Abstract:
The invention disclosed in this patent document relates to transmembrane receptors, more particularly to endogenous, human orphan G protein-coupled receptors. The invention provides, in part, polynucleotides encoding the endogenous, human orphan G protein-coupled receptors.

Description:
[0001]    All references contained herein, whether to issued patents, patent applications, or non-patent references are hereby incorporated in their entirety for any purpose.  
         FIELD OF THE INVENTION  
         [0002]    The invention disclosed in this patent document relates to transmembrane receptors, and more particularly to endogenous, orphan, human G protein-coupled receptors (“GPCRs”).  
         BACKGROUND OF THE INVENTION  
         [0003]    Although a number of receptor classes exist in humans, by far the most abundant and therapeutically relevant is represented by the G protein-coupled receptor (GPCR or GPCRs) class. It is estimated that there are some 100,000 genes within the human genome, and of these, approximately 2% or 2,000 genes, are estimated to code for GPCRs. Receptors, including GPCRs, for which the endogenous ligand has been identified are referred to as “known” receptors, while receptors for which the endogenous ligand has not been identified are referred to as “orphan” receptors. GPCRs represent an important area for the development of pharmaceutical products: from approximately 20 of the 100 known GPCRs, 60% of all prescription pharmaceuticals have been developed. This distinction is not merely semantic, particularly in the case of GPCRs. Thus, the orphan GPCRs are to the pharmaceutical industry what gold was to California in the late 19 th  century—an opportunity to drive growth, expansion, enhancement and development.  
           [0004]    GPCRs share a common structural motif. All these receptors have seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane (each span is identified by number, i.e., transmembrane-1 (TM-1), transmebrane-2 (TM-2), etc.). The transmembrane helices are joined by strands of amino acids between transmembrane-2 and transmembrane-3, transmembrane-4 and transmembrane-5, and transmembrane-6 and transmembrane-7 on the exterior, or “extracellular” side, of the cell membrane (these are referred to as “extracellular” regions 1, 2 and 3 (EC-1, EC-2 and EC-3), respectively). The transmembrane helices are also joined by strands of amino acids between transmembrane-1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and transmembrane-6 on the interior, or “intracellular” side, of the cell membrane (these are referred to as “intracellular” regions 1, 2 and 3 (IC-1, IC-2 and IC-3), respectively). The “carboxy” (“C”) terminus of the receptor lies in the intracellular space within the cell, and the “amino” (“N”) terminus of the receptor lies in the extracellular space outside of the cell.  
           [0005]    Generally, when an endogenous ligand binds with the receptor (often referred to as “activation” of the receptor), there is a change in the conformation of the intracellular region that allows for coupling between the intracellular region and an intracellular “G-protein.” It has been reported that GPCRs are “promiscuous” with respect to G proteins, i.e., that a GPCR can interact with more than one G protein. See, Kenakin, T., 43  Life Sciences  1095 (1988). Although other G proteins exist, currently, Gq, Gs, Gi, and Go are G proteins that have been identified. Endogenous ligand-activated GPCR coupling with the G-protein begins a signaling cascade process (referred to as “signal transduction”). Under normal conditions, signal transduction ultimately results in cellular activation or cellular inhibition. It is thought that the IC-3 loop as well as the carboxy terminus of the receptor interact with the G protein.  
           [0006]    Under physiological conditions, GPCRs exist in the cell membrane in equilibrium between two different conformations: an “inactive” state and an “active”state. A receptor in an inactive state is unable to link to the intracellular signaling transduction pathway to produce a biological response. Changing the receptor conformation to the active state allows linkage to the transduction pathway (via the G-protein) and produces a biological response. A receptor may be stabilized in an active state by an endogenous ligand or a compound such as a drug.  
         SUMMARY OF THE INVENTION  
         [0007]    Disclosed herein are human endogenous orphan G protein-coupled receptors. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]    [0008]FIGS. 1A and 1B provide reference “grids” for certain dot-blots provided herein (see also, FIG. 2A and 2B, respectively).  
         [0009]    [0009]FIGS. 2A and 2B provide reproductions of the results of certain dot-blot analyses resulting from hCHN3 and hCHN8, respectively (see also, FIGS. 1A and 1B, respectively).  
         [0010]    [0010]FIG. 3 provides a reproduction of the results of RT-PCR analysis of hRUP3.  
         [0011]    [0011]FIG. 4 provides a reproduction of the results of RT-PCR analysis of hRUP4.  
         [0012]    [0012]FIG. 5 provides a reproduction of the results of RT-PCR analysis of hRUP6. 
     
    
     DETAILED DESCRIPTION  
       [0013]    The scientific literature that has evolved around receptors has adopted a number of terms to refer to ligands having various effects on receptors. For clarity and consistency, the following definitions will be used throughout this patent document. To the extent that these definitions conflict with other definitions for these terms, the following definitions shall control:  
         [0014]    AMINO ACID ABBREVIATIONS used herein are set out in Table 1:  
                               TABLE 1                                       ALANINE   ALA   A           ARGININE   ARG   R           ASPARAGINE   ASN   N           ASPARTIC ACID   ASP   D           CYSTEINE   CYS   C           GLUTAMIC ACID   GLU   E           GLUTAMINE   GLN   Q           GLYCINE   GLY   G           HISTIDINE   HIS   H           ISOLEUCINE   ILE   I           LEUCINE   LEU   L           LYSINE   LYS   K           METHIONINE   MET   M           PHENYLALANINE   PHE   F           PROLINE   PRO   P           SERINE   SER   S           THREONINE   THR   T           TRYPTOPHAN   TRP   W           TYROSINE   TYR   Y           VALINE   VAL   V                      
 
         [0015]    COMPOSITION means a material comprising at least one component.  
         [0016]    ENDOGENOUS shall mean a material that a mammal naturally produces. ENDOGENOUS in reference to, for example and not limitation, the term “receptor,” shall mean that which is naturally produced by a mammal (for example, and not limitation, a human) or a virus. By contrast, the term NON-ENDOGENOUS in this context shall mean that which is not naturally produced by a mammal (for example, and not limitation, a human) or a virus.  
         [0017]    HOST CELL shall mean a cell capable of having a Plasmid and/or Vector incorporated therein. In the case of a prokaryotic Host Cell, a Plasmid is typically replicated as a autonomous molecule as the Host Cell replicates (generally, the Plasmid is thereafter isolated for introduction into a eukaryotic Host Cell); in the case of a eukaryotic Host Cell, a Plasmid is integrated into the cellular DNA of the Host Cell such that when the eukaryotic Host Cell replicates, the Plasmid replicates. Preferably, for the purposes of the invention disclosed herein, the Host Cell is eukaryotic, more preferably, mammalian, and most preferably selected from the group consisting of 293, 293T and COS-7 cells.  
         [0018]    LIGAND shall mean an endogenous, naturally occurring molecule specific for an endogenous, naturally occurring receptor.  
         [0019]    NON-ORPHAN RECEPTOR shall mean an endogenous naturally occurring molecule specific for an endogenous naturally occurring ligand wherein the binding of a ligand to a receptor activates an intracellular signaling pathway.  
         [0020]    ORPHAN RECEPTOR shall mean an endogenous receptor for which the endogenous ligand specific for that receptor has not been identified or is not known.  
         [0021]    PLASMID shall mean the combination of a Vector and cDNA. Generally, a Plasmid is introduced into a Host Cell for the purposes of replication and/or expression of the cDNA as a protein.  
         [0022]    VECTOR sin reference to cDNA shall mean a circular DNA capable of incorporating at least one cDNA and capable of incorporation into a Host Cell.  
         [0023]    The order of the following sections is set forth for presentational efficiency and is not intended, nor should be construed, as a limitation on the disclosure or the claims to follow.  
         [0024]    A. Identification of Human GPCRs  
         [0025]    The efforts of the Human Genome project have led to the identification of a plethora of information regarding nucleic acid sequences located within the human genome; it has been the case in this endeavor that genetic sequence information has been made available without an understanding or recognition as to whether or not any particular genomic sequence does or may contain open-reading frame information that translate human proteins. Several methods of identifying nucleic acid sequences within the human genome are within the purview of those having ordinary skill in the art. For example, and not limitation, a variety of GPCRs, disclosed herein, were discovered by reviewing the GenBank™ database, while other GPCRs were discovered by utilizing a nucleic acid sequence of a GPCR, previously sequenced, to conduct a BLAST™ search of the EST database. Table A, below, lists the disclosed endogenous orphan GPCRs along with a GPCR&#39;s respective homologous GPCR:  
                               TABLE A                               Open       Reference To       Disclosed       Reading   Per Cent   Homologous       Human   Accession   Frame   Homology To   GPCR       Orphan   Number   (Base   Designated   (Accession       GPCRs   Identified   Pairs)   GPCR   No.)                   hARE-3   AL033379   1,260 bp   52.3% LPA-R   U92642       hARE-4   AC006087   1,119 bp   36% P2Y5   AF000546       hARE-5   AC006255   1,104 bp   32%  Oryzias     D43633                     latipes         hGPR27   AA775870   1,128 bp       hARE-1   AI090920     999 bp   43%   D13626                   KIAA0001       hARE-2   AA359504   1,122 bp   53% GPR27       hPPR1   H67224   1,053 bp   39% EBI1   L31581       hG2A   AA754702   1,113 bp   31% GPR4   L36148       hRUP3   AL035423   1,005 bp   30%   2133653                     Drosophila                       melanogaster         hRUP4   AI307658   1,296 bp   32% pNPGPR   NP_004876                   28% and 29 %   AAC41276                     Zebra fish  Ya   and                   and Yb,   AAB94616                   respectively       hRUP5   AC005849   1,413 bp   25% DEZ   Q99788                   23% FMLPR   P21462       hRUP6   AC005871   1,245 bp   48% GPR66   NP_006047       hRUP7   AC007922   1,173 bp   43% H3R   AF140538       hCHN3   EST 36581   1,113 bp   53% GPR27       hCHN4   AA804531   1,077 bp   32% thrombin   4503637       hCHN6   EST 2134670   1,503 bp   36% edg-1   NP_001391       hCHN8   EST 764455   1,029 bp   47%   D13626                   KIAA0001       hCHN9   EST 1541536   1,077 bp   41% LTB4R   NM_000752       hCHN10   EST 1365839   1,055 bp   35% P2Y   NM_002563                  
 
         [0026]    Receptor homology is useful in terms of gaining an appreciation of a role of the disclosed receptors within the human body. Additionally, such homology can provide insight as to possible endogenous ligand(s) that may be natural activators for the disclosed orphan GPCRs.  
         [0027]    The ARE-2 receptor disclosed herein was discovered by screening a human genomic library using EST clone 68530 (GenBank Accession Number AA359504). An analysis of this sequence by the named invnetor herein has led to the discovery of a 1,122 base-pair open reading-frame, and upon analysis thereof, this open reading-frame sequence evidences sequence homology with the human GPR27, seven-transmembrane receptor.  
         [0028]    The nucleic-acid sequence of the novel human receptor ARE-2 is set forth in SEQ.ID.NO.19 and the putative amino acid sequence thereof is set forth in SEQ.ID.NO.20. An alignment report comparing the sequence set forth in SEQ.ID.NO.20 and the reported amino acid sequence for the human GPR27, seven-transmembrane receptor (see FIG. 1) indicates there is a 53% sequence homology between these receptors.  
         [0029]    B. Receptor Screening  
         [0030]    Techniques have become more readily available over the past few years for endogenous-ligand identification (this, primarily, for the purpose of providing a means of conducting receptor-binding assays that require a receptor&#39;s endogenous ligand) because the traditional study of receptors has always proceeded from the a priori assumption (historically based) that the endogenous ligand must first be identified before discovery could proceed to find antagonists and other molecules that could affect the receptor. Even in cases where an antagonist might have been known first, the search immediately extended to looking for the endogenous ligand. This mode of thinking has persisted in receptor research even after the discovery of constitutively activated receptors. What has not been heretofore recognized is that it is the active state of the receptor that is most useful for discovering agonists, partial agonists, and inverse agonists of the receptor. For those diseases which result from an overly active receptor or an under-active receptor, what is desired in a therapeutic drug is a compound which acts to diminish the active state of a receptor or enhance the activity of the receptor, respectively, not necessarily a drug which is an antagonist to the endogenous ligand. This is because a compound that reduces or enhances the activity of the active receptor state need not bind at the same site as the endogenous ligand. Thus, as taught by a method of this invention, any search for therapeutic compounds should start by screening compounds against the ligand-independent active state.  
         [0031]    As is known in the art, GPCRs can be “active” in their endogenous state even without the binding of the receptor&#39;s endogenous ligand thereto. Such naturally-active receptors can be screened for the direct identification (i.e., without the need for the receptor&#39;s endogenous ligand) of, in particular, inverse agonists. Alternatively, the receptor can be “activated” via, e.g., mutation of the receptor to establish a non-endogenous version of the receptor that is active in the absence of the receptor&#39;s endogenous ligand.  
         [0032]    Screening candidate compounds against an endogenous or non-endogenous, constitutively activated version of the human orphan GPCRs disclosed herein can provide for the direct identification of candidate compounds which act at this cell surface receptor, without requiring use of the receptor&#39;s endogenous ligand. By determining areas within the body where the endogenous version of human GPCRs disclosed herein is expressed and/or over-expressed, it is possible to determine related disease/disorder states which are associated with the expression and/or over-expression of the receptor; such an approach is disclosed in this patent document.  
         [0033]    With respect to creation of a mutation that may evidence constitutive activation of human orphan GPCRs disclosed herein is based upon the distance from the proline residue at which is presumed to be located within TM6 of the GPCR typically nears the TM6/IC3 interface (such proline residue appears to be quite conserved). By mutating the amino acid residue located 16 amino acid residues from this residue (presumably located in the IC3 region of the receptor) to, most preferably, a lysine residue, such activation may be obtained. Other amino acid residues may be useful in the mutation at this position to achieve this objective.  
         [0034]    C. Disease/Disorder Identification and/or Selection  
         [0035]    Preferably, the DNA sequence of the human orphan GPCR can be used to make a probe for (a) dot-blot analysis against tissue-mRNA, and/or (b) RT-PCR identification of the expression of the receptor in tissue samples. The presence of a receptor in a tissue source, or a diseased tissue, or the presence of the receptor at elevated concentrations in diseased tissue compared to a normal tissue, can be preferably utilized to identify a correlation with a treatment regimen, including but not limited to, a disease associated with that disease. Receptors can equally well be localized to regions of organs by this technique. Based on the known functions of the specific tissues to which the receptor is localized, the putative functional role of the receptor can be deduced.  
         [0036]    D. Screening of Candidate Compounds  
         [0037]    1. Generic GPCR Screening Assay Techniques  
         [0038]    When a G protein receptor becomes constitutively active (i.e., active in the absence of endogenous ligand binding thereto), it binds to a G protein (e.g., Gq, Gs, Gi, Go) and stimulates the binding of GTP to the G protein. The G protein then acts as a GTPase and slowly hydrolyzes the GTP to GDP, whereby the receptor, under normal conditions, becomes deactivated. However, constitutively activated receptors continue to exchange GDP to GTP. A non-hydrolyzable analog of GTP, [ 35 S]GTPΓS, can be used to monitor enhanced binding to membranes which express constitutively activated receptors. It is reported that [ 35 S]GTPΓS can be used to monitor G protein coupling to membranes in the absence and presence of ligand. An example of this monitoring, among other examples well-known and available to those in the art, was reported by Traynor and Nahorski in 1995. The preferred use of this assay system is for initial screening of candidate compounds because the system is generically applicable to all G protein-coupled receptors regardless of the particular G protein that interacts with the intracellular domain of the receptor.  
         [0039]    2. Specific GPCR Screening Assay Techniques  
         [0040]    Once candidate compounds are identified using the “generic” G protein-coupled receptor assay (i.e., an assay to select compounds that are agonists, partial agonists, or inverse agonists), further screening to confirm that the compounds have interacted at the receptor site is preferred. For example, a compound identified by the “generic” assay may not bind to the receptor, but may instead merely “uncouple” the G protein from the intracellular domain.  
         [0041]    a. Gs and Gi.  
         [0042]    Gs stimulates the enzyme adenylyl cyclase. Gi (and Go), on the other hand, inhibit this enzyme. Adenylyl cyclase catalyzes the conversion of ATP to cAMP; thus, constitutively activated GPCRs that couple the Gs protein are associated with increased cellular levels of cAMP. On the other hand, constitutively activated GPCRs that couple the Gi (or Go) protein are associated with decreased cellular levels of cAMP. See, generally, “Indirect Mechanisms of Synaptic Transmission,” Chpt. 8,  From Neuron To Brain  (3 rd  Ed.) Nichols, J. G. et al eds. Sinauer Associates, Inc. (1992). Thus, assays that detect cAMP can be utilized to determine if a candidate compound is, e.g., an inverse agonist to the receptor (i.e., such a compound would decrease the levels of cAMP). A variety of approaches known in the art for measuring cAMP can be utilized; a most preferred approach relies upon the use of anti-cAMP antibodies in an ELISA-based format. Another type of assay that can be utilized is a whole cell second messenger reporter system assay. Promoters on genes drive the expression of the proteins that a particular gene encodes. Cyclic AMP drives gene expression by promoting the binding of a cAMP-responsive DNA binding protein or transcription factor (CREB) which then binds to the promoter at specific sites called cAMP response elements and drives the expression of the gene. Reporter systems can be constructed which have a promoter containing multiple cAMP response elements before the reporter gene, e.g., β-galactosidase or luciferase. Thus, a constitutively activated Gs-linked receptor causes the accumulation of cAMP that then activates the gene and expression of the reporter protein. The reporter protein such as β-galactosidase or luciferase can then be detected using standard biochemical assays (Chen et al. 1995).  
         [0043]    b. Go and Gq.  
         [0044]    Gq and Go are associated with activation of the enzyme phospholipase C, which in turn hydrolyzes the phospholipid PIP 2 , releasing two intracellular messengers: diacycloglycerol (DAG) and inistol 1,4,5-triphoisphate (IP 3 ). Increased accumulation of IP 3  is associated with activation of Gq- and Go-associated receptors. See, generally, “Indirect Mechanisms of Synaptic Transmission,” Chpt. 8,  From Neuron To Brain  (3 rd  Ed.) Nichols, J. G. et al eds. Sinauer Associates, Inc. (1992). Assays that detect IP 3  accumulation can be utilized to determine if a candidate compound is, e.g., an inverse agonist to a Gq- or Go-associated receptor (i.e., such a compound would decrease the levels of IP 3 ). Gq-associated receptors can also been examined using an AP1 reporter assay in that Gq-dependent phospholipase C causes activation of genes containing AP1 elements; thus, activated Gq-associated receptors will evidence an increase in the expression of such genes, whereby inverse agonists thereto will evidence a decrease in such expression, and agonists will evidence an increase in such expression. Commercially available assays for such detection are available.  
         [0045]    3. GPCR Fusion Protein  
         [0046]    The use of an endogenous, constitutively activated orphan GPCR, or a non-endogenous, constitutively activated orphan GPCR, for screening of candidate compounds for the direct identification of inverse agonists, agonists and partial agonists provides a unique challenge in that, by definition, the receptor is active even in the absence of an endogenous ligand bound thereto. Thus, it is often useful that an approach be utilized that can enhance the signal obtained by the activated receptor. A preferred approach is the use of a GPCR Fusion Protein.  
         [0047]    Generally, once it is determined that a GPCR is or has been constitutively activated, using the assay techniques set forth above (as well as others), it is possible to determine the predominant G protein that couples with the endogenous GPCR. Coupling of the G protein to the GPCR provides a signaling pathway that can be assessed. Because it is most preferred that screening take place by use of a mammalian expression system, such a system will be expected to have endogenous G protein therein. Thus, by definition, in such a system, the constitutively activated orphan GPCR will continuously signal. In this regard, it is preferred that this signal be enhanced such that in the presence of, e.g., an inverse agonist to the receptor, it is more likely that it will be able to more readily differentiate, particularly in the context of screening, between the receptor when it is contacted with the inverse agonist.  
         [0048]    The GPCR Fusion Protein is intended to enhance the efficacy of G protein coupling with the GPCR. The GPCR Fusion Protein is preferred for screening with a non-endogenous, constitutively activated GPCR because such an approach increases the signal that is most preferably utilized in such screening techniques, although the GPCR Fusion Protein can also be (and preferably is) used with an endogenous, constitutively activated GPCR. This is important in facilitating a significant “signal to noise” ratio; such a significant ratio is import preferred for the screening of candidate compounds as disclosed herein.  
         [0049]    The construction of a construct useful for expression of a GPCR Fusion Protein is within the purview of those having ordinary skill in the art. Commercially available expression vectors and systems offer a variety of approaches that can fit the particular needs of an investigator. The criteria of importance for such a GPCR Fusion Protein construct is that the GPCR sequence and the G protein sequence both be in-frame (preferably, the sequence for the GPCR is upstream of the G protein sequence) and that the “stop” codon of the GPCR must be deleted or replaced such that upon expression of the GPCR, the G protein can also be expressed. The GPCR can be linked directly to the G protein, or there can be spacer residues between the two (preferably, no more than about 12, although this number can be readily ascertained by one of ordinary skill in the art). We have a preference (based upon convenience) of use of a spacer in that some restriction sites that are not used will, effectively, upon expression, become a spacer. Most preferably, the G protein that couples to the GPCR will have been identified prior to the creation of the GPCR Fusion Protein construct. Because there are only a few G proteins that have been identified, it is preferred that a construct comprising the sequence of the G protein (i.e., a universal G protein construct) be available for insertion of an endogenous GPCR sequence therein; this provides for efficiency in the context of large-scale screening of a variety of different endogenous GPCRs having different sequences.  
         [0050]    E. Other Utility  
         [0051]    Although a preferred use of the human orphan GPCRs disclosed herein may be for the direct identification of candidate compounds as inverse agonists, agonists or partial agonists (preferably for use as pharmaceutical agents), these versions of human GPCRs can also be utilized in research settings. For example, in vitro and in vivo systems incorporating GPCRs can be utilized to further elucidate and understand the roles these receptors play in the human condition, both normal and diseased, as well as understanding the role of constitutive activation as it applies to understanding the signaling cascade. The value in human orphan GPCRs is that its utility as a research tool is enhanced in that by determining the location(s) of such receptors within the body, the GPCRs can be used to understand the role of these receptors in the human body before the endogenous ligand therefor is identified. Other uses of the disclosed receptors will become apparent to those in the art based upon, inter alia, a review of this patent document.  
       EXAMPLES  
       [0052]    The following examples are presented for purposes of elucidation, and not limitation, of the present invention. While specific nucleic acid and amino acid sequences are disclosed herein, those of ordinary skill in the art are credited with the ability to make minor modifications to these sequences while achieving the same or substantially similar results reported below. Unless otherwise indicated below, all nucleic acid sequences for the disclosed endogenous orphan human GPCRs have been sequenced and verified. For purposes of equivalent receptors, those of ordinary skill in the art will readily appreciate that conservative substitutions can be made to the disclosed sequences to obtain a functionally equivalent receptor.  
       Example 1  
     Endogenous Human GPCRs  
       [0053]    1. Identification of Human GPCRs  
         [0054]    Several of the disclosed endogenous human GPCRs were identified based upon a review of the GenBank database information. While searching the database, the following cDNA clones were identified as evidenced below.  
                                                                             Disclosed                           Human       Complete DNA   Open Reading   Nucleic Acid       Orphan   Accession   Sequence   Frame   SEQ. ID.   Amino Acid       GPCRs   Number   (Base Pairs)   (Base Pairs)   NO.   SEQ. ID. NO.                                hARE-3   AL033379   111,389 bp   1,260 bp   1   2       hARE-4   AC006087   226,925 bp   1,119 bp   3   4       hARE-5   AC006255   127,605 bp   1,104 bp   5   6       hRUP3   AL035423   140,094 bp   1,005 bp   7   8       hRUP5   AC005849   169,144 bp   1,413 bp   9   10       hRUP6   AC005871   218,807 bp   1,245 bp   11   12       hRUP7   AC007922   158,858 bp   1,173 bp   13   14                  
 
