agcccaggca atggcactga cgcttcccat taaagctcca 1080 cctaagaacc ccctttgaaa gttaaaaaaa aaaaaaaa 1118 <210> 30 <211> 1241 <212> DNA <213> Homo sapiens <400> 30 accgcccaca cgcaaggctg cctgcctcta cacattctcc caagagttgt ctgagccgcc 60 gagtggacag tggctgatta tggagagcag aggcccactg gctacctcgc gcctgctgct 120 gttgctgctg ttgctactac tgcgtcacac ccgccaggga tgggccctga gacctgttct 180 ccccacccag agtgcccacg accctccggc tgtccacctc agcaatggcc caggacaaga 240 gcctatcgct gtcatgacct ttgacctcac caagatcaca aaaacctcct cctcctttga 300 ggttcgaacc tgggacccag agggagtgat tttttatggg gataccaacc ctaaggatga 360 ctggtttatg ctgggacttc gagacggcag gcctgagatc caactgcaca atcactgggc 420 ccagcttacg gtgggtgctg cgcctgagac aggtctctgg gcccctgacc agcaaacgcc 480 atcccatcat gaggattgcg cttggggggc tgctcttccc cgcttccaac cttcggttgc 540 cgctggttcc tgccctggat ggctgcctgc gccgggattc ctggctggac aaacaggccg 600 agatctcagc atctgccccc actagcctca gaagctgtga tgtagaatca aatcccggga 660 tatttctccc tccagggact caggcagaat tcaatctccg agacattccc cagcctcatg 720 cagagccctg ggccttctct ttggacctgg gactcaagca ggcagcaggc tcaggccacc 780 tccttgctct tgggacacca gagaacccat cttggctcag tctccacctc caagatcaaa 840 aggtggtgtt gtcttctggg tcggggccag ggctggatct gcccctggtc ttgggactcc 900 ctcttcagct gaagctgagt atgtccaggg tggtcttgag ccaagggtcg aagatgaagg 960 cccttgccct gcctccctta ggcctggctc ccctccttaa cctctgggcc aagcctcaag 1020 ggcgtctctt cctgggggct ttaccaggag aagactcttc cacctctttt tgcctgaatg 1080 gcctttgggc acaaggtcag aggctggatg tggaccaggc cctgaacaga agccatgaga 1140 tctggactca cagctgcccc cagagcccag gcaatggcac tgacgcttcc cattaaagct 1200 ccacctaaga accccctttg aaagttaaaa aaaaaaaaaa a 1241

Claims (13)

To provide the information necessary for the diagnosis of early menopause, Complete Component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and sex hormone-binding globulin in the subject's blood Analytical method comprising measuring the over-expression of a gene encoding a protein selected from one or more groups consisting of. The method of claim 1, wherein the gene encoding the protein is a gene encoding a protein selected from one or more proteins consisting of the amino acid sequence of SEQ ID NOs: 1 to 15. The method of claim 2, wherein the gene is selected from one or more genes consisting of the nucleotide sequence of SEQ ID NOs: 16 to 30. The method according to claim 1, wherein the measurement is two kinds from the group consisting of completion component 3, fibrinogen α, fibrinogen β, fibrinogen γ, cellulose plasmin, and sex hormone-binding globulin. Analysis method characterized in that it is carried out by measuring the over-expression of the gene encoding the protein selected above. The method according to any one of claims 1 to 4, wherein the overexpression of the gene measures the amount of mRNA or protein. The method according to claim 5, wherein the measurement of the amount of the protein is performed by Western blotting. The method of claim 5, wherein the measurement of the amount of mRNA is performed by performing RT-PCR or real-time PCR. Overexpression of a gene encoding one or more proteins selected from the group consisting of Complete Component 3, Fibrinogen α, Fibrinogen β, Fibrinogen γ, Celluloplasmin, and sex hormone-binding globulin As a kit for diagnosing premenopause comprising a molecule capable of measuring,
An antibody, substrate, ligand, or cofactor to which the molecule specifically binds to the protein; Or a kit for diagnosing premenopause, which is a primer having a complementary sequence specific to a gene encoding the protein. The kit for diagnosing premenopause according to claim 8, wherein the gene encoding the protein is a gene encoding one or more proteins selected from proteins consisting of amino acid sequences of SEQ ID NOs: 1 to 15. The kit for diagnosing premenopause according to claim 9, wherein the gene is selected from one or more genes consisting of nucleotide sequences of SEQ ID NOs: 16 to 30. 9. The protein of claim 8, selected from the group consisting of Complement Component 3, fibrinogen α, fibrinogen β, fibrinogen γ, celluloplasmin, and sex hormone-binding globulin. Kit for early menopause diagnosis, characterized in that it comprises a molecule capable of measuring the overexpression of the gene encoding the. The kit for diagnosing premenopause according to claim 8, wherein the molecule is labeled with a detectable label. The kit for diagnosing premenopause according to claim 8, wherein the primer is in the form of a microarray immobilized on a substrate.

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