         [0055]    Other disclosed endogenous human GPCRs were identified by conducting a BLAST search of EST database (dbest) using the following EST clones as query sequences. The following EST clones identified were then used as a probe to screen a human genomic library.  
                                                   Disclosed           Open               Human       EST Clone/   Reading       Orphan   Query   Accession No.   Frame   Nucleic Acid   Amino Acid       GPCRs   (Sequence)   Identified   (Base Pairs)   SEQ. ID. NO.   SEQ. ID. NO.                   hGPCR27   Mouse   AA775870   1,125 bp   15   16           GPCR27       hARE-1   TDAG   1689643     999 bp   17   18               AI090920       hARE-2   GPCR27   68530   1,122 bp   19   20               AA359504       hPPR1   Bovine   238667   1,053 bp   21   22           PPR1   H67224       hG2A   Mouse   See Example 2(a),   1,113 bp   23   24           1179426   below       hCHN3   N.A.   EST 36581   1,113 bp   25   26               (full length)       hCHN4   TDAG   1184934   1,077 bp   27   28               AA804531       hCHN6   N.A.   EST 2134670   1,503 bp   29   30               (full length)       hCHN8   KIAA0001   EST 764455   1,029 bp   31   32       hCHN9   1365839   EST 1541536   1,077 bp   33   34       hCHN10   Mouse EST   Human 1365839   1,005 bp   35   36           1365839       hRUP4   N.A.   AI307658   1,296 bp   37   38                          
 
         [0056]    1.a Identification of Human ARE-2  
         [0057]    The disclosed human ARE-2 was identified based upon the use of EST database information. The nucleic acid sequence of human GPR27 was used to conduct a BLAST search of the EST database (“dbest” search). EST clone 68530 (Genbank Accession Number AA359504) was identified from this search and then used as a probe to screen a human genomic library (Stratagene, #942503), following manufacturer instructions. This resulted in a positive genomic clone; the fragment containing a coding sequence was localized with restriction mapping and Southern blot analysis. This fragment was then subcloned into pBluScript (Stratagene), followed by sequencing (SEQ.ID.NO.:1) of human ARE-2. This sequence was then-sub-cloned into pCMV (see infra). The putative amino acid sequence for ARE-2 is set forth in SEQ.ID.NO.:2.  
         [0058]    1.b Preparation of Non-Endogenous, Constitutively Activated ARE-2  
         [0059]    Preparation of the non-endogenous human ARE-2 receptor that may evidence constitutive activation of the receptor disclosed herein may be accomplished by creating a mutation at position 285G, most preferably an G285K mutation. Mutagenesis can preferably be performed using a Transformer Site-Directed™ Mutagenesis Kit (Clontech) according to manufacturer&#39;s instructions. The two mutagenesis primers are to be utilized, a lysine mutagenesis oligonucleotide that creates the lysine mutation at amino acid position 285G (e.g., changing GGC to AAA at nucelotides 853-855) and a selection marker oligonucleotide.  
         [0060]    2. Full Length Cloning  
         [0061]    a. hG2A (Seq. Id. Nos. 23 &amp; 24) Mouse EST clone 1179426 was used to obtain a human genomic clone containing all but three amino acid hG2A coding sequences. The 5′end of this coding sequence was obtained by using 5′RACE™, and the template for PCR was Clontech&#39;s Human Spleen Marathon-ready™ cDNA. The disclosed human G2A was amplified by PCR using the G2A cDNA specific primers for the first and second round PCR as shown in SEQ.ID.NO.:39 and SEQ.ID.NO.:40 as follows:  
                               5′-CTGTGTACAGCAGTTCGCAGAGTG-3′   (SEQ. ID. NO.: 39;               1 st  round PCR)               5′-GAGTGCCAGGCAGAGCAGGTAGAC-3′.   (SEQ. ID. NO.: 40;           second round PCR)          
 
         [0062]    PCR was performed using Advantage™ GC Polymerase Kit (Clontech; manufacturing instructions will be followed), at 94° C. for 30 sec followed by 5 cycles of 94° C. for 5 sec and 72° C. for 4 min; and 30 cycles of 94° for 5 sec and 70° for 4 min. An approximate 1.3 Kb PCR fragment was purified from agarose gel, digested with Hind III and Xba I and cloned into the expression vector pRC/CMV2 (Invitrogen). The cloned-insert was sequenced using the T7 Sequenase™ kit (USB Amersham; manufacturer instructions will be followed) and the sequence was compared with the presented sequence. Expression of the human G2A will be detected by probing an RNA dot blot (Clontech; manufacturer instructions will be followed) with the P 32 -labeled fragment.  
         [0063]    b. hCHN9 (Seq. Id. Nos. 33 &amp; 34)  
         [0064]    Sequencing of the EST clone 1541536 indicated that hCHN9 is a partial cDNA clone having only an initiation codon; i.e., the termination codon was missing. When hCHN9 was used to “blast” against the data base (nr), the 3′ sequence of hCHN9 was 100% homologous to the 5′ untranslated region of the leukotriene B4 receptor cDNA, which contained a termination codon in the frame with hCHN9 coding sequence. To determine whether the 5′ untranslated region of LTB4R cDNA was the 3′ sequence of hCHN9, PCR was performed using primers based upon the 5′ sequence flanking the initiation codon found in hCHN9 and the 3′ sequence around the termination codon found in the LTB4R 5′ untranslated region. The 5′ primer sequence utilized was as follows:  
                               5′-CCCGAATTCCTGCTTGCTCCCAGCTTGGCCC-3′   (SEQ. ID. NO.: 41; sense)           and               5′-TGTGGATCCTGCTGTCAAAGGTCCCATTCCGG-3′.   (SEQ. ID. NO.: 42; antisense)          
 
         [0065]    PCR was performed using thymus cDNA as a template and rTth polymerase (Perkin Elmer) with the buffer system provided by the manufacturer, 0.25 uM of each primer, and 0.2 mM of each 4 nucleotides. The cycle condition was 30 cycles of 94° C. for 1 min, 65° C. for min and 72° C. for 1 min and 10 sec. A 1.1 kb fragment consistent with the predicted size was obtained from PCR. This PCR fragment was subcloned into pCMV (see below) and sequenced (see, SEQ.ID.NO.:33).  
         [0066]    c. hRUP 4 (Seq. Id. Nos. 37 &amp; 38)  
         [0067]    The full length hRUP4 was cloned by RT-PCR with human brain cDNA (Clontech) as templates:  
                               5′-TCACAATGCTAGGTGTGGTC-3′   (SEQ. ID. NO.: 43;           and   sense)               5′-TGCATAGACAATGGGATTACAG-3′.   (SEQ. ID. NO.: 44;           antisense)          
 
         [0068]    PCR was performed using TaqPlus™ Precision™ polymerase (Stratagene; manufacturing instructions will be followed) by the following cycles: 94° C. for 2 min; 94° C. 30 sec; 55° C. for 30 sec, 72° C. for 45 sec, and 72° C. for 10 min. Cycles 2 through 4 were repeated 30 times.  
         [0069]    The PCR products were separated on a 1% agarose gel and a 500 bp PCR fragment was isolated and cloned into the pCRII-TOPO vector (Invitrogen) and sequenced using the T7 DNA Sequenase™ kit (Amsham) and the SP6/T7 primers (Stratagene). Sequence analysis revealed that the PCR fragment was indeed an alternatively spliced form of AI307658 having a continuous open reading frame with similarity to other GPCRs. The completed sequence of this PCR fragment was as follows:  
                               5′-TCACAATGCTAGGTGTGGTCTGGCTGGTG   (SEQ. ID. NO.: 45)                   GCAGTCATCGTAGGATCACCCATGTGGCACGT               GCAACAACTTGAGATCAAATATGACTTCCTAT               ATGAAAAGGAACACATCTGCTGCTTAGAAGAG               TGGACCAGCCCTGTGCACCAGAAGATCTACAC               CACCTTCATCCTTGTCATCCTCTTCCTCCTGC               CTCTTATGGTGATGCTTATTCTGTACGTAAAA               TTGGTTATGAACTTTGGATAAAGAAAAGAGTT               GGGGATGGTTCAGTGCTTCGAACTATTCATGG               AAAAGAAATGTCCAAAATAGCCAGGAAGAAGA               AACGAGCTGTCATTATGATGGTGACAGTGGTG               GCTCTCTTTGCTGTGTGCTGGGCACCATTCCA               TGTTGTCCATATGATGATTGAATACAGTAATT               TTGAAAAGGAATATGATGATGTCACAATCAAG               ATGATTTTTGCTATCGTGCAAATTATTGGATT               TTCCAACTCCATCTGTAATCCCATTGTCTATG               CA-3′          
 
         [0070]    Based on the above sequence, two sense oligonucleotide primer sets:  
                               5′-CTGCTTAGAAGAGTGGACCAG-3′,   (SEQ. ID. NO.: 46;               oligo 1)               5′-CTGTGCACCAGAAGATCTACAC-3′   (SEQ. IDNO.: 47;           oligo 2)          
 
         [0071]    and two antisense oligonucleotide primer sets:  
                               5′-CAAGGATGAAGGTGGTGTAGA-3′   (SEQ. ID. NO.: 48;               oligo 3)               5′-GTGTAGATGTTCTGGTGCACAGG-3′   (SEQ. ID. NO.: 49;           oligo 4)          
 
         [0072]    were used for 3′- and 5′-race PCR with a human brain Marathon-Ready™ cDNA (Clontech, Cat# 7400-1) as template, according to manufacture&#39;s instructions. DNA fragments generated by the RACE PCR were cloned into the pCRII-TOPO™ vector (Invitrogen) and sequenced using the SP6/T7 primers (Stratagene) and some internal primers. The 3′ RACE product contained a poly(A) tail and a completed open reading frame ending at a TAA stop codon. The 5′ RACE product contained an incomplete 5′ end; i.e., the ATG initiation codon was not present.  
         [0073]    Based on the new 5′ sequence, oligo 3 and the following primer:  
         [0074]    5′-GCAATGCAGGTCATAGTGAGC -3′ (SEQ.ID.NO.: 50; oligo 5)  
         [0075]    were used for the second round of 5′ RACE PCR and the PCR products were analyzed as above. A third round of 5′ RACE PCR was carried out utilizing antisense primers:  
                               5′-TGGAGCATGGTGACGGGAATGCAGAAG-3′ and   (SEQ. ID. NO.: 51; oligo 6)                   5′-GTGATGAGCAGGTCACTGAGCGCCAAG-3′.   (SEQ. ID. NO.: 52; oligo 7)          
 
         [0076]    The sequence of the 5′ RACE PCR products revealed the presence of the initiation codon ATG, and further round of 5′ RACE PCR did not generate any more 5′ sequence. The completed 5′ sequence was confirmed by RT-PCR using sense primer  
         [0077]    5′-GCAATGCAGGCGCTTAACATTAC-3′ (SEQ.ID.NO.: 53; oligo 8)  
         [0078]    and oligo 4 as primers and sequence analysis of the 650 bp PCR product generated from human brain and heart cDNA templates (Clontech, Cat# 7404-1). The completed 3′ sequence was confirmed by RT-PCR using oligo 2 and the following antisense primer:  
         [0079]    5′-TTGGGTTACAATCTGAAGGGCA-3′ (SEQ.ID.NO.: 54; oligo 9)  
         [0080]    and sequence analysis of the 670 bp PCR product generated from human brain and heart cDNA templates. (Clontech, Cat# 7404-1).  
         [0081]    d. hRUP5 (Seq. Id. Nos. 9 &amp; 10)  
         [0082]    The full length hRUP5 was cloned by RT-PCR using a sense primer upstream from ATG, the initiation codon (SEQ.ID.NO.: 55), and an antisense primer containing TCA as the stop codon (SEQ.ID.NO.: 56), which had the following sequences:  
                               5′-ACTCCGTGTCCAGCAGGACTCTG-3′   (SEQ. ID. NO. :55)                   5′-TGCGTGTTCCTGGACCCTCACGTG-3′   (SEQ. ID. NO.: 56)          
 
         [0083]    and human peripheral leukocyte cDNA (Clontech) as a template. Advantage cDNA polymerase (Clontech) was used for the amplification in a 50 ul reaction by the following cycle with step 2 through step 4 repeated 30 times: 94° C. for 30 sec; 94° for 15 sec; 69° for 40 sec; 72° C. for 3 min; and 72° C. fro 6 min. A 1.4 kb PCR fragment was isolated and cloned with the pCRII-TOPO™ vector (Invitrogen) and completely sequenced using the T7 DNA Sequenase™ kit (Amsham). See, SEQ.ID.NO.: 9.  
         [0084]    e. hRUP6 (Seq. Id. Nos. 11 &amp; 12)  
         [0085]    The full length hRUP6 was cloned by RT-PCR using primers:  
                               5′-CAGGCCTTGGATTTTAATGTCAGGGATGG-3′ and   (SEQ. ID. NO.: 57)                   5′-GGAGAGTCAGCTCTGAAAGAATTCAGG-3′;   (SEQ. ID. NO.: 58)          
 
         [0086]    and human thymus Marathon-Ready™ cDNA (Clontech) as a template. Advantage cDNA polymerase (Clontech, according to manufacturer&#39;s instructions) was used for the amplification in a 50 ul reaction by the following cycle: 94° C. for 30 sec; 94° C. for 5 sec; 66° C. for 40 sec; 72° C. for 2.5 sec and 72° C. for 7 min. Cycles 2 through 4 were repeated 30 times. A 1.3 Kb PCR fragment was isolated and cloned into the pCRII-TOPO™ vector (Invitrogen) and completely sequenced (see, SEQ.ID.NO.: 11) using the ABI Big Dye Terminator™ kit (P.E. Biosystem).  
         [0087]    f. hRUP7 (Seq. Id. Nos. 13 &amp; 14)  
         [0088]    The full length RUP7 was cloned by RT-PCR using primers:  
                               5′-TGATGTGATGCCAGATACTAATAGCAC-3′   (SEQ. ID. NO.:           and   59; sense)               5′-CCTGATTCATTTAGGTGAGATTGAGAC-3′   (SEQ. ID. NO.:           60; antisense)          
 
         [0089]    and human peripheral leukocyte cDNA (Clontech) as a template. Advantage™ cDNA polymerase (Clontech) was used for the amplification in a 50 ul reaction by the following cycle with step 2 to step 4 repeated 30 times: 94° C. for 2 minutes; 94° C. for 15 seconds; 60° C. for 20 seconds; 72° C. for 2 minutes; 72° C. for 10 minutes. A 1.25 Kb PCR fragment was isolated and cloned into the pCRII-TOPO™ vector (Invitrogen) and completely sequenced using the ABI Big Dye Terminator™ kit (P.E. Biosystem). See, SEQ.ID.NO.: 13.  
         [0090]    g. hARE-5 (Seq. Id. Nos. 5 &amp; 6)  
         [0091]    The full length hARE-5 was cloned by PCR using the hARE5 specific primers 5′-CAGCGCAGGGTGAAGCCTGAGAGC-3′ SEQ.ID.NO.: 69 (sense, 5′ of initiation codon ATG) and 5′-GGCACCTGCTGTGACCTGTGCAGG-3′ SEQ.ID.NO.:70 (antisense, 3′ of stop codon TGA) and human genomic DNA as template. TaqPlus Precision™ DNA polymerase (Stratagene) was used for the amplification by the following cycle with step 2 to step 4 repeated 35 times: 96° C., 2 minutes; 96° C., 20 seconds; 58° C., 30 seconds; 72° C., 2 minutes; and 72° C., 10 minutes  
         [0092]    A 1.1 Kb PCR fragment of predicated size was isolated and cloned into the pCRII-TOPO™ vector (Invitrogen) and completely sequenced (SEQ.ID.NO.:5) using the T7 DNA Sequenase™ kit (Amsham).  
         [0093]    h. hARE-4 (Seq. Id. Nos.: 3 &amp; 4)  
         [0094]    The full length hARE-4 was cloned by PCR using the hARE-4 specific primers 5′-CTGGTGTGCTCCATGGCATCCC-3′ SEQ.ID.NO.:67 (sense, 5′ of initiation codon ATG) and 5′-GTAAGCCTCCCAGAACGAGAGG-3′ SEQ.ID.NO.: 68 (antisense, 3′ of stop codon TGA) and human genomic DNA as template. Taq DNA polymerase (Stratagene) and 5% DMSO was used for the amplification by the following cycle with step 2 to step 3 repeated 35 times: 94° C., 3 minutes; 94° C., 30 seconds; 59° C., 2 minutes; 72° C., 10 minutes  
         [0095]    A 1.12 Kb PCR fragment of predicated size was isolated and cloned into the pCRII-TOPO™ vector (Invitrogen) and completely sequenced (SEQ.ID.NO.:3) using the T7 DNA Sequenase™ kit (Amsham).  
         [0096]    i. hARE-3 (Seq.Id.Nos.: 1 &amp; 2)  
         [0097]    The full length hARE-3 was cloned by PCR using the hARE-3 specific primers 5′-gatcaagcttCCATCCTACTGAAACCATGGTC-3′ SEQ.ID.NO.:65 (sense, lower case nucleotides represent Hind III overhang, ATG as initiation codon) and 5′-gatcagatctCAGTTCCAATATTCACACCACCGTC-3′ SEQ.ID.NO.:66 (antisense, lower case nucleotides represent Xba I overhang, TCA as stop codon) and human genomic DNA as template. TaqPlus Precision™ DNA polymerase (Stratagene) was used for the amplification by the following cycle with step 2 to step 4 repeated 35 times: 94° C., 3 minutes; 94° C., 1 minute; 55° C., 1 minute; 72° C., 2 minutes; 72° C., 10 minutes.  
         [0098]    A 1.3 Kb PCR fragment of predicated size was isolated and digested with Hind III and Xba I, cloned into the pRC/CMV2 vector (Invitrogen) at the Hind III and Xba I sites and completely sequenced (SEQ.ID.NO.:1) using the T7 DNA Sequenase™ kit (Amsham).  
         [0099]    j. hRUP3 (Seq. Id. Nos.:7 &amp; 8)  
         [0100]    The full length hRUP3 was cloned by PCR using the hRUP3 specific primers 5′-GTCCTGCCACTTCGAGACATGG-3′ SEQ.ID.NO.:71 (sense, ATG as initiation codon) and 5′-GAAACTTCTCTGCCCTTACCGTC-3′ SEQ.ID.NO.:72 (antisense, 3′ of stop codon TAA) and human genomic DNA as template. TaqPlus Precision™ DNA polymerase (Stratagene) was used for the amplification by the following cycle with step 2 to step 4 repeated 35 times: 94° C., 3 minutes; 94° C., 1 minute; 58° C., 1 minute; 72° C., 2 minutes; 72° C., 10 minutes  
         [0101]    A 1.0 Kb PCR fragment of predicated size was isolated and cloned into the pCRII-TOPO™ vector (Invitrogen) and completely sequenced (SEQ.ID.NO.: 7) using the T7 DNA sequenase kit (Amsham).  
       Example 2  
     Receptor Expression  
       [0102]    Although a variety of cells are available to the art for the expression of proteins, it is most preferred that mammalian cells be utilized. The primary reason for this is predicated upon practicalities, i.e., utilization of, e.g., yeast cells for the expression of a GPCR, while possible, introduces into the protocol a non-mammalian cell which may not (indeed, in the case of yeast, does not) include the receptor-coupling, genetic-mechanism and secretary pathways that have evolved for mammalian systems—thus, results obtained in non-mammalian cells, while of potential use, are not as preferred as that obtained from mammalian cells. Of the mammalian cells, COS-7, 293 and 293T cells are particularly preferred, although the specific mammalian cell utilized can be predicated upon the particular needs of the artisan. The general procedure for expression of the disclosed GPCRs is as follows.  
         [0103]    On day one, 1×10 7  293T cells per 150 mm plate were plated out. On day two, two reaction tubes will be prepared (the proportions to follow for each tube are per plate): tube A will be prepared by mixing 20 μg DNA (e.g., pCMV vector; pCMV vector with receptor cDNA, etc.) in 1.2 ml serum free DMEM (Irvine Scientific, Irvine, Calif.); tube B will be prepared by mixing 120 μl lipofectamine (Gibco BRL) in 1.2 ml serum free DMEM. Tubes A and B are admixed by inversions (several times), followed by incubation at room temperature for 30-45 min. The admixture can be referred to as the “transfection mixture”. Plated 293T cells are washed with 1XPBS, followed by addition of 10 ml serum free DMEM. 2.4 ml of the transfection mixture will then be added to the cells, followed by incubation for 4 hrs at 37° C./5% CO 2 . The transfection mixture was then be removed by aspiration, followed by the addition of 25 ml of DMEM/10% Fetal Bovine Serum. Cells will then be incubated at 37° C./5% CO 2 . After 72 hr incubation, cells can then be harvested and utilized for analysis.  
       Example 3  
     Tissue Distribution of the Disclosed Human GPCRS  
       [0104]    Several approaches can be used for determination of the tissue distribution of the GPCRs disclosed herein.  
         [0105]    1. Dot-Blot Analysis  
         [0106]    Using a commercially available human-tissue dot-blot format, endogenous orphan GPCRs were probed for a determination of the areas where such receptors are localized. cDNA fragments from the GPCRs of Example 1 (radiolabelled) were (or can be) used as the probe: radiolabeled probe was (or can be) generated using the complete receptor cDNA (excised from the vector) using a Prime-It II™ Random Primer Labeling Kit (Stratagene, #300385), according to manufacturer&#39;s instructions. A human RNA Master Blot™ (Clontech, #7770-1) was hybridized with the endogenous human GPCR radiolabeled probe and washed under stringent conditions according manufacturer&#39;s instructions. The blot was exposed to Kodak BioMax™ Autoradiography film overnight at −80° C. Results are summarized for several receptors in Table B and C (see FIGS. 1A and 1B for a grid identifying the various tissues and their locations, respectively). Exemplary dot-blots are provided in FIG. 2A and 2B for results derived using hCHN3 and hCHN8, respectively.  
                   TABLE B                       ORPHAN   Tissue Distribution       GPCR   (highest levels, relative to other tissues in the dot-blot)                   hGPCR27   Fetal brain, Putamen, Pituitary gland, Caudate nucleus       hARE-1   Spleen, Peripheral leukocytes, Fetal spleen       hPPR1   Pituitary gland, Heart, salivary gland, Small intestine, Testis       hRUP3   Pancreas       hCHN3   Fetal brain, Putamen, Occipital cortex       hCHN9   Pancreas, Small intestine, Liver       hCHN10   Kidney, Thryoid                  
 
         [0107]    [0107]                   TABLE C                           Tissue Distribution       ORPHAN GPCR   (highest levels, relative to other tissues in the dot-blot)                   hARE-3   Cerebellum left, Cerebellum right, Testis, Accumbens       hGPCR3   Corpus collusum, Caudate nucleus, Liver, Heart, Inter-           Ventricular Septum       hARE-2   Cerebellum left, Cerebellum right, Substantia       hCHN8   Cerebellum left, Cerebellum right, Kidney, Lung                    
         [0108]    2. RT-PCR  
         [0109]    a. hRUP3  
         [0110]    To ascertain the tissue distribution of hRUP3 mRNA, RT-PCR was performed using hRUP3-specific primers and human multiple tissue cDNA panels (MTC, Clontech) as templates. Taq DNA polymerase (Stratagene) was utilized for the PCR reaction, using the following reaction cycles in a 40 ul reaction: 94° C. for 2 min; 94° C. for 15 sec; 55° C. for 30 sec; 72° C. for 1 min; 72° C., for 10 min. Primers were as follows:  
                               5′-GACAGGTACCTTGCCATCAAG-3′;   (SEQ.ID.NO.: 61;               sense)               5′-CTGCACAATGCCAGTGATAAGG-3′;   (SEQ.ID.NO.: 62;           antisense).          
 
         [0111]    20 ul of the reaction was loaded onto a 1% agarose gel; results are set forth in FIG. 3.  
         [0112]    As is supported by the data of FIG. 3, of the 16 human tissues in the cDNA panel utilized (brain, colon, heart, kidney, lung, ovary, pancreas, placenta, prostate, skeleton, small intestine, spleen, testis, thymus leukocyte, and liver) a single hRUP3 band is evident only from the pancreas. Additional comparative analysis of the protein sequence of hRUP3 with other GPCRs suggest that hRUP3 is related to GPCRs having small molecule endogenous ligand such that it is predicted that the endogenous ligand for hRUP3 is a small molecule.  
         [0113]    b. hRUP4  
         [0114]    RT-PCR was performed using hRUP4 oligo&#39;s 8 and 4 as primers and the human multiple tissue cDNA panels (MTC, Clontech) as templates. Taq DNA polymerase (Stratagene) was used for the amplification in a 40 ul reaction by the following cycles: 94° C. for 30 seconds, 94° C. for 10 seconds, 55° C. for 30 seconds, 72° C. for 2 minutes, and 72° C. for 5 minutes with cycles 2 through 4 repeated 30 times.  
         [0115]    20 μl of the reaction were loaded on a 1% agarose gel to analyze the RT-PCR products, and hRUP4 mRNA was found expressed in many human tissues, with the strongest expression in heart and kidney. (see, FIG. 4). To confirm the authenticity of the PCR fragments, a 300 bp fragment derived from the 5′ end of hRUP4 was used as a probe for the Southern Blot analysis. The probe was labeled with  32 P-dCTP using the Prime-It II™ Random Primer Labeling Kit (Stratagene) and purified using the ProbeQuant™ G-50 micro columns (Amersham). Hybridization was done overnight at 42° C. following a 12 hr pre-hybridization. The blot was finally washed at 65° C. with 0.1×SSC. The Southern blot did confirm the PCR fragments as hRUP4.  
         [0116]    c. hRUP5  
         [0117]    RT-PCR was performed using the following hRUP5 specific primers:  
                               5′-CTGACTTCTTGTTCCTGGCAGCAGCGG-3′;   (SEQ.ID.NO.:               63; sense)               5′-AGACCAGCCAGGGCACGCTGAAGAGTG-3′;   (SEQ.ID.NO.:           64; antisense)          
 
         [0118]    and the human multiple tissue cDNA panels (MTC, Clontech) as templates. Taq DNA polymerase (Stratagene) was used for the amplification in a 40 ul reaction by the following cycles: 94° C. for 30 sec, 94° C. for 10 sec, 62° C. for 1.5 min, 72° C. for 5 min, and with cycles 2 through 3 repeated 30 times. 20 μl of the reaction were loaded on a 1.5% agarose gel to analyze the RT-PCR products, and hRUP5 mRNA was found expressed only in the peripheral blood leukocytes (data not shown).  
         [0119]    d. hRUP6  
         [0120]    RT-PCR was applied to confirm the expression and to determine the tissue distribution of hRUP6. Oligonucleotides used, based on an alignment of AC005871 and GPR66 segments, had the following sequences:  
                               5′-CCAACACCAGCATCCATGGCATCAAG-3′;   (SEQ.ID.NO.:               73; sense),               5′-GGAGAGTCAGCTCTGAAAGAATTCAGG-3′;   (SEQ.ID.NO.:           74; antisense)          
 
         [0121]    and the human multiple tissue cDNA panels (MTC, Clontech) were used as templates. PCR was performed using TaqPlus Precision™ polymerase (Stratagene; manufacturing instructions will be followed) in a 40 ul reaction by the following cycles: 94° C. for 30 sec; 94° C. 5 sec; 66° C. for 40 sec, 72° C. for 2.5 min, and 72° C. for 7 min. Cycles 2 through 4 were repeated 30 times.  
         [0122]    20 ul of the reaction were loaded on a 1.2% agarose gel to analyze the RT-PCR products, and a specific 760 bp DNA fragment representing hRUP6 was expressed predominantly in the thymus and with less expression in the heart, kidney, lung, prostate small intestine and testis. (see, FIG. 5).  
         [0123]    References, including but limited to patent applications, that are cited throughout this patent document, unless otherwise indicated, are incorporated herein by reference. Modifications and extension of the disclosed inventions that are within the purview of the skilled artisan are encompassed within the above disclosure and the claims that follow.  
         [0124]    Although a variety of Vectors are available to those in the art, for purposes of utilization for both endogenous and non-endogenous human GPCRs, it is most preferred that the Vector utilized be pCMV. This vector was deposited with the American Type Culture Collection (ATCC) on Oct. 13, 1998 (10801 University Blvd., Manassas, Va. 20110-2209 USA) under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure. The DNA was tested by the ATCC and determined to be. The ATCC has assigned the following deposit number to pCMV: ATCC #203351.  
     
       
       
         1 
         
           
             74  
           
           
             1  
             1260  
             DNA  
             Homo sapiens  
           
            1 

atggtcttct cggcagtgtt gactgcgttc cataccggga catccaacac aacatttgtc     60 

gtgtatgaaa acacctacat gaatattaca ctccctccac cattccagca tcctgacctc    120 

agtccattgc ttagatatag ttttgaaacc atggctccca ctggtttgag ttccttgacc    180 

gtgaatagta cagctgtgcc cacaacacca gcagcattta agagcctaaa cttgcctctt    240 

cagatcaccc tttctgctat aatgatattc attctgtttg tgtcttttct tgggaacttg    300 

gttgtttgcc tcatggttta ccaaaaagct gccatgaggt ctgcaattaa catcctcctt    360 

gccagcctag cttttgcaga catgttgctt gcagtgctga acatgccctt tgccctggta    420 

actattctta ctacccgatg gatttttggg aaattcttct gtagggtatc tgctatgttt    480 

ttctggttat ttgtgataga aggagtagcc atcctgctca tcattagcat agataggttc    540 

cttattatag tccagaggca ggataagcta aacccatata gagctaaggt tctgattgca    600 

gtttcttggg caacttcctt ttgtgtagct tttcctttag ccgtaggaaa ccccgacctg    660 

cagatacctt cccgagctcc ccagtgtgtg tttgggtaca caaccaatcc aggctaccag    720 

gcttatgtga ttttgatttc tctcatttct ttcttcatac ccttcctggt aatactgtac    780 

tcatttatgg gcatactcaa cacccttcgg cacaatgcct tgaggatcca tagctaccct    840 

gaaggtatat gcctcagcca ggccagcaaa ctgggtctca tgagtctgca gagacctttc    900 

cagatgagca ttgacatggg ctttaaaaca cgtgccttca ccactatttt gattctcttt    960 

gctgtcttca ttgtctgctg ggccccattc accacttaca gccttgtggc aacattcagt   1020 

aagcactttt actatcagca caactttttt gagattagca cctggctact gtggctctgc   1080 

tacctcaagt ctgcattgaa tccgctgatc tactactgga ggattaagaa attccatgat   1140 

gcttgcctgg acatgatgcc taagtccttc aagtttttgc cgcagctccc tggtcacaca   1200 

aagcgacgga tacgtcctag tgctgtctat gtgtgtgggg aacatcggac ggtggtgtga   1260 

 
           
             2  
             419  
             PRT  
             Homo sapiens  
           
            2 

Met Val Phe Ser Ala Val Leu Thr Ala Phe His Thr Gly Thr Ser Asn 
  1               5                  10                  15 

Thr Thr Phe Val Val Tyr Glu Asn Thr Tyr Met Asn Ile Thr Leu Pro 
             20                  25                  30 

Pro Pro Phe Gln His Pro Asp Leu Ser Pro Leu Leu Arg Tyr Ser Phe 
         35                  40                  45 

Glu Thr Met Ala Pro Thr Gly Leu Ser Ser Leu Thr Val Asn Ser Thr 
     50                  55                  60 

Ala Val Pro Thr Thr Pro Ala Ala Phe Lys Ser Leu Asn Leu Pro Leu 
 65                  70                  75                  80 

Gln Ile Thr Leu Ser Ala Ile Met Ile Phe Ile Leu Phe Val Ser Phe 
                 85                  90                  95 

Leu Gly Asn Leu Val Val Cys Leu Met Val Tyr Gln Lys Ala Ala Met 
            100                 105                 110 

Arg Ser Ala Ile Asn Ile Leu Leu Ala Ser Leu Ala Phe Ala Asp Met 
        115                 120                 125 

Leu Leu Ala Val Leu Asn Met Pro Phe Ala Leu Val Thr Ile Leu Thr 
    130                 135                 140 

Thr Arg Trp Ile Phe Gly Lys Phe Phe Cys Arg Val Ser Ala Met Phe 
145                 150                 155                 160 

Phe Trp Leu Phe Val Ile Glu Gly Val Ala Ile Leu Leu Ile Ile Ser 
                165                 170                 175 

Ile Asp Arg Phe Leu Ile Ile Val Gln Arg Gln Asp Lys Leu Asn Pro 
            180                 185                 190 

Tyr Arg Ala Lys Val Leu Ile Ala Val Ser Trp Ala Thr Ser Phe Cys 
        195                 200                 205 

Val Ala Phe Pro Leu Ala Val Gly Asn Pro Asp Leu Gln Ile Pro Ser 
    210                 215                 220 

Arg Ala Pro Gln Cys Val Phe Gly Tyr Thr Thr Asn Pro Gly Tyr Gln 
225                 230                 235                 240 

Ala Tyr Val Ile Leu Ile Ser Leu Ile Ser Phe Phe Ile Pro Phe Leu 
                245                 250                 255 

Val Ile Leu Tyr Ser Phe Met Gly Ile Leu Asn Thr Leu Arg His Asn 
            260                 265                 270 

Ala Leu Arg Ile His Ser Tyr Pro Glu Gly Ile Cys Leu Ser Gln Ala 
        275                 280                 285 

Ser Lys Leu Gly Leu Met Ser Leu Gln Arg Pro Phe Gln Met Ser Ile 
    290                 295                 300 

Asp Met Gly Phe Lys Thr Arg Ala Phe Thr Thr Ile Leu Ile Leu Phe 
305                 310                 315                 320 

Ala Val Phe Ile Val Cys Trp Ala Pro Phe Thr Thr Tyr Ser Leu Val 
                325                 330                 335 

Ala Thr Phe Ser Lys His Phe Tyr Tyr Gln His Asn Phe Phe Glu Ile 
            340                 345                 350 

Ser Thr Trp Leu Leu Trp Leu Cys Tyr Leu Lys Ser Ala Leu Asn Pro 
        355                 360                 365 

Leu Ile Tyr Tyr Trp Arg Ile Lys Lys Phe His Asp Ala Cys Leu Asp 
    370                 375                 380 

Met Met Pro Lys Ser Phe Lys Phe Leu Pro Gln Leu Pro Gly His Thr 
385                 390                 395                 400 

Lys Arg Arg Ile Arg Pro Ser Ala Val Tyr Val Cys Gly Glu His Arg 
                405                 410                 415 

Thr Val Val 

 
           
             3  
             1119  
             DNA  
             Homo sapiens  
           
            3 

atgttagcca acagctcctc aaccaacagt tctgttctcc cgtgtcctga ctaccgacct     60 

acccaccgcc tgcacttggt ggtctacagc ttggtgctgg ctgccgggct ccccctcaac    120 

gcgctagccc tctgggtctt cctgcgcgcg ctgcgcgtgc actcggtggt gagcgtgtac    180 

atgtgtaacc tggcggccag cgacctgctc ttcaccctct cgctgcccgt tcgtctctcc    240 

tactacgcac tgcaccactg gcccttcccc gacctcctgt gccagacgac gggcgccatc    300 

ttccagatga acatgtacgg cagctgcatc ttcctgatgc tcatcaacgt ggaccgctac    360 

gccgccatcg tgcacccgct gcgactgcgc cacctgcggc ggccccgcgt ggcgcggctg    420 

ctctgcctgg gcgtgtgggc gctcatcctg gtgtttgccg tgcccgccgc ccgcgtgcac    480 

aggccctcgc gttgccgcta ccgggacctc gaggtgcgcc tatgcttcga gagcttcagc    540 

gacgagctgt ggaaaggcag gctgctgccc ctcgtgctgc tggccgaggc gctgggcttc    600 

ctgctgcccc tggcggcggt ggtctactcg tcgggccgag tcttctggac gctggcgcgc    660 

cccgacgcca cgcagagcca gcggcggcgg aagaccgtgc gcctcctgct ggctaacctc    720 

gtcatcttcc tgctgtgctt cgtgccctac aacagcacgc tggcggtcta cgggctgctg    780 

cggagcaagc tggtggcggc cagcgtgcct gcccgcgatc gcgtgcgcgg ggtgctgatg    840 

gtgatggtgc tgctggccgg cgccaactgc gtgctggacc cgctggtgta ctactttagc    900 

gccgagggct tccgcaacac cctgcgcggc ctgggcactc cgcaccgggc caggacctcg    960 

gccaccaacg ggacgcgggc ggcgctcgcg caatccgaaa ggtccgccgt caccaccgac   1020 

gccaccaggc cggatgccgc cagtcagggg ctgctccgac cctccgactc ccactctctg   1080 

tcttccttca cacagtgtcc ccaggattcc gccctctga                          1119 

 
           
             4  
             372  
             PRT  
             Homo sapiens  
           
            4 

Met Leu Ala Asn Ser Ser Ser Thr Asn Ser Ser Val Leu Pro Cys Pro 
  1               5                  10                  15 

Asp Tyr Arg Pro Thr His Arg Leu His Leu Val Val Tyr Ser Leu Val 
             20                  25                  30 

Leu Ala Ala Gly Leu Pro Leu Asn Ala Leu Ala Leu Trp Val Phe Leu 
         35                  40                  45 

Arg Ala Leu Arg Val His Ser Val Val Ser Val Tyr Met Cys Asn Leu 
     50                  55                  60 

Ala Ala Ser Asp Leu Leu Phe Thr Leu Ser Leu Pro Val Arg Leu Ser 
 65                  70                  75                  80 

Tyr Tyr Ala Leu His His Trp Pro Phe Pro Asp Leu Leu Cys Gln Thr 
                 85                  90                  95 

Thr Gly Ala Ile Phe Gln Met Asn Met Tyr Gly Ser Cys Ile Phe Leu 
            100                 105                 110 

Met Leu Ile Asn Val Asp Arg Tyr Ala Ala Ile Val His Pro Leu Arg 
        115                 120                 125 

Leu Arg His Leu Arg Arg Pro Arg Val Ala Arg Leu Leu Cys Leu Gly 
    130                 135                 140 

Val Trp Ala Leu Ile Leu Val Phe Ala Val Pro Ala Ala Arg Val His 
145                 150                 155                 160 

Arg Pro Ser Arg Cys Arg Tyr Arg Asp Leu Glu Val Arg Leu Cys Phe 
                165                 170                 175 

Glu Ser Phe Ser Asp Glu Leu Trp Lys Gly Arg Leu Leu Pro Leu Val 
            180                 185                 190 

Leu Leu Ala Glu Ala Leu Gly Phe Leu Leu Pro Leu Ala Ala Val Val 
        195                 200                 205 

Tyr Ser Ser Gly Arg Val Phe Trp Thr Leu Ala Arg Pro Asp Ala Thr 
    210                 215                 220 

Gln Ser Gln Arg Arg Arg Lys Thr Val Arg Leu Leu Leu Ala Asn Leu 
225                 230                 235                 240 

Val Ile Phe Leu Leu Cys Phe Val Pro Tyr Asn Ser Thr Leu Ala Val 
                245                 250                 255 

Tyr Gly Leu Leu Arg Ser Lys Leu Val Ala Ala Ser Val Pro Ala Arg 
            260                 265                 270 

Asp Arg Val Arg Gly Val Leu Met Val Met Val Leu Leu Ala Gly Ala 
        275                 280                 285 

Asn Cys Val Leu Asp Pro Leu Val Tyr Tyr Phe Ser Ala Glu Gly Phe 
    290                 295                 300 

Arg Asn Thr Leu Arg Gly Leu Gly Thr Pro His Arg Ala Arg Thr Ser 
305                 310                 315                 320 

Ala Thr Asn Gly Thr Arg Ala Ala Leu Ala Gln Ser Glu Arg Ser Ala 
                325                 330                 335 

Val Thr Thr Asp Ala Thr Arg Pro Asp Ala Ala Ser Gln Gly Leu Leu 
            340                 345                 350 

Arg Pro Ser Asp Ser His Ser Leu Ser Ser Phe Thr Gln Cys Pro Gln 
        355                 360                 365 

Asp Ser Ala Leu 
    370 

 
           
             5  
             1107  
             DNA  
             Homo sapiens  
           
            5 

atggccaact ccacagggct gaacgcctca gaagtcgcag gctcgttggg gttgatcctg     60 

gcagctgtcg tggaggtggg ggcactgctg ggcaacggcg cgctgctggt cgtggtgctg    120 

cgcacgccgg gactgcgcga cgcgctctac ctggcgcacc tgtgcgtcgt ggacctgctg    180 

gcggccgcct ccatcatgcc gctgggcctg ctggccgcac cgccgcccgg gctgggccgc    240 

gtgcgcctgg gccccgcgcc atgccgcgcc gctcgcttcc tctccgccgc tctgctgccg    300 

gcctgcacgc tcggggtggc cgcacttggc ctggcacgct accgcctcat cgtgcacccg    360 

ctgcggccag gctcgcggcc gccgcctgtg ctcgtgctca ccgccgtgtg ggccgcggcg    420 

ggactgctgg gcgcgctctc cctgctcggc ccgccgcccg caccgccccc tgctcctgct    480 

cgctgctcgg tcctggctgg gggcctcggg cccttccggc cgctctgggc cctgctggcc    540 

ttcgcgctgc ccgccctcct gctgctcggc gcctacggcg gcatcttcgt ggtggcgcgt    600 

cgcgctgccc tgaggccccc acggccggcg cgcgggtccc gactccgctc ggactctctg    660 

gatagccgcc tttccatctt gccgccgctc cggcctcgcc tgcccggggg caaggcggcc    720 

ctggccccag cgctggccgt gggccaattt gcagcctgct ggctgcctta tggctgcgcg    780 

tgcctggcgc ccgcagcgcg ggccgcggaa gccgaagcgg ctgtcacctg ggtcgcctac    840 

tcggccttcg cggctcaccc cttcctgtac gggctgctgc agcgccccgt gcgcttggca    900 

ctgggccgcc tctctcgccg tgcactgcct ggacctgtgc gggcctgcac tccgcaagcc    960 

tggcacccgc gggcactctt gcaatgcctc cagagacccc cagagggccc tgccgtaggc   1020 

ccttctgagg ctccagaaca gacccccgag ttggcaggag ggcggagccc cgcataccag   1080 

gggccacctg agagttctct ctcctga                                       1107 

 
           
             6  
             368  
             PRT  
             Homo sapiens  
           
            6 

Met Ala Asn Ser Thr Gly Leu Asn Ala Ser Glu Val Ala Gly Ser Leu 
  1               5                  10                  15 

Gly Leu Ile Leu Ala Ala Val Val Glu Val Gly Ala Leu Leu Gly Asn 
             20                  25                  30 

Gly Ala Leu Leu Val Val Val Leu Arg Thr Pro Gly Leu Arg Asp Ala 
         35                  40                  45 

Leu Tyr Leu Ala His Leu Cys Val Val Asp Leu Leu Ala Ala Ala Ser 
     50                  55                  60 

Ile Met Pro Leu Gly Leu Leu Ala Ala Pro Pro Pro Gly Leu Gly Arg 
 65                  70                  75                  80 

Val Arg Leu Gly Pro Ala Pro Cys Arg Ala Ala Arg Phe Leu Ser Ala 
                 85                  90                  95 

Ala Leu Leu Pro Ala Cys Thr Leu Gly Val Ala Ala Leu Gly Leu Ala 
            100                 105                 110 

Arg Tyr Arg Leu Ile Val His Pro Leu Arg Pro Gly Ser Arg Pro Pro 
        115                 120                 125 

Pro Val Leu Val Leu Thr Ala Val Trp Ala Ala Ala Gly Leu Leu Gly 
    130                 135                 140 

Ala Leu Ser Leu Leu Gly Pro Pro Pro Ala Pro Pro Pro Ala Pro Ala 
145                 150                 155                 160 

Arg Cys Ser Val Leu Ala Gly Gly Leu Gly Pro Phe Arg Pro Leu Trp 
                165                 170                 175 

Ala Leu Leu Ala Phe Ala Leu Pro Ala Leu Leu Leu Leu Gly Ala Tyr 
            180                 185                 190 

Gly Gly Ile Phe Val Val Ala Arg Arg Ala Ala Leu Arg Pro Pro Arg 
        195                 200                 205 

Pro Ala Arg Gly Ser Arg Leu Arg Ser Asp Ser Leu Asp Ser Arg Leu 
    210                 215                 220 

Ser Ile Leu Pro Pro Leu Arg Pro Arg Leu Pro Gly Gly Lys Ala Ala 
225                 230                 235                 240 

Leu Ala Pro Ala Leu Ala Val Gly Gln Phe Ala Ala Cys Trp Leu Pro 
                245                 250                 255 

Tyr Gly Cys Ala Cys Leu Ala Pro Ala Ala Arg Ala Ala Glu Ala Glu 
            260                 265                 270 

Ala Ala Val Thr Trp Val Ala Tyr Ser Ala Phe Ala Ala His Pro Phe 
        275                 280                 285 

Leu Tyr Gly Leu Leu Gln Arg Pro Val Arg Leu Ala Leu Gly Arg Leu 
    290                 295                 300 

Ser Arg Arg Ala Leu Pro Gly Pro Val Arg Ala Cys Thr Pro Gln Ala 
305                 310                 315                 320 

Trp His Pro Arg Ala Leu Leu Gln Cys Leu Gln Arg Pro Pro Glu Gly 
                325                 330                 335 

Pro Ala Val Gly Pro Ser Glu Ala Pro Glu Gln Thr Pro Glu Leu Ala 
            340                 345                 350 

Gly Gly Arg Ser Pro Ala Tyr Gln Gly Pro Pro Glu Ser Ser Leu Ser 
        355                 360                 365 

 
           
             7  
             1008  
             DNA  
             Homo sapiens  
           
            7 

atggaatcat ctttctcatt tggagtgatc cttgctgtcc tggcctccct catcattgct     60 

actaacacac tagtggctgt ggctgtgctg ctgttgatcc acaagaatga tggtgtcagt    120 

ctctgcttca ccttgaatct ggctgtggct gacaccttga ttggtgtggc catctctggc    180 

ctactcacag accagctctc cagcccttct cggcccacac agaagaccct gtgcagcctg    240 

cggatggcat ttgtcacttc ctccgcagct gcctctgtcc tcacggtcat gctgatcacc    300 

tttgacaggt accttgccat caagcagccc ttccgctact tgaagatcat gagtgggttc    360 

gtggccgggg cctgcattgc cgggctgtgg ttagtgtctt acctcattgg cttcctccca    420 

ctcggaatcc ccatgttcca gcagactgcc tacaaagggc agtgcagctt ctttgctgta    480 

tttcaccctc acttcgtgct gaccctctcc tgcgttggct tcttcccagc catgctcctc    540 

tttgtcttct tctactgcga catgctcaag attgcctcca tgcacagcca gcagattcga    600 

aagatggaac atgcaggagc catggctgga ggttatcgat ccccacggac tcccagcgac    660 

ttcaaagctc tccgtactgt gtctgttctc attgggagct ttgctctatc ctggaccccc    720 

ttccttatca ctggcattgt gcaggtggcc tgccaggagt gtcacctcta cctagtgctg    780 

gaacggtacc tgtggctgct cggcgtgggc aactccctgc tcaacccact catctatgcc    840 

tattggcaga aggaggtgcg actgcagctc taccacatgg ccctaggagt gaagaaggtg    900 

ctcacctcat tcctcctctt tctctcggcc aggaattgtg gcccagagag gcccagggaa    960 

agttcctgtc acatcgtcac tatctccagc tcagagtttg atggctaa                1008 

 
           
             8  
             335  
             PRT  
             Homo sapiens  
           
            8 

Met Glu Ser Ser Phe Ser Phe Gly Val Ile Leu Ala Val Leu Ala Ser 
  1               5                  10                  15 

Leu Ile Ile Ala Thr Asn Thr Leu Val Ala Val Ala Val Leu Leu Leu 
             20                  25                  30 

Ile His Lys Asn Asp Gly Val Ser Leu Cys Phe Thr Leu Asn Leu Ala 
         35                  40                  45 

Val Ala Asp Thr Leu Ile Gly Val Ala Ile Ser Gly Leu Leu Thr Asp 
     50                  55                  60 

Gln Leu Ser Ser Pro Ser Arg Pro Thr Gln Lys Thr Leu Cys Ser Leu 
 65                  70                  75                  80 

Arg Met Ala Phe Val Thr Ser Ser Ala Ala Ala Ser Val Leu Thr Val 
                 85                  90                  95 

Met Leu Ile Thr Phe Asp Arg Tyr Leu Ala Ile Lys Gln Pro Phe Arg 
            100                 105                 110 

Tyr Leu Lys Ile Met Ser Gly Phe Val Ala Gly Ala Cys Ile Ala Gly 
        115                 120                 125 

Leu Trp Leu Val Ser Tyr Leu Ile Gly Phe Leu Pro Leu Gly Ile Pro 
    130                 135                 140 

Met Phe Gln Gln Thr Ala Tyr Lys Gly Gln Cys Ser Phe Phe Ala Val 
145                 150                 155                 160 

Phe His Pro His Phe Val Leu Thr Leu Ser Cys Val Gly Phe Phe Pro 
                165                 170                 175 

Ala Met Leu Leu Phe Val Phe Phe Tyr Cys Asp Met Leu Lys Ile Ala 
            180                 185                 190 

Ser Met His Ser Gln Gln Ile Arg Lys Met Glu His Ala Gly Ala Met 
        195                 200                 205 

Ala Gly Gly Tyr Arg Ser Pro Arg Thr Pro Ser Asp Phe Lys Ala Leu 
    210                 215                 220 

Arg Thr Val Ser Val Leu Ile Gly Ser Phe Ala Leu Ser Trp Thr Pro 
225                 230                 235                 240 

Phe Leu Ile Thr Gly Ile Val Gln Val Ala Cys Gln Glu Cys His Leu 
                245                 250                 255 

Tyr Leu Val Leu Glu Arg Tyr Leu Trp Leu Leu Gly Val Gly Asn Ser 
            260                 265                 270 

Leu Leu Asn Pro Leu Ile Tyr Ala Tyr Trp Gln Lys Glu Val Arg Leu 
        275                 280                 285 

Gln Leu Tyr His Met Ala Leu Gly Val Lys Lys Val Leu Thr Ser Phe 
    290                 295                 300 

Leu Leu Phe Leu Ser Ala Arg Asn Cys Gly Pro Glu Arg Pro Arg Glu 
305                 310                 315                 320 

Ser Ser Cys His Ile Val Thr Ile Ser Ser Ser Glu Phe Asp Gly 
                325                 330                 335 

 
           
             9  
             1413  
             DNA  
             Homo sapiens  
           
            9 

atggacacta ccatggaagc tgacctgggt gccactggcc acaggccccg cacagagctt     60 

gatgatgagg actcctaccc ccaaggtggc tgggacacgg tcttcctggt ggccctgctg    120 

ctccttgggc tgccagccaa tgggttgatg gcgtggctgg ccggctccca ggcccggcat    180 

ggagctggca cgcgtctggc gctgctcctg ctcagcctgg ccctctctga cttcttgttc    240 

ctggcagcag cggccttcca gatcctagag atccggcatg ggggacactg gccgctgggg    300 

acagctgcct gccgcttcta ctacttccta tggggcgtgt cctactcctc cggcctcttc    360 

ctgctggccg ccctcagcct cgaccgctgc ctgctggcgc tgtgcccaca ctggtaccct    420 

gggcaccgcc cagtccgcct gcccctctgg gtctgcgccg gtgtctgggt gctggccaca    480 

ctcttcagcg tgccctggct ggtcttcccc gaggctgccg tctggtggta cgacctggtc    540 

atctgcctgg acttctggga cagcgaggag ctgtcgctga ggatgctgga ggtcctgggg    600 

ggcttcctgc ctttcctcct gctgctcgtc tgccacgtgc tcacccaggc cacagcctgt    660 

cgcacctgcc accgccaaca gcagcccgca gcctgccggg gcttcgcccg tgtggccagg    720 

accattctgt cagcctatgt ggtcctgagg ctgccctacc agctggccca gctgctctac    780 

ctggccttcc tgtgggacgt ctactctggc tacctgctct gggaggccct ggtctactcc    840 

gactacctga tcctactcaa cagctgcctc agccccttcc tctgcctcat ggccagtgcc    900 

gacctccgga ccctgctgcg ctccgtgctc tcgtccttcg cggcagctct ctgcgaggag    960 

cggccgggca gcttcacgcc cactgagcca cagacccagc tagattctga gggtccaact   1020 

ctgccagagc cgatggcaga ggcccagtca cagatggatc ctgtggccca gcctcaggtg   1080 

aaccccacac tccagccacg atcggatccc acagctcagc cacagctgaa ccctacggcc   1140 

cagccacagt cggatcccac agcccagcca cagctgaacc tcatggccca gccacagtca   1200 

gattctgtgg cccagccaca ggcagacact aacgtccaga cccctgcacc tgctgccagt   1260 

tctgtgccca gtccctgtga tgaagcttcc ccaaccccat cctcgcatcc taccccaggg   1320 

gcccttgagg acccagccac acctcctgcc tctgaaggag aaagccccag cagcaccccg   1380 

ccagaggcgg ccccgggcgc aggccccacg tga                                1413 

 
           
             10  
             468  
             PRT  
             Homo sapiens  
           
            10 

Met Asp Thr Thr Met Glu Ala Asp Leu Gly Ala Thr Gly His Arg Pro 
  1               5                  10                  15 

Arg Thr Glu Leu Asp Asp Glu Asp Ser Tyr Pro Gln Gly Gly Trp Asp 
             20                  25                  30 

Thr Val Phe Leu Val Ala Leu Leu Leu Leu Gly Leu Pro Ala Asn Gly 
         35                  40                  45 

Leu Met Ala Trp Leu Ala Gly Ser Gln Ala Arg His Gly Ala Gly Thr 
     50                  55                  60 

Arg Leu Ala Leu Leu Leu Leu Ser Leu Ala Leu Ser Asp Phe Leu Phe 
 65                  70                  75                  80 

Leu Ala Ala Ala Ala Phe Gln Ile Leu Glu Ile Arg His Gly Gly His 
                 85                  90                  95 

Trp Pro Leu Gly Thr Ala Ala Cys Arg Phe Tyr Tyr Phe Leu Trp Gly 
            100                 105                 110 

Val Ser Tyr Ser Ser Gly Leu Phe Leu Leu Ala Ala Leu Ser Leu Asp 
        115                 120                 125 

Arg Cys Leu Leu Ala Leu Cys Pro His Trp Tyr Pro Gly His Arg Pro 
    130                 135                 140 

Val Arg Leu Pro Leu Trp Val Cys Ala Gly Val Trp Val Leu Ala Thr 
145                 150                 155                 160 

Leu Phe Ser Val Pro Trp Leu Val Phe Pro Glu Ala Ala Val Trp Trp 
                165                 170                 175 

Tyr Asp Leu Val Ile Cys Leu Asp Phe Trp Asp Ser Glu Glu Leu Ser 
            180                 185                 190 

Leu Arg Met Leu Glu Val Leu Gly Gly Phe Leu Pro Phe Leu Leu Leu 
        195                 200                 205 

Leu Val Cys His Val Leu Thr Gln Ala Thr Arg Thr Cys His Arg Gln 
    210                 215                 220 

Gln Gln Pro Ala Ala Cys Arg Gly Phe Ala Arg Val Ala Arg Thr Ile 
225                 230                 235                 240 

Leu Ser Ala Tyr Val Val Leu Arg Leu Pro Tyr Gln Leu Ala Gln Leu 
                245                 250                 255 

Leu Tyr Leu Ala Phe Leu Trp Asp Val Tyr Ser Gly Tyr Leu Leu Trp 
            260                 265                 270 

Glu Ala Leu Val Tyr Ser Asp Tyr Leu Ile Leu Leu Asn Ser Cys Leu 
        275                 280                 285 

Ser Pro Phe Leu Cys Leu Met Ala Ser Ala Asp Leu Arg Thr Leu Leu 
    290                 295                 300 

Arg Ser Val Leu Ser Ser Phe Ala Ala Ala Leu Cys Glu Glu Arg Pro 
305                 310                 315                 320 

Gly Ser Phe Thr Pro Thr Glu Pro Gln Thr Gln Leu Asp Ser Glu Gly 
                325                 330                 335 

Pro Thr Leu Pro Glu Pro Met Ala Glu Ala Gln Ser Gln Met Asp Pro 
            340                 345                 350 

Val Ala Gln Pro Gln Val Asn Pro Thr Leu Gln Pro Arg Ser Asp Pro 
        355                 360                 365 

Thr Ala Gln Pro Gln Leu Asn Pro Thr Ala Gln Pro Gln Ser Asp Pro 
    370                 375                 380 

Thr Ala Gln Pro Gln Leu Asn Leu Met Ala Gln Pro Gln Ser Asp Ser 
385                 390                 395                 400 

Val Ala Gln Pro Gln Ala Asp Thr Asn Val Gln Thr Pro Ala Pro Ala 
                405                 410                 415 

Ala Ser Ser Val Pro Ser Pro Cys Asp Glu Ala Ser Pro Thr Pro Ser 
            420                 425                 430 

Ser His Pro Thr Pro Gly Ala Leu Glu Asp Pro Ala Thr Pro Pro Ala 
        435                 440                 445 

Ser Glu Gly Glu Ser Pro Ser Ser Thr Pro Pro Glu Ala Ala Pro Gly 
    450                 455                 460 

Ala Gly Pro Thr 
465 

 
           
             11  
             1248  
             DNA  
             Homo sapiens  
           
            11 

atgtcaggga tggaaaaact tcagaatgct tcctggatct accagcagaa actagaagat     60 

ccattccaga aacacctgaa cagcaccgag gagtatctgg ccttcctctg cggacctcgg    120 

cgcagccact tcttcctccc cgtgtctgtg gtgtatgtgc caatttttgt ggtgggggtc    180 

attggcaatg tcctggtgtg cctggtgatt ctgcagcacc aggctatgaa gacgcccacc    240 

aactactacc tcttcagcct ggcggtctct gacctcctgg tcctgctcct tggaatgccc    300 

ctggaggtct atgagatgtg gcgcaactac cctttcttgt tcgggcccgt gggctgctac    360 

ttcaagacgg ccctctttga gaccgtgtgc ttcgcctcca tcctcagcat caccaccgtc    420 

agcgtggagc gctacgtggc catcctacac ccgttccgcg ccaaactgca gagcacccgg    480 

cgccgggccc tcaggatcct cggcatcgtc tggggcttct ccgtgctctt ctccctgccc    540 

aacaccagca tccatggcat caagttccac tacttcccca atgggtccct ggtcccaggt    600 

tcggccacct gtacggtcat caagcccatg tggatctaca atttcatcat ccaggtcacc    660 

tccttcctat tctacctcct ccccatgact gtcatcagtg tcctctacta cctcatggca    720 

ctcagactaa agaaagacaa atctcttgag gcagatgaag ggaatgcaaa tattcaaaga    780 

ccctgcagaa aatcagtcaa caagatgctg tttgtcttgg tcttagtgtt tgctatctgt    840 

tgggccccgt tccacattga ccgactcttc ttcagctttg tggaggagtg gagtgaatcc    900 

ctggctgctg tgttcaacct cgtccatgtg gtgtcaggtg tcttcttcta cctgagctca    960 

gctgtcaacc ccattatcta taacctactg tctcgccgct tccaggcagc attccagaat   1020 

gtgatctctt ctttccacaa acagtggcac tcccagcatg acccacagtt gccacctgcc   1080 

cagcggaaca tcttcctgac agaatgccac tttgtggagc tgaccgaaga tataggtccc   1140 

caattcccat gtcagtcatc catgcacaac tctcacctcc caacagccct ctctagtgaa   1200 

cagatgtcaa gaacaaacta tcaaagcttc cactttaaca aaacctga                1248 

 
           
             12  
             415  
             PRT  
             Homo sapiens  
           
            12 

Met Ser Gly Met Glu Lys Leu Gln Asn Ala Ser Trp Ile Tyr Gln Gln 
  1               5                  10                  15 

Lys Leu Glu Asp Pro Phe Gln Lys His Leu Asn Ser Thr Glu Glu Tyr 
             20                  25                  30 

Leu Ala Phe Leu Cys Gly Pro Arg Arg Ser His Phe Phe Leu Pro Val 
         35                  40                  45 

Ser Val Val Tyr Val Pro Ile Phe Val Val Gly Val Ile Gly Asn Val 
     50                  55                  60 

Leu Val Cys Leu Val Ile Leu Gln His Gln Ala Met Lys Thr Pro Thr 
 65                  70                  75                  80 

Asn Tyr Tyr Leu Phe Ser Leu Ala Val Ser Asp Leu Leu Val Leu Leu 
                 85                  90                  95 

Leu Gly Met Pro Leu Glu Val Tyr Glu Met Trp Arg Asn Tyr Pro Phe 
            100                 105                 110 

Leu Phe Gly Pro Val Gly Cys Tyr Phe Lys Thr Ala Leu Phe Glu Thr 
        115                 120                 125 

Val Cys Phe Ala Ser Ile Leu Ser Ile Thr Thr Val Ser Val Glu Arg 
    130                 135                 140 

Tyr Val Ala Ile Leu His Pro Phe Arg Ala Lys Leu Gln Ser Thr Arg 
145                 150                 155                 160 

Arg Arg Ala Leu Arg Ile Leu Gly Ile Val Trp Gly Phe Ser Val Leu 
                165                 170                 175 

Phe Ser Leu Pro Asn Thr Ser Ile His Gly Ile Lys Phe His Tyr Phe 
            180                 185                 190 

Pro Asn Gly Ser Leu Val Pro Gly Ser Ala Thr Cys Thr Val Ile Lys 
        195                 200                 205 

Pro Met Trp Ile Tyr Asn Phe Ile Ile Gln Val Thr Ser Phe Leu Phe 
    210                 215                 220 

Tyr Leu Leu Pro Met Thr Val Ile Ser Val Leu Tyr Tyr Leu Met Ala 
225                 230                 235                 240 

Leu Arg Leu Lys Lys Asp Lys Ser Leu Glu Ala Asp Glu Gly Asn Ala 
                245                 250                 255 

Asn Ile Gln Arg Pro Cys Arg Lys Ser Val Asn Lys Met Leu Phe Val 
            260                 265                 270 

Leu Val Leu Val Phe Ala Ile Cys Trp Ala Pro Phe His Ile Asp Arg 
        275                 280                 285 

Leu Phe Phe Ser Phe Val Glu Glu Trp Ser Glu Ser Leu Ala Ala Val 
    290                 295                 300 

Phe Asn Leu Val His Val Val Ser Gly Val Phe Phe Tyr Leu Ser Ser 
305                 310                 315                 320 

Ala Val Asn Pro Ile Ile Tyr Asn Leu Leu Ser Arg Arg Phe Gln Ala 
                325                 330                 335 

Ala Phe Gln Asn Val Ile Ser Ser Phe His Lys Gln Trp His Ser Gln 
            340                 345                 350 

His Asp Pro Gln Leu Pro Pro Ala Gln Arg Asn Ile Phe Leu Thr Glu 
        355                 360                 365 

Cys His Phe Val Glu Leu Thr Glu Asp Ile Gly Pro Gln Phe Pro Cys 
    370                 375                 380 

Gln Ser Ser Met His Asn Ser His Leu Pro Thr Ala Leu Ser Ser Glu 
385                 390                 395                 400 

Gln Met Ser Arg Thr Asn Tyr Gln Ser Phe His Phe Asn Lys Thr 
                405                 410                 415 

 
           
             13  
             1173  
             DNA  
             Homo sapiens  
           
            13 

atgccagata ctaatagcac aatcaattta tcactaagca ctcgtgttac tttagcattt     60 

tttatgtcct tagtagcttt tgctataatg ctaggaaatg ctttggtcat tttagctttt    120 

gtggtggaca aaaaccttag acatcgaagt agttattttt ttcttaactt ggccatctct    180 

gacttctttg tgggtgtgat ctccattcct ttgtacatcc ctcacacgct gttcgaatgg    240 

gattttggaa aggaaatctg tgtattttgg ctcactactg actatctgtt atgtacagca    300 

tctgtatata acattgtcct catcagctat gatcgatacc tgtcagtctc aaatgctgtg    360 

tcttatagaa ctcaacatac tggggtcttg aagattgtta ctctgatggt ggccgtttgg    420 

gtgctggcct tcttagtgaa tgggccaatg attctagttt cagagtcttg gaaggatgaa    480 

ggtagtgaat gtgaacctgg atttttttcg gaatggtaca tccttgccat cacatcattc    540 

ttggaattcg tgatcccagt catcttagtc gcttatttca acatgaatat ttattggagc    600 

ctgtggaagc gtgatcatct cagtaggtgc caaagccatc ctggactgac tgctgtctct    660 

tccaacatct gtggacactc attcagaggt agactatctt caaggagatc tctttctgca    720 

tcgacagaag ttcctgcatc ctttcattca gagagacaga ggagaaagag tagtctcatg    780 

ttttcctcaa gaaccaagat gaatagcaat acaattgctt ccaaaatggg ttccttctcc    840 

caatcagatt ctgtagctct tcaccaaagg gaacatgttg aactgcttag agccaggaga    900 

ttagccaagt cactggccat tctcttaggg gtttttgctg tttgctgggc tccatattct    960 

ctgttcacaa ttgtcctttc attttattcc tcagcaacag gtcctaaatc agtttggtat   1020 

agaattgcat tttggcttca gtggttcaat tcctttgtca atcctctttt gtatccattg   1080 

tgtcacaagc gctttcaaaa ggctttcttg aaaatatttt gtataaaaaa gcaacctcta   1140 

ccatcacaac acagtcggtc agtatcttct taa                                1173 

 
           
             14  
             390  
             PRT  
             Homo sapiens  
           
            14 

Met Pro Asp Thr Asn Ser Thr Ile Asn Leu Ser Leu Ser Thr Arg Val 
  1               5                  10                  15 

Thr Leu Ala Phe Phe Met Ser Leu Val Ala Phe Ala Ile Met Leu Gly 
             20                  25                  30 

Asn Ala Leu Val Ile Leu Ala Phe Val Val Asp Lys Asn Leu Arg His 
         35                  40                  45 

Arg Ser Ser Tyr Phe Phe Leu Asn Leu Ala Ile Ser Asp Phe Phe Val 
     50                  55                  60 

Gly Val Ile Ser Ile Pro Leu Tyr Ile Pro His Thr Leu Phe Glu Trp 
 65                  70                  75                  80 

Asp Phe Gly Lys Glu Ile Cys Val Phe Trp Leu Thr Thr Asp Tyr Leu 
                 85                  90                  95 

Leu Cys Thr Ala Ser Val Tyr Asn Ile Val Leu Ile Ser Tyr Asp Arg 
            100                 105                 110 

Tyr Leu Ser Val Ser Asn Ala Val Ser Tyr Arg Thr Gln His Thr Gly 
        115                 120                 125 

Val Leu Lys Ile Val Thr Leu Met Val Ala Val Trp Val Leu Ala Phe 
    130                 135                 140 

Leu Val Asn Gly Pro Met Ile Leu Val Ser Glu Ser Trp Lys Asp Glu 
145                 150                 155                 160 

Gly Ser Glu Cys Glu Pro Gly Phe Phe Ser Glu Trp Tyr Ile Leu Ala 
                165                 170                 175 

Ile Thr Ser Phe Leu Glu Phe Val Ile Pro Val Ile Leu Val Ala Tyr 
            180                 185                 190 

Phe Asn Met Asn Ile Tyr Trp Ser Leu Trp Lys Arg Asp His Leu Ser 
        195                 200                 205 

Arg Cys Gln Ser His Pro Gly Leu Thr Ala Val Ser Ser Asn Ile Cys 
    210                 215                 220 

Gly His Ser Phe Arg Gly Arg Leu Ser Ser Arg Arg Ser Leu Ser Ala 
225                 230                 235                 240 

Ser Thr Glu Val Pro Ala Ser Phe His Ser Glu Arg Gln Arg Arg Lys 
                245                 250                 255 

Ser Ser Leu Met Phe Ser Ser Arg Thr Lys Met Asn Ser Asn Thr Ile 
            260                 265                 270 

Ala Ser Lys Met Gly Ser Phe Ser Gln Ser Asp Ser Val Ala Leu His 
        275                 280                 285 

Gln Arg Glu His Val Glu Leu Leu Arg Ala Arg Arg Leu Ala Lys Ser 
    290                 295                 300 

Leu Ala Ile Leu Leu Gly Val Phe Ala Val Cys Trp Ala Pro Tyr Ser 
305                 310                 315                 320 

Leu Phe Thr Ile Val Leu Ser Phe Tyr Ser Ser Ala Thr Gly Pro Lys 
                325                 330                 335 

Ser Val Trp Tyr Arg Ile Ala Phe Trp Leu Gln Trp Phe Asn Ser Phe 
            340                 345                 350 

Val Asn Pro Leu Leu Tyr Pro Leu Cys His Lys Arg Phe Gln Lys Ala 
        355                 360                 365 

Phe Leu Lys Ile Phe Cys Ile Lys Lys Gln Pro Leu Pro Ser Gln His 
    370                 375                 380 

Ser Arg Ser Val Ser Ser 
385                 390 

 
           
             15  
             1128  
             DNA  
             Homo sapiens  
           
            15 

atggcgaacg cgagcgagcc gggtggcagc ggcggcggcg aggcggccgc cctgggcctc     60 

aagctggcca cgctcagcct gctgctgtgc gtgagcctag cgggcaacgt gctgttcgcg    120 

ctgctgatcg tgcgggagcg cagcctgcac cgcgccccgt actacctgct gctcgacctg    180 

tgcctggccg acgggctgcg cgcgctcgcc tgcctcccgg ccgtcatgct ggcggcgcgg    240 

cgtgcggcgg ccgcggcggg ggcgccgccg ggcgcgctgg gctgcaagct gctcgccttc    300 

ctggccgcgc tcttctgctt ccacgccgcc ttcctgctgc tgggcgtggg cgtcacccgc    360 

tacctggcca tcgcgcacca ccgcttctat gcagagcgcc tggccggctg gccgtgcgcc    420 

gccatgctgg tgtgcgccgc ctgggcgctg gcgctggccg cggccttccc gccagtgctg    480 

gacggcggtg gcgacgacga ggacgcgccg tgcgccctgg agcagcggcc cgacggcgcc    540 

cccggcgcgc tgggcttcct gctgctgctg gccgtggtgg tgggcgccac gcacctcgtc    600 

tacctccgcc tgctcttctt catccacgac cgccgcaaga tgcggcccgc gcgcctggtg    660 

cccgccgtca gccacgactg gaccttccac ggcccgggcg ccaccggcca ggcggccgcc    720 

aactggacgg cgggcttcgg ccgcgggccc acgccgcccg cgcttgtggg catccggccc    780 

gcagggccgg gccgcggcgc gcgccgcctc ctcgtgctgg aagaattcaa gacggagaag    840 

aggctgtgca agatgttcta cgccgtcacg ctgctcttcc tgctcctctg ggggccctac    900 

gtcgtggcca gctacctgcg ggtcctggtg cggcccggcg ccgtccccca ggcctacctg    960 

acggcctccg tgtggctgac cttcgcgcag gccggcatca accccgtcgt gtgcttcctc   1020 

ttcaacaggg agctgaggga ctgcttcagg gcccagttcc cctgctgcca gagcccccgg   1080 

accacccagg cgacccatcc ctgcgacctg aaaggcattg gtttatga                1128 

 
           
             16  
             375  
             PRT  
             Homo sapiens  
           
            16 

Met Ala Asn Ala Ser Glu Pro Gly Gly Ser Gly Gly Gly Glu Ala Ala 
  1               5                  10                  15 

Ala Leu Gly Leu Lys Leu Ala Thr Leu Ser Leu Leu Leu Cys Val Ser 
             20                  25                  30 

Leu Ala Gly Asn Val Leu Phe Ala Leu Leu Ile Val Arg Glu Arg Ser 
         35                  40                  45 

Leu His Arg Ala Pro Tyr Tyr Leu Leu Leu Asp Leu Cys Leu Ala Asp 
     50                  55                  60 

Gly Leu Arg Ala Leu Ala Cys Leu Pro Ala Val Met Leu Ala Ala Arg 
 65                  70                  75                  80 

Arg Ala Ala Ala Ala Ala Gly Ala Pro Pro Gly Ala Leu Gly Cys Lys 
                 85                  90                  95 

Leu Leu Ala Phe Leu Ala Ala Leu Phe Cys Phe His Ala Ala Phe Leu 
            100                 105                 110 

Leu Leu Gly Val Gly Val Thr Arg Tyr Leu Ala Ile Ala His His Arg 
        115                 120                 125 

Phe Tyr Ala Glu Arg Leu Ala Gly Trp Pro Cys Ala Ala Met Leu Val 
    130                 135                 140 

Cys Ala Ala Trp Ala Leu Ala Leu Ala Ala Ala Phe Pro Pro Val Leu 
145                 150                 155                 160 

Asp Gly Gly Gly Asp Asp Glu Asp Ala Pro Cys Ala Leu Glu Gln Arg 
                165                 170                 175 

Pro Asp Gly Ala Pro Gly Ala Leu Gly Phe Leu Leu Leu Leu Ala Val 
            180                 185                 190 

Val Val Gly Ala Thr His Leu Val Tyr Leu Arg Leu Leu Phe Phe Ile 
        195                 200                 205 

His Asp Arg Arg Lys Met Arg Pro Ala Arg Leu Val Pro Ala Val Ser 
    210                 215                 220 

His Asp Trp Thr Phe His Gly Pro Gly Ala Thr Gly Gln Ala Ala Ala 
225                 230                 235                 240 

Asn Trp Thr Ala Gly Phe Gly Arg Gly Pro Thr Pro Pro Ala Leu Val 
                245                 250                 255 

Gly Ile Arg Pro Ala Gly Pro Gly Arg Gly Ala Arg Arg Leu Leu Val 
            260                 265                 270 

Leu Glu Glu Phe Lys Thr Glu Lys Arg Leu Cys Lys Met Phe Tyr Ala 
        275                 280                 285 

Val Thr Leu Leu Phe Leu Leu Leu Trp Gly Pro Tyr Val Val Ala Ser 
    290                 295                 300 

Tyr Leu Arg Val Leu Val Arg Pro Gly Ala Val Pro Gln Ala Tyr Leu 
305                 310                 315                 320 

Thr Ala Ser Val Trp Leu Thr Phe Ala Gln Ala Gly Ile Asn Pro Val 
                325                 330                 335 

Val Cys Phe Leu Phe Asn Arg Glu Leu Arg Asp Cys Phe Arg Ala Gln 
            340                 345                 350 

Phe Pro Cys Cys Gln Ser Pro Arg Thr Thr Gln Ala Thr His Pro Cys 
        355                 360                 365 

Asp Leu Lys Gly Ile Gly Leu 
    370                 375 

 
           
             17  
             1002  
             DNA  
             Homo sapiens  
           
            17 

atgaacacca cagtgatgca aggcttcaac agatctgagc ggtgccccag agacactcgg     60 

atagtacagc tggtattccc agccctctac acagtggttt tcttgaccgg catcctgctg    120 

aatactttgg ctctgtgggt gtttgttcac atccccagct cctccacctt catcatctac    180 

ctcaaaaaca ctttggtggc cgacttgata atgacactca tgcttccttt caaaatcctc    240 

tctgactcac acctggcacc ctggcagctc agagcttttg tgtgtcgttt ttcttcggtg    300 

atattttatg agaccatgta tgtgggcatc gtgctgttag ggctcatagc ctttgacaga    360 

ttcctcaaga tcatcagacc tttgagaaat atttttctaa aaaaacctgt ttttgcaaaa    420 

acggtctcaa tcttcatctg gttctttttg ttcttcatct ccctgccaaa tacgatcttg    480 

agcaacaagg aagcaacacc atcgtctgtg aaaaagtgtg cttccttaaa ggggcctctg    540 

gggctgaaat ggcatcaaat ggtaaataac atatgccagt ttattttctg gactgttttt    600 

atcctaatgc ttgtgtttta tgtggttatt gcaaaaaaag tatatgattc ttatagaaag    660 

tccaaaagta aggacagaaa aaacaacaaa aagctggaag gcaaagtatt tgttgtcgtg    720 

gctgtcttct ttgtgtgttt tgctccattt cattttgcca gagttccata tactcacagt    780 

caaaccaaca ataagactga ctgtagactg caaaatcaac tgtttattgc taaagaaaca    840 

actctctttt tggcagcaac taacatttgt atggatccct taatatacat attcttatgt    900 

aaaaaattca cagaaaagct accatgtatg caagggagaa agaccacagc atcaagccaa    960 

gaaaatcata gcagtcagac agacaacata accttaggct ga                      1002 

 
           
             18  
             333  
             PRT  
             Homo sapiens  
           
            18 

Met Asn Thr Thr Val Met Gln Gly Phe Asn Arg Ser Glu Arg Cys Pro 
  1               5                  10                  15 

Arg Asp Thr Arg Ile Val Gln Leu Val Phe Pro Ala Leu Tyr Thr Val 
             20                  25                  30 

Val Phe Leu Thr Gly Ile Leu Leu Asn Thr Leu Ala Leu Trp Val Phe 
         35                  40                  45 

Val His Ile Pro Ser Ser Ser Thr Phe Ile Ile Tyr Leu Lys Asn Thr 
     50                  55                  60 

Leu Val Ala Asp Leu Ile Met Thr Leu Met Leu Pro Phe Lys Ile Leu 
 65                  70                  75                  80 

Ser Asp Ser His Leu Ala Pro Trp Gln Leu Arg Ala Phe Val Cys Arg 
                 85                  90                  95 

Phe Ser Ser Val Ile Phe Tyr Glu Thr Met Tyr Val Gly Ile Val Leu 
            100                 105                 110 

Leu Gly Leu Ile Ala Phe Asp Arg Phe Leu Lys Ile Ile Arg Pro Leu 
        115                 120                 125 

Arg Asn Ile Phe Leu Lys Lys Pro Val Phe Ala Lys Thr Val Ser Ile 
    130                 135                 140 

Phe Ile Trp Phe Phe Leu Phe Phe Ile Ser Leu Pro Asn Thr Ile Leu 
145                 150                 155                 160 

Ser Asn Lys Glu Ala Thr Pro Ser Ser Val Lys Lys Cys Ala Ser Leu 
                165                 170                 175 

Lys Gly Pro Leu Gly Leu Lys Trp His Gln Met Val Asn Asn Ile Cys 
            180                 185                 190 

Gln Phe Ile Phe Trp Thr Val Phe Ile Leu Met Leu Val Phe Tyr Val 
        195                 200                 205 

Val Ile Ala Lys Lys Val Tyr Asp Ser Tyr Arg Lys Ser Lys Ser Lys 
    210                 215                 220 

Asp Arg Lys Asn Asn Lys Lys Leu Glu Gly Lys Val Phe Val Val Val 
225                 230                 235                 240 

Ala Val Phe Phe Val Cys Phe Ala Pro Phe His Phe Ala Arg Val Pro 
                245                 250                 255 

Tyr Thr His Ser Gln Thr Asn Asn Lys Thr Asp Cys Arg Leu Gln Asn 
            260                 265                 270 

Gln Leu Phe Ile Ala Lys Glu Thr Thr Leu Phe Leu Ala Ala Thr Asn 
        275                 280                 285 

Ile Cys Met Asp Pro Leu Ile Tyr Ile Phe Leu Cys Lys Lys Phe Thr 
    290                 295                 300 

Glu Lys Leu Pro Cys Met Gln Gly Arg Lys Thr Thr Ala Ser Ser Gln 
305                 310                 315                 320 

Glu Asn His Ser Ser Gln Thr Asp Asn Ile Thr Leu Gly 
                325                 330 

 
           
             19  
             1122  
             DNA  
             Homo sapiens  
           
            19 

atggccaaca ctaccggaga gcctgaggag gtgagcggcg ctctgtcccc accgtccgca     60 

tcagcttatg tgaagctggt actgctggga ctgattatgt gcgtgagcct ggcgggtaac    120 

gccatcttgt ccctgctggt gctcaaggag cgtgccctgc acaaggctcc ttactacttc    180 

ctgctggacc tgtgcctggc cgatggcata cgctctgccg tctgcttccc ctttgtgctg    240 

gcttctgtgc gccacggctc ttcatggacc ttcagtgcac tcagctgcaa gattgtggcc    300 

tttatggccg tgctcttttg cttccatgcg gccttcatgc tgttctgcat cagcgtcacc    360 

cgctacatgg ccatcgccca ccaccgcttc tacgccaagc gcatgacact ctggacatgc    420 

gcggctgtca tctgcatggc ctggaccctg tctgtggcca tggccttccc acctgtcttt    480 

gacgtgggca cctacaagtt tattcgggag gaggaccagt gcatctttga gcatcgctac    540 

ttcaaggcca atgacacgct gggcttcatg cttatgttgg ctgtgctcat ggcagctacc    600 

catgctgtct acggcaagct gctcctcttc gagtatcgtc accgcaagat gaagccagtg    660 

cagatggtgc cagccatcag ccagaactgg acattccatg gtcccggggc caccggccag    720 

gctgctgcca actggatcgc cggctttggc cgtgggccca tgccaccaac cctgctgggt    780 

atccggcaga atgggcatgc agccagccgg cggctactgg gcatggacga ggtcaagggt    840 

gaaaagcagc tgggccgcat gttctacgcg atcacactgc tctttctgct cctctggtca    900 

ccctacatcg tggcctgcta ctggcgagtg tttgtgaaag cctgtgctgt gccccaccgc    960 

tacctggcca ctgctgtttg gatgagcttc gcccaggctg ccgtcaaccc aattgtctgc   1020 

ttcctgctca acaaggacct caagaagtgc ctgaccactc acgccccctg ctggggcaca   1080 

ggaggtgccc cggctcccag agaaccctac tgtgtcatgt ga                      1122 

 
           
             20  
             373  
             PRT  
             Homo sapiens  
           
            20 

Met Ala Asn Thr Thr Gly Glu Pro Glu Glu Val Ser Gly Ala Leu Ser 
  1               5                  10                  15 

Pro Pro Ser Ala Ser Ala Tyr Val Lys Leu Val Leu Leu Gly Leu Ile 
             20                  25                  30 

Met Cys Val Ser Leu Ala Gly Asn Ala Ile Leu Ser Leu Leu Val Leu 
         35                  40                  45 

Lys Glu Arg Ala Leu His Lys Ala Pro Tyr Tyr Phe Leu Leu Asp Leu 
     50                  55                  60 

Cys Leu Ala Asp Gly Ile Arg Ser Ala Val Cys Phe Pro Phe Val Leu 
 65                  70                  75                  80 

Ala Ser Val Arg His Gly Ser Ser Trp Thr Phe Ser Ala Leu Ser Cys 
                 85                  90                  95 

Lys Ile Val Ala Phe Met Ala Val Leu Phe Cys Phe His Ala Ala Phe 
            100                 105                 110 

Met Leu Phe Cys Ile Ser Val Thr Arg Tyr Met Ala Ile Ala His His 
        115                 120                 125 

Arg Phe Tyr Ala Lys Arg Met Thr Leu Trp Thr Cys Ala Ala Val Ile 
    130                 135                 140 

Cys Met Ala Trp Thr Leu Ser Val Ala Met Ala Phe Pro Pro Val Phe 
145                 150                 155                 160 

Asp Val Gly Thr Tyr Lys Phe Ile Arg Glu Glu Asp Gln Cys Ile Phe 
                165                 170                 175 

Glu His Arg Tyr Phe Lys Ala Asn Asp Thr Leu Gly Phe Met Leu Met 
            180                 185                 190 

Leu Ala Val Leu Met Ala Ala Thr His Ala Val Tyr Gly Lys Leu Leu 
        195                 200                 205 

Leu Phe Glu Tyr Arg His Arg Lys Met Lys Pro Val Gln Met Val Pro 
    210                 215                 220 

Ala Ile Ser Gln Asn Trp Thr Phe His Gly Pro Gly Ala Thr Gly Gln 
225                 230                 235                 240 

Ala Ala Ala Asn Trp Ile Ala Gly Phe Gly Arg Gly Pro Met Pro Pro 
                245                 250                 255 

Thr Leu Leu Gly Ile Arg Gln Asn Gly His Ala Ala Ser Arg Arg Leu 
            260                 265                 270 

Leu Gly Met Asp Glu Val Lys Gly Glu Lys Gln Leu Gly Arg Met Phe 
        275                 280                 285 

Tyr Ala Ile Thr Leu Leu Phe Leu Leu Leu Trp Ser Pro Tyr Ile Val 
    290                 295                 300 

Ala Cys Tyr Trp Arg Val Phe Val Lys Ala Cys Ala Val Pro His Arg 
305                 310                 315                 320 

Tyr Leu Ala Thr Ala Val Trp Met Ser Phe Ala Gln Ala Ala Val Asn 
                325                 330                 335 

Pro Ile Val Cys Phe Leu Leu Asn Lys Asp Leu Lys Lys Cys Leu Thr 
            340                 345                 350 

Thr His Ala Pro Cys Trp Gly Thr Gly Gly Ala Pro Ala Pro Arg Glu 
        355                 360                 365 

Pro Tyr Cys Val Met 
    370 

 
           
             21  
             1053  
             DNA  
             Homo sapiens  
           
            21 

atggctttgg aacagaacca gtcaacagat tattattatg aggaaaatga aatgaatggc     60 

acttatgact acagtcaata tgaattgatc tgtatcaaag aagatgtcag agaatttgca    120 

aaagttttcc tccctgtatt cctcacaata gctttcgtca ttggacttgc aggcaattcc    180 

atggtagtgg caatttatgc ctattacaag aaacagagaa ccaaaacaga tgtgtacatc    240 

ctgaatttgg ctgtagcaga tttactcctt ctattcactc tgcctttttg ggctgttaat    300 

gcagttcatg ggtgggtttt agggaaaata atgtgcaaaa taacttcagc cttgtacaca    360 

ctaaactttg tctctggaat gcagtttctg gcttgcatca gcatagacag atatgtggca    420 

gtaactaatg tccccagcca atcaggagtg ggaaaaccat gctggatcat ctgtttctgt    480 

gtctggatgg ctgccatctt gctgagcata ccccagctgg ttttttatac agtaaatgac    540 

aatgctaggt gcattcccat tttcccccgc tacctaggaa catcaatgaa agcattgatt    600 

caaatgctag agatctgcat tggatttgta gtaccctttc ttattatggg ggtgtgctac    660 

tttatcacgg caaggacact catgaagatg ccaaacatta aaatatctcg acccctaaaa    720 

gttctgctca cagtcgttat agttttcatt gtcactcaac tgccttataa cattgtcaag    780 

ttctgccgag ccatagacat catctactcc ctgatcacca gctgcaacat gagcaaacgc    840 

atggacatcg ccatccaagt cacagaaagc attgcactct ttcacagctg cctcaaccca    900 

atcctttatg tttttatggg agcatctttc aaaaactacg ttatgaaagt ggccaagaaa    960 

tatgggtcct ggagaagaca gagacaaagt gtggaggagt ttccttttga ttctgagggt   1020 

cctacagagc caaccagtac ttttagcatt taa                                1053 

 
           
             22  
             350  
             PRT  
             Homo sapiens  
           
            22 

Met Ala Leu Glu Gln Asn Gln Ser Thr Asp Tyr Tyr Tyr Glu Glu Asn 
  1               5                  10                  15 

Glu Met Asn Gly Thr Tyr Asp Tyr Ser Gln Tyr Glu Leu Ile Cys Ile 
             20                  25                  30 

Lys Glu Asp Val Arg Glu Phe Ala Lys Val Phe Leu Pro Val Phe Leu 
         35                  40                  45 

Thr Ile Ala Phe Val Ile Gly Leu Ala Gly Asn Ser Met Val Val Ala 
     50                  55                  60 

Ile Tyr Ala Tyr Tyr Lys Lys Gln Arg Thr Lys Thr Asp Val Tyr Ile 
 65                  70                  75                  80 

Leu Asn Leu Ala Val Ala Asp Leu Leu Leu Leu Phe Thr Leu Pro Phe 
                 85                  90                  95 

Trp Ala Val Asn Ala Val His Gly Trp Val Leu Gly Lys Ile Met Cys 
            100                 105                 110 

Lys Ile Thr Ser Ala Leu Tyr Thr Leu Asn Phe Val Ser Gly Met Gln 
        115                 120                 125 

Phe Leu Ala Cys Ile Ser Ile Asp Arg Tyr Val Ala Val Thr Asn Val 
    130                 135                 140 

Pro Ser Gln Ser Gly Val Gly Lys Pro Cys Trp Ile Ile Cys Phe Cys 
145                 150                 155                 160 

Val Trp Met Ala Ala Ile Leu Leu Ser Ile Pro Gln Leu Val Phe Tyr 
                165                 170                 175 

Thr Val Asn Asp Asn Ala Arg Cys Ile Pro Ile Phe Pro Arg Tyr Leu 
            180                 185                 190 

Gly Thr Ser Met Lys Ala Leu Ile Gln Met Leu Glu Ile Cys Ile Gly 
        195                 200                 205 

Phe Val Val Pro Phe Leu Ile Met Gly Val Cys Tyr Phe Ile Thr Ala 
    210                 215                 220 

Arg Thr Leu Met Lys Met Pro Asn Ile Lys Ile Ser Arg Pro Leu Lys 
225                 230                 235                 240 

Val Leu Leu Thr Val Val Ile Val Phe Ile Val Thr Gln Leu Pro Tyr 
                245                 250                 255 

Asn Ile Val Lys Phe Cys Arg Ala Ile Asp Ile Ile Tyr Ser Leu Ile 
            260                 265                 270 

Thr Ser Cys Asn Met Ser Lys Arg Met Asp Ile Ala Ile Gln Val Thr 
        275                 280                 285 

Glu Ser Ile Ala Leu Phe His Ser Cys Leu Asn Pro Ile Leu Tyr Val 
    290                 295                 300 

Phe Met Gly Ala Ser Phe Lys Asn Tyr Val Met Lys Val Ala Lys Lys 
305                 310                 315                 320 

Tyr Gly Ser Trp Arg Arg Gln Arg Gln Ser Val Glu Glu Phe Pro Phe 
                325                 330                 335 

Asp Ser Glu Gly Pro Thr Glu Pro Thr Ser Thr Phe Ser Ile 
            340                 345                 350 

 
           
             23  
             1116  
             DNA  
             Homo sapiens  
           
            23 

atgccaggaa acgccacccc agtgaccacc actgccccgt gggcctccct gggcctctcc     60 

gccaagacct gcaacaacgt gtccttcgaa gagagcagga tagtcctggt cgtggtgtac    120 

agcgcggtgt gcacgctggg ggtgccggcc aactgcctga ctgcgtggct ggcgctgctg    180 

caggtactgc agggcaacgt gctggccgtc tacctgctct gcctggcact ctgcgaactg    240 

ctgtacacag gcacgctgcc actctgggtc atctatatcc gcaaccagca ccgctggacc    300 

ctaggcctgc tggcctcgaa ggtgaccgcc tacatcttct tctgcaacat ctacgtcagc    360 

atcctcttcc tgtgctgcat ctcctgcgac cgcttcgtgg ccgtggtgta cgcgctggag    420 

agtcggggcc gccgccgccg gaggaccgcc atcctcatct ccgcctgcat cttcatcctc    480 

gtcgggatcg ttcactaccc ggtgttccag acggaagaca aggagacctg ctttgacatg    540 

ctgcagatgg acagcaggat tgccgggtac tactacgcca ggttcaccgt tggctttgcc    600 

atccctctct ccatcatcgc cttcaccaac caccggattt tcaggagcat caagcagagc    660 

atgggcttaa gcgctgccca gaaggccaag gtgaagcact cggccatcgc ggtggttgtc    720 

atcttcctag tctgcttcgc cccgtaccac ctggttctcc tcgtcaaagc cgctgccttt    780 

tcctactaca gaggagacag gaacgccatg tgcggcttgg aggaaaggct gtacacagcc    840 

tctgtggtgt ttctgtgcct gtccacggtg aacggcgtgg ctgaccccat tatctacgtg    900 

ctggccacgg accattcccg ccaagaagtg tccagaatcc ataaggggtg gaaagagtgg    960 

tccatgaaga cagacgtcac caggctcacc cacagcaggg acaccgagga gctgcagtcg   1020 

cccgtggccc ttgcagacca ctacaccttc tccaggcccg tgcacccacc agggtcacca   1080 

tgccctgcaa agaggctgat tgaggagtcc tgctga                             1116 

 
           
             24  
             371  
             PRT  
             Homo sapiens  
           
            24 

Met Pro Gly Asn Ala Thr Pro Val Thr Thr Thr Ala Pro Trp Ala Ser 
  1               5                  10                  15 

Leu Gly Leu Ser Ala Lys Thr Cys Asn Asn Val Ser Phe Glu Glu Ser 
             20                  25                  30 

Arg Ile Val Leu Val Val Val Tyr Ser Ala Val Cys Thr Leu Gly Val 
         35                  40                  45 

Pro Ala Asn Cys Leu Thr Ala Trp Leu Ala Leu Leu Gln Val Leu Gln 
     50                  55                  60 

Gly Asn Val Leu Ala Val Tyr Leu Leu Cys Leu Ala Leu Cys Glu Leu 
 65                  70                  75                  80 

Leu Tyr Thr Gly Thr Leu Pro Leu Trp Val Ile Tyr Ile Arg Asn Gln 
                 85                  90                  95 

His Arg Trp Thr Leu Gly Leu Leu Ala Ser Lys Val Thr Ala Tyr Ile 
            100                 105                 110 

Phe Phe Cys Asn Ile Tyr Val Ser Ile Leu Phe Leu Cys Cys Ile Ser 
        115                 120                 125 

Cys Asp Arg Phe Val Ala Val Val Tyr Ala Leu Glu Ser Arg Gly Arg 
    130                 135                 140 

Arg Arg Arg Arg Thr Ala Ile Leu Ile Ser Ala Cys Ile Phe Ile Leu 
145                 150                 155                 160 

Val Gly Ile Val His Tyr Pro Val Phe Gln Thr Glu Asp Lys Glu Thr 
                165                 170                 175 

Cys Phe Asp Met Leu Gln Met Asp Ser Arg Ile Ala Gly Tyr Tyr Tyr 
            180                 185                 190 

Ala Arg Phe Thr Val Gly Phe Ala Ile Pro Leu Ser Ile Ile Ala Phe 
        195                 200                 205 

Thr Asn His Arg Ile Phe Arg Ser Ile Lys Gln Ser Met Gly Leu Ser 
    210                 215                 220 

Ala Ala Gln Lys Ala Lys Val Lys His Ser Ala Ile Ala Val Val Val 
225                 230                 235                 240 

Ile Phe Leu Val Cys Phe Ala Pro Tyr His Leu Val Leu Leu Val Lys 
                245                 250                 255 

Ala Ala Ala Phe Ser Tyr Tyr Arg Gly Asp Arg Asn Ala Met Cys Gly 
            260                 265                 270 

Leu Glu Glu Arg Leu Tyr Thr Ala Ser Val Val Phe Leu Cys Leu Ser 
        275                 280                 285 

Thr Val Asn Gly Val Ala Asp Pro Ile Ile Tyr Val Leu Ala Thr Asp 
    290                 295                 300 

His Ser Arg Gln Glu Val Ser Arg Ile His Lys Gly Trp Lys Glu Trp 
305                 310                 315                 320 

Ser Met Lys Thr Asp Val Thr Arg Leu Thr His Ser Arg Asp Thr Glu 
                325                 330                 335 

Glu Leu Gln Ser Pro Val Ala Leu Ala Asp His Tyr Thr Phe Ser Arg 
            340                 345                 350 

Pro Val His Pro Pro Gly Ser Pro Cys Pro Ala Lys Arg Leu Ile Glu 
        355                 360                 365 

Glu Ser Cys 
    370 

 
           
             25  
             1113  
             DNA  
             Homo sapiens  
           
            25 

atggcgaact atagccatgc agctgacaac attttgcaaa atctctcgcc tctaacagcc     60 

tttctgaaac tgacttcctt gggtttcata ataggagtca gcgtggtggg caacctcctg    120 

atctccattt tgctagtgaa agataagacc ttgcatagag caccttacta cttcctgttg    180 

gatctttgct gttcagatat cctcagatct gcaatttgtt tcccatttgt gttcaactct    240 

gtcaaaaatg gctctacctg gacttatggg actctgactt gcaaagtgat tgcctttctg    300 

ggggttttgt cctgtttcca cactgctttc atgctcttct gcatcagtgt caccagatac    360 

ttagctatcg cccatcaccg cttctataca aagaggctga ccttttggac gtgtctggct    420 

gtgatctgta tggtgtggac tctgtctgtg gccatggcat ttcccccggt tttagacgtg    480 

ggcacttact cattcattag ggaggaagat caatgcacct tccaacaccg ctccttcagg    540 

gctaatgatt ccttaggatt tatgctgctt cttgctctca tcctcctagc cacacagctt    600 

gtctacctca agctgatatt tttcgtccac gatcgaagaa aaatgaagcc agtccagttt    660 

gtagcagcag tcagccagaa ctggactttt catggtcctg gagccagtgg ccaggcagct    720 

gccaattggc tagcaggatt tggaaggggt cccacaccac ccaccttgct gggcatcagg    780 

caaaatgcaa acaccacagg cagaagaagg ctattggtct tagacgagtt caaaatggag    840 

aaaagaatca gcagaatgtt ctatataatg acttttctgt ttctaacctt gtggggcccc    900 

tacctggtgg cctgttattg gagagttttt gcaagagggc ctgtagtacc agggggattt    960 

ctaacagctg ctgtctggat gagttttgcc caagcaggaa tcaatccttt tgtctgcatt   1020 

ttctcaaaca gggagctgag gcgctgtttc agcacaaccc ttctttactg cagaaaatcc   1080 

aggttaccaa gggaacctta ctgtgttata tga                                1113 

 
           
             26  
             370  
             PRT  
             Homo sapiens  
           
            26 

Met Ala Asn Tyr Ser His Ala Ala Asp Asn Ile Leu Gln Asn Leu Ser 
  1               5                  10                  15 

Pro Leu Thr Ala Phe Leu Lys Leu Thr Ser Leu Gly Phe Ile Ile Gly 
             20                  25                  30 

Val Ser Val Val Gly Asn Leu Leu Ile Ser Ile Leu Leu Val Lys Asp 
         35                  40                  45 

Lys Thr Leu His Arg Ala Pro Tyr Tyr Phe Leu Leu Asp Leu Cys Cys 
     50                  55                  60 

Ser Asp Ile Leu Arg Ser Ala Ile Cys Phe Pro Phe Val Phe Asn Ser 
 65                  70                  75                  80 

Val Lys Asn Gly Ser Thr Trp Thr Tyr Gly Thr Leu Thr Cys Lys Val 
                 85                  90                  95 

Ile Ala Phe Leu Gly Val Leu Ser Cys Phe His Thr Ala Phe Met Leu 
            100                 105                 110 

Phe Cys Ile Ser Val Thr Arg Tyr Leu Ala Ile Ala His His Arg Phe 
        115                 120                 125 

Tyr Thr Lys Arg Leu Thr Phe Trp Thr Cys Leu Ala Val Ile Cys Met 
    130                 135                 140 

Val Trp Thr Leu Ser Val Ala Met Ala Phe Pro Pro Val Leu Asp Val 
145                 150                 155                 160 

Gly Thr Tyr Ser Phe Ile Arg Glu Glu Asp Gln Cys Thr Phe Gln His 
                165                 170                 175 

Arg Ser Phe Arg Ala Asn Asp Ser Leu Gly Phe Met Leu Leu Leu Ala 
            180                 185                 190 

Leu Ile Leu Leu Ala Thr Gln Leu Val Tyr Leu Lys Leu Ile Phe Phe 
        195                 200                 205 

Val His Asp Arg Arg Lys Met Lys Pro Val Gln Phe Val Ala Ala Val 
    210                 215                 220 

Ser Gln Asn Trp Thr Phe His Gly Pro Gly Ala Ser Gly Gln Ala Ala 
225                 230                 235                 240 

Ala Asn Trp Leu Ala Gly Phe Gly Arg Gly Pro Thr Pro Pro Thr Leu 
                245                 250                 255 

Leu Gly Ile Arg Gln Asn Ala Asn Thr Thr Gly Arg Arg Arg Leu Leu 
            260                 265                 270 

Val Leu Asp Glu Phe Lys Met Glu Lys Arg Ile Ser Arg Met Phe Tyr 
        275                 280                 285 

Ile Met Thr Phe Leu Phe Leu Thr Leu Trp Gly Pro Tyr Leu Val Ala 
    290                 295                 300 

Cys Tyr Trp Arg Val Phe Ala Arg Gly Pro Val Val Pro Gly Gly Phe 
305                 310                 315                 320 

Leu Thr Ala Ala Val Trp Met Ser Phe Ala Gln Ala Gly Ile Asn Pro 
                325                 330                 335 

Phe Val Cys Ile Phe Ser Asn Arg Glu Leu Arg Arg Cys Phe Ser Thr 
            340                 345                 350 

Thr Leu Leu Tyr Cys Arg Lys Ser Arg Leu Pro Arg Glu Pro Tyr Cys 
        355                 360                 365 

Val Ile 
    370 

 
           
             27  
             1080  
             DNA  
             Homo sapiens  
           
            27 

atgcaggtcc cgaacagcac cggcccggac aacgcgacgc tgcagatgct gcggaacccg     60 

gcgatcgcgg tggccctgcc cgtggtgtac tcgctggtgg cggcggtcag catcccgggc    120 

aacctcttct ctctgtgggt gctgtgccgg cgcatggggc ccagatcccc gtcggtcatc    180 

ttcatgatca acctgagcgt cacggacctg atgctggcca gcgtgttgcc tttccaaatc    240 

tactaccatt gcaaccgcca ccactgggta ttcggggtgc tgctttgcaa cgtggtgacc    300 

gtggcctttt acgcaaacat gtattccagc atcctcacca tgacctgtat cagcgtggag    360 

cgcttcctgg gggtcctgta cccgctcagc tccaagcgct ggcgccgccg tcgttacgcg    420 

gtggccgcgt gtgcagggac ctggctgctg ctcctgaccg ccctgtgccc gctggcgcgc    480 

accgatctca cctacccggt gcacgccctg ggcatcatca cctgcttcga cgtcctcaag    540 

tggacgatgc tccccagcgt ggccatgtgg gccgtgttcc tcttcaccat cttcatcctg    600 

ctgttcctca tcccgttcgt gatcaccgtg gcttgttaca cggccaccat cctcaagctg    660 

ttgcgcacgg aggaggcgca cggccgggag cagcggaggc gcgcggtggg cctggccgcg    720 

gtggtcttgc tggcctttgt cacctgcttc gcccccaaca acttcgtgct cctggcgcac    780 

atcgtgagcc gcctgttcta cggcaagagc tactaccacg tgtacaagct cacgctgtgt    840 

ctcagctgcc tcaacaactg tctggacccg tttgtttatt actttgcgtc ccgggaattc    900 

cagctgcgcc tgcgggaata tttgggctgc cgccgggtgc ccagagacac cctggacacg    960 

cgccgcgaga gcctcttctc cgccaggacc acgtccgtgc gctccgaggc cggtgcgcac   1020 

cctgaaggga tggagggagc caccaggccc ggcctccaga ggcaggagag tgtgttctga   1080 

 
           
             28  
             359  
             PRT  
             Homo sapiens  
           
            28 

Met Gln Val Pro Asn Ser Thr Gly Pro Asp Asn Ala Thr Leu Gln Met 
  1               5                  10                  15 

Leu Arg Asn Pro Ala Ile Ala Val Ala Leu Pro Val Val Tyr Ser Leu 
             20                  25                  30 

Val Ala Ala Val Ser Ile Pro Gly Asn Leu Phe Ser Leu Trp Val Leu 
         35                  40                  45 

Cys Arg Arg Met Gly Pro Arg Ser Pro Ser Val Ile Phe Met Ile Asn 
     50                  55                  60 

Leu Ser Val Thr Asp Leu Met Leu Ala Ser Val Leu Pro Phe Gln Ile 
 65                  70                  75                  80 

Tyr Tyr His Cys Asn Arg His His Trp Val Phe Gly Val Leu Leu Cys 
                 85                  90                  95 

Asn Val Val Thr Val Ala Phe Tyr Ala Asn Met Tyr Ser Ser Ile Leu 
            100                 105                 110 

Thr Met Thr Cys Ile Ser Val Glu Arg Phe Leu Gly Val Leu Tyr Pro 
        115                 120                 125 

Leu Ser Ser Lys Arg Trp Arg Arg Arg Arg Tyr Ala Val Ala Ala Cys 
    130                 135                 140 

Ala Gly Thr Trp Leu Leu Leu Leu Thr Ala Leu Cys Pro Leu Ala Arg 
145                 150                 155                 160 

Thr Asp Leu Thr Tyr Pro Val His Ala Leu Gly Ile Ile Thr Cys Phe 
                165                 170                 175 

Asp Val Leu Lys Trp Thr Met Leu Pro Ser Val Ala Met Trp Ala Val 
            180                 185                 190 

Phe Leu Phe Thr Ile Phe Ile Leu Leu Phe Leu Ile Pro Phe Val Ile 
        195                 200                 205 

Thr Val Ala Cys Tyr Thr Ala Thr Ile Leu Lys Leu Leu Arg Thr Glu 
    210                 215                 220 

Glu Ala His Gly Arg Glu Gln Arg Arg Arg Ala Val Gly Leu Ala Ala 
225                 230                 235                 240 

Val Val Leu Leu Ala Phe Val Thr Cys Phe Ala Pro Asn Asn Phe Val 
                245                 250                 255 

Leu Leu Ala His Ile Val Ser Arg Leu Phe Tyr Gly Lys Ser Tyr Tyr 
            260                 265                 270 

His Val Tyr Lys Leu Thr Leu Cys Leu Ser Cys Leu Asn Asn Cys Leu 
        275                 280                 285 

Asp Pro Phe Val Tyr Tyr Phe Ala Ser Arg Glu Phe Gln Leu Arg Leu 
    290                 295                 300 

Arg Glu Tyr Leu Gly Cys Arg Arg Val Pro Arg Asp Thr Leu Asp Thr 
305                 310                 315                 320 

Arg Arg Glu Ser Leu Phe Ser Ala Arg Thr Thr Ser Val Arg Ser Glu 
                325                 330                 335 

Ala Gly Ala His Pro Glu Gly Met Glu Gly Ala Thr Arg Pro Gly Leu 
            340                 345                 350 

Gln Arg Gln Glu Ser Val Phe 
        355 

 
           
             29  
             1503  
             DNA  
             Homo sapiens  
           
            29 

atggagcgtc cctgggagga cagcccaggc ccggaggggg cagctgaggg ctcgcctgtg     60 

ccagtcgccg ccggggcgcg ctccggtgcc gcggcgagtg gcacaggctg gcagccatgg    120 

gctgagtgcc cgggacccaa ggggaggggg caactgctgg cgaccgccgg ccctttgcgt    180 

cgctggcccg ccccctcgcc tgccagctcc agccccgccc ccggagcggc gtccgctcac    240 

tcggttcaag gcagcgcgac tgcgggtggc gcacgaccag ggcgcagacc ttggggcgcg    300 

cggcccatgg agtcggggct gctgcggccg gcgccggtga gcgaggtcat cgtcctgcat    360 

tacaactaca ccggcaagct ccgcggtgcg agctaccagc cgggtgccgg cctgcgcgcc    420 

gacgccgtgg tgtgcctggc ggtgtgcgcc ttcatcgtgc tagagaatct agccgtgttg    480 

ttggtgctcg gacgccaccc gcgcttccac gctcccatgt tcctgctcct gggcagcctc    540 

acgttgtcgg atctgctggc aggcgccgcc tacgccgcca acatcctact gtcggggccg    600 

ctcacgctga aactgtcccc cgcgctctgg ttcgcacggg agggaggcgt cttcgtggca    660 

ctcactgcgt ccgtgctgag cctcctggcc atcgcgctgg agcgcagcct caccatggcg    720 

cgcagggggc ccgcgcccgt ctccagtcgg gggcgcacgc tggcgatggc agccgcggcc    780 

tggggcgtgt cgctgctcct cgggctcctg ccagcgctgg gctggaattg cctgggtcgc    840 

ctggacgctt gctccactgt cttgccgctc tacgccaagg cctacgtgct cttctgcgtg    900 

ctcgccttcg tgggcatcct ggccgcgatc tgtgcactct acgcgcgcat ctactgccag    960 

gtacgcgcca acgcgcggcg cctgccggca cggcccggga ctgcggggac cacctcgacc   1020 

cgggcgcgtc gcaagccgcg ctctctggcc ttgctgcgca cgctcagcgt ggtgctcctg   1080 

gcctttgtgg catgttgggg ccccctcttc ctgctgctgt tgctcgacgt ggcgtgcccg   1140 

gcgcgcacct gtcctgtact cctgcaggcc gatcccttcc tgggactggc catggccaac   1200 

tcacttctga accccatcat ctacacgctc accaaccgcg acctgcgcca cgcgctcctg   1260 

cgcctggtct gctgcggacg ccactcctgc ggcagagacc cgagtggctc ccagcagtcg   1320 

gcgagcgcgg ctgaggcttc cgggggcctg cgccgctgcc tgcccccggg ccttgatggg   1380 

agcttcagcg gctcggagcg ctcatcgccc cagcgcgacg ggctggacac cagcggctcc   1440 

acaggcagcc ccggtgcacc cacagccgcc cggactctgg tatcagaacc ggctgcagac   1500 

tga                                                                 1503 

 
           
             30  
             500  
             PRT  
             Homo sapiens  
           
            30 

Met Glu Arg Pro Trp Glu Asp Ser Pro Gly Pro Glu Gly Ala Ala Glu 
  1               5                  10                  15 

Gly Ser Pro Val Pro Val Ala Ala Gly Ala Arg Ser Gly Ala Ala Ala 
             20                  25                  30 

Ser Gly Thr Gly Trp Gln Pro Trp Ala Glu Cys Pro Gly Pro Lys Gly 
         35                  40                  45 

Arg Gly Gln Leu Leu Ala Thr Ala Gly Pro Leu Arg Arg Trp Pro Ala 
     50                  55                  60 

Pro Ser Pro Ala Ser Ser Ser Pro Ala Pro Gly Ala Ala Ser Ala His 
 65                  70                  75                  80 

Ser Val Gln Gly Ser Ala Thr Ala Gly Gly Ala Arg Pro Gly Arg Arg 
                 85                  90                  95 

Pro Trp Gly Ala Arg Pro Met Glu Ser Gly Leu Leu Arg Pro Ala Pro 
            100                 105                 110 

Val Ser Glu Val Ile Val Leu His Tyr Asn Tyr Thr Gly Lys Leu Arg 
        115                 120                 125 

Gly Ala Ser Tyr Gln Pro Gly Ala Gly Leu Arg Ala Asp Ala Val Val 
    130                 135                 140 

Cys Leu Ala Val Cys Ala Phe Ile Val Leu Glu Asn Leu Ala Val Leu 
145                 150                 155                 160 

Leu Val Leu Gly Arg His Pro Arg Phe His Ala Pro Met Phe Leu Leu 
                165                 170                 175 

Leu Gly Ser Leu Thr Leu Ser Asp Leu Leu Ala Gly Ala Ala Tyr Ala 
            180                 185                 190 

Ala Asn Ile Leu Leu Ser Gly Pro Leu Thr Leu Lys Leu Ser Pro Ala 
        195                 200                 205 

Leu Trp Phe Ala Arg Glu Gly Gly Val Phe Val Ala Leu Thr Ala Ser 
    210                 215                 220 

Val Leu Ser Leu Leu Ala Ile Ala Leu Glu Arg Ser Leu Thr Met Ala 
225                 230                 235                 240 

Arg Arg Gly Pro Ala Pro Val Ser Ser Arg Gly Arg Thr Leu Ala Met 
                245                 250                 255 

Ala Ala Ala Ala Trp Gly Val Ser Leu Leu Leu Gly Leu Leu Pro Ala 
            260                 265                 270 

Leu Gly Trp Asn Cys Leu Gly Arg Leu Asp Ala Cys Ser Thr Val Leu 
        275                 280                 285 

Pro Leu Tyr Ala Lys Ala Tyr Val Leu Phe Cys Val Leu Ala Phe Val 
    290                 295                 300 

Gly Ile Leu Ala Ala Ile Cys Ala Leu Tyr Ala Arg Ile Tyr Cys Gln 
305                 310                 315                 320 

Val Arg Ala Asn Ala Arg Arg Leu Pro Ala Arg Pro Gly Thr Ala Gly 
                325                 330                 335 

Thr Thr Ser Thr Arg Ala Arg Arg Lys Pro Arg Ser Leu Ala Leu Leu 
            340                 345                 350 

Arg Thr Leu Ser Val Val Leu Leu Ala Phe Val Ala Cys Trp Gly Pro 
        355                 360                 365 

Leu Phe Leu Leu Leu Leu Leu Asp Val Ala Cys Pro Ala Arg Thr Cys 
    370                 375                 380 

Pro Val Leu Leu Gln Ala Asp Pro Phe Leu Gly Leu Ala Met Ala Asn 
385                 390                 395                 400 

Ser Leu Leu Asn Pro Ile Ile Tyr Thr Leu Thr Asn Arg Asp Leu Arg 
                405                 410                 415 

His Ala Leu Leu Arg Leu Val Cys Cys Gly Arg His Ser Cys Gly Arg 
            420                 425                 430 

Asp Pro Ser Gly Ser Gln Gln Ser Ala Ser Ala Ala Glu Ala Ser Gly 
        435                 440                 445 

Gly Leu Arg Arg Cys Leu Pro Pro Gly Leu Asp Gly Ser Phe Ser Gly 
    450                 455                 460 

Ser Glu Arg Ser Ser Pro Gln Arg Asp Gly Leu Asp Thr Ser Gly Ser 
465                 470                 475                 480 

Thr Gly Ser Pro Gly Ala Pro Thr Ala Ala Arg Thr Leu Val Ser Glu 
                485                 490                 495 

Pro Ala Ala Asp 
            500 

 
           
             31  
             1029  
             DNA  
             Homo sapiens  
           
            31 

atgcaagccg tcgacaatct cacctctgcg cctgggaaca ccagtctgtg caccagagac     60 

tacaaaatca cccaggtcct cttcccactg ctctacactg tcctgttttt tgttggactt    120 

atcacaaatg gcctggcgat gaggattttc tttcaaatcc ggagtaaatc aaactttatt    180 

atttttctta agaacacagt catttctgat cttctcatga ttctgacttt tccattcaaa    240 

attcttagtg atgccaaact gggaacagga ccactgagaa cttttgtgtg tcaagttacc    300 

tccgtcatat tttatttcac aatgtatatc agtatttcat tcctgggact gataactatc    360 

gatcgctacc agaagaccac caggccattt aaaacatcca accccaaaaa tctcttgggg    420 

gctaagattc tctctgttgt catctgggca ttcatgttct tactctcttt gcctaacatg    480 

attctgacca acaggcagcc gagagacaag aatgtgaaga aatgctcttt ccttaaatca    540 

gagttcggtc tagtctggca tgaaatagta aattacatct gtcaagtcat tttctggatt    600 

aatttcttaa ttgttattgt atgttataca ctcattacaa aagaactgta ccggtcatac    660 

gtaagaacga ggggtgtagg taaagtcccc aggaaaaagg tgaacgtcaa agttttcatt    720 

atcattgctg tattctttat ttgttttgtt cctttccatt ttgcccgaat tccttacacc    780 

ctgagccaaa cccgggatgt ctttgactgc actgctgaaa atactctgtt ctatgtgaaa    840 

gagagcactc tgtggttaac ttccttaaat gcatgcctgg atccgttcat ctattttttc    900 

ctttgcaagt ccttcagaaa ttccttgata agtatgctga agtgccccaa ttctgcaaca    960 

tctctgtccc aggacaatag gaaaaaagaa caggatggtg gtgacccaaa tgaagagact   1020 

ccaatgtaa                                                           1029 

 
           
             32  
             342  
             PRT  
             Homo sapiens  
           
            32 

Met Gln Ala Val Asp Asn Leu Thr Ser Ala Pro Gly Asn Thr Ser Leu 
  1               5                  10                  15 

Cys Thr Arg Asp Tyr Lys Ile Thr Gln Val Leu Phe Pro Leu Leu Tyr 
             20                  25                  30 

Thr Val Leu Phe Phe Val Gly Leu Ile Thr Asn Gly Leu Ala Met Arg 
         35                  40                  45 

Ile Phe Phe Gln Ile Arg Ser Lys Ser Asn Phe Ile Ile Phe Leu Lys 
     50                  55                  60 

Asn Thr Val Ile Ser Asp Leu Leu Met Ile Leu Thr Phe Pro Phe Lys 
 65                  70                  75                  80 

Ile Leu Ser Asp Ala Lys Leu Gly Thr Gly Pro Leu Arg Thr Phe Val 
                 85                  90                  95 

Cys Gln Val Thr Ser Val Ile Phe Tyr Phe Thr Met Tyr Ile Ser Ile 
            100                 105                 110 

Ser Phe Leu Gly Leu Ile Thr Ile Asp Arg Tyr Gln Lys Thr Thr Arg 
        115                 120                 125 

Pro Phe Lys Thr Ser Asn Pro Lys Asn Leu Leu Gly Ala Lys Ile Leu 
    130                 135                 140 

Ser Val Val Ile Trp Ala Phe Met Phe Leu Leu Ser Leu Pro Asn Met 
145                 150                 155                 160 

Ile Leu Thr Asn Arg Gln Pro Arg Asp Lys Asn Val Lys Lys Cys Ser 
                165                 170                 175 

Phe Leu Lys Ser Glu Phe Gly Leu Val Trp His Glu Ile Val Asn Tyr 
            180                 185                 190 

Ile Cys Gln Val Ile Phe Trp Ile Asn Phe Leu Ile Val Ile Val Cys 
        195                 200                 205 

Tyr Thr Leu Ile Thr Lys Glu Leu Tyr Arg Ser Tyr Val Arg Thr Arg 
    210                 215                 220 

Gly Val Gly Lys Val Pro Arg Lys Lys Val Asn Val Lys Val Phe Ile 
225                 230                 235                 240 

Ile Ile Ala Val Phe Phe Ile Cys Phe Val Pro Phe His Phe Ala Arg 
                245                 250                 255 

Ile Pro Tyr Thr Leu Ser Gln Thr Arg Asp Val Phe Asp Cys Thr Ala 
            260                 265                 270 

Glu Asn Thr Leu Phe Tyr Val Lys Glu Ser Thr Leu Trp Leu Thr Ser 
        275                 280                 285 

Leu Asn Ala Cys Leu Asp Pro Phe Ile Tyr Phe Phe Leu Cys Lys Ser 
    290                 295                 300 

Phe Arg Asn Ser Leu Ile Ser Met Leu Lys Cys Pro Asn Ser Ala Thr 
305                 310                 315                 320 

Ser Leu Ser Gln Asp Asn Arg Lys Lys Glu Gln Asp Gly Gly Asp Pro 
                325                 330                 335 

Asn Glu Glu Thr Pro Met 
            340 

 
           
             33  
             1077  
             DNA  
             Homo sapiens  
           
            33 

atgtcggtct gctaccgtcc cccagggaac gagacactgc tgagctggaa gacttcgcgg     60 

gccacaggca cagccttcct gctgctggcg gcgctgctgg ggctgcctgg caacggcttc    120 

gtggtgtgga gcttggcggg ctggcggcct gcacgggggc gaccgctggc ggccacgctt    180 

gtgctgcacc tggcgctggc cgacggcgcg gtgctgctgc tcacgccgct ctttgtggcc    240 

ttcctgaccc ggcaggcctg gccgctgggc caggcgggct gcaaggcggt gtactacgtg    300 

tgcgcgctca gcatgtacgc cagcgtgctg ctcaccggcc tgctcagcct gcagcgctgc    360 

ctcgcagtca cccgcccctt cctggcgcct cggctgcgca gcccggccct ggcccgccgc    420 

ctgctgctgg cggtctggct ggccgccctg ttgctcgccg tcccggccgc cgtctaccgc    480 

cacctgtgga gggaccgcgt atgccagctg tgccacccgt cgccggtcca cgccgccgcc    540 

cacctgagcc tggagactct gaccgctttc gtgcttcctt tcgggctgat gctcggctgc    600 

tacagcgtga cgctggcacg gctgcggggc gcccgctggg gctccgggcg gcacggggcg    660 

cgggtgggcc ggctggtgag cgccatcgtg cttgccttcg gcttgctctg ggccccctac    720 

cacgcagtca accttctgca ggcggtcgca gcgctggctc caccggaagg ggccttggcg    780 

aagctgggcg gagccggcca ggcggcgcga gcgggaacta cggccttggc cttcttcagt    840 

tctagcgtca acccggtgct ctacgtcttc accgctggag atctgctgcc ccgggcaggt    900 

ccccgtttcc tcacgcggct cttcgaaggc tctggggagg cccgaggggg cggccgctct    960 

agggaaggga ccatggagct ccgaactacc cctcagctga aagtggtggg gcagggccgc   1020 

ggcaatggag acccgggggg tgggatggag aaggacggtc cggaatggga cctttga      1077 

 
           
             34  
             358  
             PRT  
             Homo sapiens  
           
            34 

Met Ser Val Cys Tyr Arg Pro Pro Gly Asn Glu Thr Leu Leu Ser Trp 
  1               5                  10                  15 

Lys Thr Ser Arg Ala Thr Gly Thr Ala Phe Leu Leu Leu Ala Ala Leu 
             20                  25                  30 

Leu Gly Leu Pro Gly Asn Gly Phe Val Val Trp Ser Leu Ala Gly Trp 
         35                  40                  45 

Arg Pro Ala Arg Gly Arg Pro Leu Ala Ala Thr Leu Val Leu His Leu 
     50                  55                  60 

Ala Leu Ala Asp Gly Ala Val Leu Leu Leu Thr Pro Leu Phe Val Ala 
 65                  70                  75                  80 

Phe Leu Thr Arg Gln Ala Trp Pro Leu Gly Gln Ala Gly Cys Lys Ala 
                 85                  90                  95 

Val Tyr Tyr Val Cys Ala Leu Ser Met Tyr Ala Ser Val Leu Leu Thr 
            100                 105                 110 

Gly Leu Leu Ser Leu Gln Arg Cys Leu Ala Val Thr Arg Pro Phe Leu 
        115                 120                 125 

Ala Pro Arg Leu Arg Ser Pro Ala Leu Ala Arg Arg Leu Leu Leu Ala 
    130                 135                 140 

Val Trp Leu Ala Ala Leu Leu Leu Ala Val Pro Ala Ala Val Tyr Arg 
145                 150                 155                 160 

His Leu Trp Arg Asp Arg Val Cys Gln Leu Cys His Pro Ser Pro Val 
                165                 170                 175 

His Ala Ala Ala His Leu Ser Leu Glu Thr Leu Thr Ala Phe Val Leu 
            180                 185                 190 

Pro Phe Gly Leu Met Leu Gly Cys Tyr Ser Val Thr Leu Ala Arg Leu 
        195                 200                 205 

Arg Gly Ala Arg Trp Gly Ser Gly Arg His Gly Ala Arg Val Gly Arg 
    210                 215                 220 

Leu Val Ser Ala Ile Val Leu Ala Phe Gly Leu Leu Trp Ala Pro Tyr 
225                 230                 235                 240 

His Ala Val Asn Leu Leu Gln Ala Val Ala Ala Leu Ala Pro Pro Glu 
                245                 250                 255 

Gly Ala Leu Ala Lys Leu Gly Gly Ala Gly Gln Ala Ala Arg Ala Gly 
            260                 265                 270 

Thr Thr Ala Leu Ala Phe Phe Ser Ser Ser Val Asn Pro Val Leu Tyr 
        275                 280                 285 

Val Phe Thr Ala Gly Asp Leu Leu Pro Arg Ala Gly Pro Arg Phe Leu 
    290                 295                 300 

Thr Arg Leu Phe Glu Gly Ser Gly Glu Ala Arg Gly Gly Gly Arg Ser 
305                 310                 315                 320 

Arg Glu Gly Thr Met Glu Leu Arg Thr Thr Pro Gln Leu Lys Val Val 
                325                 330                 335 

Gly Gln Gly Arg Gly Asn Gly Asp Pro Gly Gly Gly Met Glu Lys Asp 
            340                 345                 350 

Gly Pro Glu Trp Asp Leu 
        355 

 
           
             35  
             1005  
             DNA  
             Homo sapiens  
           
            35 

atgctgggga tcatggcatg gaatgcaact tgcaaaaact ggctggcagc agaggctgcc     60 

ctggaaaagt actacctttc cattttttat gggattgagt tcgttgtggg agtccttgga    120 

aataccattg ttgtttacgg ctacatcttc tctctgaaga actggaacag cagtaatatt    180 

tatctcttta acctctctgt ctctgactta gcttttctgt gcaccctccc catgctgata    240 

aggagttatg ccaatggaaa ctggatatat ggagacgtgc tctgcataag caaccgatat    300 

gtgcttcatg ccaacctcta taccagcatt ctctttctca cttttatcag catagatcga    360 

tacttgataa ttaagtatcc tttccgagaa caccttctgc aaaagaaaga gtttgctatt    420 

ttaatctcct tggccatttg ggttttagta accttagagt tactacccat acttcccctt    480 

ataaatcctg ttataactga caatggcacc acctgtaatg attttgcaag ttctggagac    540 

cccaactaca acctcattta cagcatgtgt ctaacactgt tggggttcct tattcctctt    600 

tttgtgatgt gtttctttta ttacaagatt gctctcttcc taaagcagag gaataggcag    660 

gttgctactg ctctgcccct tgaaaagcct ctcaacttgg tcatcatggc agtggtaatc    720 

ttctctgtgc tttttacacc ctatcacgtc atgcggaatg tgaggatcgc ttcacgcctg    780 

gggagttgga agcagtatca gtgcactcag gtcgtcatca actcctttta cattgtgaca    840 

cggcctttgg cctttctgaa cagtgtcatc aaccctgtct tctattttct tttgggagat    900 

cacttcaggg acatgctgat gaatcaactg agacacaact tcaaatccct tacatccttt    960 

agcagatggg ctcatgaact cctactttca ttcagagaaa agtga                   1005 

 
           
             36  
             334  
             PRT  
             Homo sapiens  
           
            36 

Met Leu Gly Ile Met Ala Trp Asn Ala Thr Cys Lys Asn Trp Leu Ala 
  1               5                  10                  15 

Ala Glu Ala Ala Leu Glu Lys Tyr Tyr Leu Ser Ile Phe Tyr Gly Ile 
             20                  25                  30 

Glu Phe Val Val Gly Val Leu Gly Asn Thr Ile Val Val Tyr Gly Tyr 
         35                  40                  45 

Ile Phe Ser Leu Lys Asn Trp Asn Ser Ser Asn Ile Tyr Leu Phe Asn 
     50                  55                  60 

Leu Ser Val Ser Asp Leu Ala Phe Leu Cys Thr Leu Pro Met Leu Ile 
 65                  70                  75                  80 

Arg Ser Tyr Ala Asn Gly Asn Trp Ile Tyr Gly Asp Val Leu Cys Ile 
                 85                  90                  95 

Ser Asn Arg Tyr Val Leu His Ala Asn Leu Tyr Thr Ser Ile Leu Phe 
            100                 105                 110 

Leu Thr Phe Ile Ser Ile Asp Arg Tyr Leu Ile Ile Lys Tyr Pro Phe 
        115                 120                 125 

Arg Glu His Leu Leu Gln Lys Lys Glu Phe Ala Ile Leu Ile Ser Leu 
    130                 135                 140 

Ala Ile Trp Val Leu Val Thr Leu Glu Leu Leu Pro Ile Leu Pro Leu 
145                 150                 155                 160 

Ile Asn Pro Val Ile Thr Asp Asn Gly Thr Thr Cys Asn Asp Phe Ala 
                165                 170                 175 

Ser Ser Gly Asp Pro Asn Tyr Asn Leu Ile Tyr Ser Met Cys Leu Thr 
            180                 185                 190 

Leu Leu Gly Phe Leu Ile Pro Leu Phe Val Met Cys Phe Phe Tyr Tyr 
        195                 200                 205 

Lys Ile Ala Leu Phe Leu Lys Gln Arg Asn Arg Gln Val Ala Thr Ala 
    210                 215                 220 

Leu Pro Leu Glu Lys Pro Leu Asn Leu Val Ile Met Ala Val Val Ile 
225                 230                 235                 240 

Phe Ser Val Leu Phe Thr Pro Tyr His Val Met Arg Asn Val Arg Ile 
                245                 250                 255 

Ala Ser Arg Leu Gly Ser Trp Lys Gln Tyr Gln Cys Thr Gln Val Val 
            260                 265                 270 

Ile Asn Ser Phe Tyr Ile Val Thr Arg Pro Leu Ala Phe Leu Asn Ser 
        275                 280                 285 

Val Ile Asn Pro Val Phe Tyr Phe Leu Leu Gly Asp His Phe Arg Asp 
    290                 295                 300 

Met Leu Met Asn Gln Leu Arg His Asn Phe Lys Ser Leu Thr Ser Phe 
305                 310                 315                 320 

Ser Arg Trp Ala His Glu Leu Leu Leu Ser Phe Arg Glu Lys 
                325                 330 

 
           
             37  
             1296  
             DNA  
             Homo sapiens  
           
            37 

atgcaggcgc ttaacattac cccggagcag ttctctcggc tgctgcggga ccacaacctg     60 

acgcgggagc agttcatcgc tctgtaccgg ctgcgaccgc tcgtctacac cccagagctg    120 

ccgggacgcg ccaagctggc cctcgtgctc accggcgtgc tcatcttcgc cctggcgctc    180 

tttggcaatg ctctggtgtt ctacgtggtg acccgcagca aggccatgcg caccgtcacc    240 

aacatcttta tctgctcctt ggcgctcagt gacctgctca tcaccttctt ctgcattccc    300 

gtcaccatgc tccagaacat ttccgacaac tggctggggg gtgctttcat ttgcaagatg    360 

gtgccatttg tccagtctac cgctgttgtg acagaaatgc tcactatgac ctgcattgct    420 

gtggaaaggc accagggact tgtgcatcct tttaaaatga agtggcaata caccaaccga    480 

agggctttca caatgctagg tgtggtctgg ctggtggcag tcatcgtagg atcacccatg    540 

tggcacgtgc aacaacttga gatcaaatat gacttcctat atgaaaagga acacatctgc    600 

tgcttagaag agtggaccag ccctgtgcac cagaagatct acaccacctt catccttgtc    660 

atcctcttcc tcctgcctct tatggtgatg cttattctgt acagtaaaat tggttatgaa    720 

ctttggataa agaaaagagt tggggatggt tcagtgcttc gaactattca tggaaaagaa    780 

atgtccaaaa tagccaggaa gaagaaacga gctgtcatta tgatggtgac agtggtggct    840 

ctctttgctg tgtgctgggc accattccat gttgtccata tgatgattga atacagtaat    900 

tttgaaaagg aatatgatga tgtcacaatc aagatgattt ttgctatcgt gcaaattatt    960 

ggattttcca actccatctg taatcccatt gtctatgcat ttatgaatga aaacttcaaa   1020 

aaaaatgttt tgtctgcagt ttgttattgc atagtaaata aaaccttctc tccagcacaa   1080 

aggcatggaa attcaggaat tacaatgatg cggaagaaag caaagttttc cctcagagag   1140 

aatccagtgg aggaaaccaa aggagaagca ttcagtgatg gcaacattga agtcaaattg   1200 

tgtgaacaga cagaggagaa gaaaaagctc aaacgacatc ttgctctctt taggtctgaa   1260 

ctggctgaga attctccttt agacagtggg cattaa                             1296 

 
           
             38  
             431  
             PRT  
             Homo sapiens  
           
            38 

Met Gln Ala Leu Asn Ile Thr Pro Glu Gln Phe Ser Arg Leu Leu Arg 
  1               5                  10                  15 

Asp His Asn Leu Thr Arg Glu Gln Phe Ile Ala Leu Tyr Arg Leu Arg 
             20                  25                  30 

Pro Leu Val Tyr Thr Pro Glu Leu Pro Gly Arg Ala Lys Leu Ala Leu 
         35                  40                  45 

Val Leu Thr Gly Val Leu Ile Phe Ala Leu Ala Leu Phe Gly Asn Ala 
     50                  55                  60 

Leu Val Phe Tyr Val Val Thr Arg Ser Lys Ala Met Arg Thr Val Thr 
 65                  70                  75                  80 

Asn Ile Phe Ile Cys Ser Leu Ala Leu Ser Asp Leu Leu Ile Thr Phe 
                 85                  90                  95 

Phe Cys Ile Pro Val Thr Met Leu Gln Asn Ile Ser Asp Asn Trp Leu 
            100                 105                 110 

Gly Gly Ala Phe Ile Cys Lys Met Val Pro Phe Val Gln Ser Thr Ala 
        115                 120                 125 

Val Val Thr Glu Met Leu Thr Met Thr Cys Ile Ala Val Glu Arg His 
    130                 135                 140 

Gln Gly Leu Val His Pro Phe Lys Met Lys Trp Gln Tyr Thr Asn Arg 
145                 150                 155                 160 

Arg Ala Phe Thr Met Leu Gly Val Val Trp Leu Val Ala Val Ile Val 
                165                 170                 175 

Gly Ser Pro Met Trp His Val Gln Gln Leu Glu Ile Lys Tyr Asp Phe 
            180                 185                 190 

Leu Tyr Glu Lys Glu His Ile Cys Cys Leu Glu Glu Trp Thr Ser Pro 
        195                 200                 205 

Val His Gln Lys Ile Tyr Thr Thr Phe Ile Leu Val Ile Leu Phe Leu 
    210                 215                 220 

Leu Pro Leu Met Val Met Leu Ile Leu Tyr Ser Lys Ile Gly Tyr Glu 
225                 230                 235                 240 

Leu Trp Ile Lys Lys Arg Val Gly Asp Gly Ser Val Leu Arg Thr Ile 
                245                 250                 255 

His Gly Lys Glu Met Ser Lys Ile Ala Arg Lys Lys Lys Arg Ala Val 
            260                 265                 270 

Ile Met Met Val Thr Val Val Ala Leu Phe Ala Val Cys Trp Ala Pro 
        275                 280                 285 

Phe His Val Val His Met Met Ile Glu Tyr Ser Asn Phe Glu Lys Glu 
    290                 295                 300 

Tyr Asp Asp Val Thr Ile Lys Met Ile Phe Ala Ile Val Gln Ile Ile 
305                 310                 315                 320 

Gly Phe Ser Asn Ser Ile Cys Asn Pro Ile Val Tyr Ala Phe Met Asn 
                325                 330                 335 

Glu Asn Phe Lys Lys Asn Val Leu Ser Ala Val Cys Tyr Cys Ile Val 
            340                 345                 350 

Asn Lys Thr Phe Ser Pro Ala Gln Arg His Gly Asn Ser Gly Ile Thr 
        355                 360                 365 

Met Met Arg Lys Lys Ala Lys Phe Ser Leu Arg Glu Asn Pro Val Glu 
    370                 375                 380 

Glu Thr Lys Gly Glu Ala Phe Ser Asp Gly Asn Ile Glu Val Lys Leu 
385                 390                 395                 400 

Cys Glu Gln Thr Glu Glu Lys Lys Lys Leu Lys Arg His Leu Ala Leu 
                405                 410                 415 

Phe Arg Ser Glu Leu Ala Glu Asn Ser Pro Leu Asp Ser Gly His 
            420                 425                 430 

 
           
             39  
             24  
             DNA  
             Homo sapiens  
           
            39 

ctgtgtacag cagttcgcag agtg                                            24 

 
           
             40  
             24  
             DNA  
             Homo sapiens  
           
            40 

gagtgccagg cagagcaggt agac                                            24 

 
           
             41  
             31  
             DNA  
             Homo sapiens  
           
            41 

cccgaattcc tgcttgctcc cagcttggcc c                                    31 

 
           
             42  
             32  
             DNA  
             Homo sapiens  
           
            42 

tgtggatcct gctgtcaaag gtcccattcc gg                                   32 

 
           
             43  
             20  
             DNA  
             Homo sapiens  
           
            43 

tcacaatgct aggtgtggtc                                                 20 

 
           
             44  
             22  
             DNA  
             Homo sapiens  
           
            44 

tgcatagaca atgggattac ag                                              22 

 
           
             45  
             511  
             DNA  
             Homo sapiens  
           
            45 

tcacaatgct aggtgtggtc tggctggtgg cagtcatcgt aggatcaccc atgtggcacg     60 

tgcaacaact tgagatcaaa tatgacttcc tatatgaaaa ggaacacatc tgctgcttag    120 

aagagtggac cagccctgtg caccagaaga tctacaccac cttcatcctt gtcatcctct    180 

tcctcctgcc tcttatggtg atgcttattc tgtacgtaaa attggttatg aactttggat    240 

aaagaaaaga gttggggatg gttcagtgct tcgaactatt catggaaaag aaatgtccaa    300 

aatagccagg aagaagaaac gagctgtcat tatgatggtg acagtggtgg ctctctttgc    360 

tgtgtgctgg gcaccattcc atgttgtcca tatgatgatt gaatacagta attttgaaaa    420 

ggaatatgat gatgtcacaa tcaagatgat ttttgctatc gtgcaaatta ttggattttc    480 

caactccatc tgtaatccca ttgtctatgc a                                   511 

 
           
             46  
             21  
             DNA  
             Homo sapiens  
           
            46 

ctgcttagaa gagtggacca g                                               21 

 
           
             47  
             22  
             DNA  
             Homo sapiens  
           
            47 

ctgtgcacca gaagatctac ac                                              22 

 
           
             48  
             21  
             DNA  
             Homo sapiens  
           
            48 

caaggatgaa ggtggtgtag a                                               21 

 
           
             49  
             23  
             DNA  
             Homo sapiens  
           
            49 

gtgtagatct tctggtgcac agg                                             23 

 
           
             50  
             21  
             DNA  
             Homo sapiens  
           
            50 

gcaatgcagg tcatagtgag c                                               21 

 
           
             51  
             27  
             DNA  
             Homo sapiens  
           
            51 

tggagcatgg tgacgggaat gcagaag                                         27 

 
           
             52  
             27  
             DNA  
             Homo sapiens  
           
            52 

gtgatgagca ggtcactgag cgccaag                                         27 

 
           
             53  
             23  
             DNA  
             Homo sapiens  
           
            53 

gcaatgcagg cgcttaacat tac                                             23 

 
           
             54  
             22  
             DNA  
             Homo sapiens  
           
            54 

ttgggttaca atctgaaggg ca                                              22 

 
           
             55  
             23  
             DNA  
             Homo sapiens  
           
            55 

actccgtgtc cagcaggact ctg                                             23 

 
           
             56  
             24  
             DNA  
             Homo sapiens  
           
            56 

tgcgtgttcc tggaccctca cgtg                                            24 

 
           
             57  
             29  
             DNA  
             Homo sapiens  
           
            57 

caggccttgg attttaatgt cagggatgg                                       29 

 
           
             58  
             27  
             DNA  
             Homo sapiens  
           
            58 

ggagagtcag ctctgaaaga attcagg                                         27 

 
           
             59  
             27  
             DNA  
             Homo sapiens  
           
            59 

tgatgtgatg ccagatacta atagcac                                         27 

 
           
             60  
             27  
             DNA  
             Homo sapiens  
           
            60 

cctgattcat ttaggtgaga ttgagac                                         27 

 
           
             61  
             21  
             DNA  
             Homo sapiens  
           
            61 

gacaggtacc ttgccatcaa g                                               21 

 
           
             62  
             22  
             DNA  
             Homo sapiens  
           
            62 

ctgcacaatg ccagtgataa gg                                              22 

 
           
             63  
             27  
             DNA  
             Homo sapiens  
           
            63 

ctgacttctt gttcctggca gcagcgg                                         27 

 
           
             64  
             27  
             DNA  
             Homo sapiens  
           
            64 

agaccagcca gggcacgctg aagagtg                                         27 

 
           
             65  
             32  
             DNA  
             Homo sapiens  
           
            65 

gatcaagctt ccatcctact gaaaccatgg tc                                   32 

 
           
             66  
             35  
             DNA  
             Homo sapiens  
           
            66 

gatcagatct cagttccaat attcacacca ccgtc                                35 

 
           
             67  
             22  
             DNA  
             Homo sapiens  
           
            67 

ctggtgtgct ccatggcatc cc                                              22 

 
           
             68  
             22  
             DNA  
             Homo sapiens  
           
            68 

gtaagcctcc cagaacgaga gg                                              22 

 
           
             69  
             24  
             DNA  
             Homo sapiens  
           
            69 

cagcgcaggg tgaagcctga gagc                                            24 

 
           
             70  
             24  
             DNA  
             Homo sapiens  
           
            70 

ggcacctgct gtgacctgtg cagg                                            24 

 
           
             71  
             22  
             DNA  
             Homo sapiens  
           
            71 

gtcctgccac ttcgagacat gg                                              22 

 
           
             72  
             23  
             DNA  
             Homo sapiens  
           
            72 

gaaacttctc tgcccttacc gtc                                             23 

 
           
             73  
             26  
             DNA  
             Homo sapiens  
           
            73 

ccaacaccag catccatggc atcaag                                          26 

 
           
             74  
             27  
             DNA  
             Homo sapiens  
           
            74 

ggagagtcag ctctgaaaga attcagg                                         27