Abstract:
The present invention relates an isolated promoter region of the mammalian transcription factor FOXC2. The invention also relates to screening methods for agents modulating the expression of FOXC2 and thereby being potentially useful for the treatment of medical conditions related to obesity. The invention further relates to a previously unknown variant of the human FOXC2 gene, derived via the use of an alternative promoter, which produces an additional exon that generates a distinct open reading frame via splicing. The alternative gene encodes a variant of the FOXC2 transcription factor, which is lacking a part of the DNA-binding domain and consequently has a potential regulatory function.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application claims priority from Swedish Patent Application No. 0003435-5, filed Sep. 26, 2000, U.S. Provisional Patent Application Serial No. 60/238,897, filed Oct. 10, 2000, and Swedish Patent Application No. 0004102-0, filed Nov. 9, 2000. These applications are incorporated herein by reference in their entirety. 
     
    
     
       TECHNICAL FIELD  
         [0002]    The present invention relates an isolated promoter region of the mammalian transcription factor FOXC2. The invention also relates to screening methods for agents modulating the expression of FOXC2 and thereby being potentially useful for the treatment of medical conditions related to obesity. The invention further relates to a previously unknown variant of the human FOXC2 gene, derived via the use of an alternative promoter, which produces an additional exon that generates a distinct open reading frame via splicing. The alternative gene encodes a variant of the FOXC2 transcription factor, which is lacking a part of the DNA-binding domain and consequently has a potential regulatory function.  
         BACKGROUND  
         [0003]    More than half of the men and women in the United States, 30 years of age and older, are now considered overweight, and nearly one-quarter are clinically obese. This high prevalence has led to increases in the medical conditions that often accompany obesity, especially non-insulin dependent diabetes mellitus (NIDDM), hypertension, cardiovascular disorders, and certain cancers. Obesity results from a chronic imbalance between energy intake (feeding) and energy expenditure. To better understand the mechanisms that lead to obesity and to develop strategies in certain patient populations to control obesity, there is a need to develop a better underlying knowledge of the molecular events that regulate the differentiation of preadipocytes and stem cells to adipocytes, the major component of adipose tissue.  
           [0004]    The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key players in a wide array of developmental processes (for a review, see Massari &amp; Murre (2000) Mol. Cell. Biol. 20: 429-440). Over 240 HLH proteins have been identified to date in organisms ranging from the yeast  Saccharomyces cerevisiae  to humans. Studies in  Xenopus laevis, Drosophila melanogaster,  and mice have convincingly demonstrated that HLH proteins are intimately involved in developmental events such as cellular differentiation, lineage commitment, and sex determination. In multicellular organisms, HLH factors are required for a multitude of important developmental processes, including neurogenesis, myogenesis, hematopoiesis, and pancreatic development.  
           [0005]    The winged helix/forkhead class of transcription factors is characterized by a 100-amino acid, monomeric DNA-binding domain. X-ray crystallography of the forkhead domain from HNF-3γ has revealed a three-dimensional structure, the “winged helix”, in which two loops (wings) are connected on the C-terminal side of the helix-loop-helix (for reviews, see Brennan, R. G. (1993) Cell 74: 773-776; and Lai, E. et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 10421-10423).  
           [0006]    The isolation of the mouse mesenchyme forkhead-1 (MFH-1) and the corresponding human (FKHL14) chromosomal genes is disclosed by Miura, N. et al. (1993) FEBS letters 326: 171-176; and (1997) Genomics 41: 489-492. The nucleotide sequences of the mouse MFH-1 gene and the human FKHL14 gene have been deposited with the EMBL/GenBank Data Libraries under accession Nos. Y08222 (SEQ ID NO:5) and Y08223 (SEQ ID NO:8), respectively. A corresponding gene has been identified in  Gallus gallus  (GenBank accession numbers U37273 and U95823).  
           [0007]    The International Patent Application WO 98/54216 discloses a gene encoding a Forkhead-Related Activator (FREAC)-11 (also known as S12), which is identical with the polypeptide encoded by the human FKHL14 gene disclosed by Miura, supra. This transcription factor is expressed in adipose tissue and involved in lipid metabolism and adipocyte differentiation (cf. Swedish patent application No. 0000531-4, filed Feb. 18, 2000).  
           [0008]    The nomenclature for the winged helix/forkhead transcription factors has been standardized and Fox (Forkhead Box) has been adopted as the unified symbol (Kaestner et al. (2000) Genes &amp; Development 14: 142-146; see also htpp.//www.biology.pomona.edu/fox). It has been agreed that the genes previously designated MFH-1 and FKHL14 (as well as FREAC-11 and S12) should be designated FOXC2. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0009]    [0009]FIG. 1 shows the general structure of the human FOXC2 gene.  
         [0010]    [0010]FIG. 2 illustrates the results from phylogenetic footprinting experiments. Shown is the fraction conserved (1.0=100%) between mouse FoxC2 and human FOXC2 sequences in the alignment generated with Clustal. Solid (bold) line indicates the fraction of the human sequence which is identical to the mouse within a 200 bp “window” over the human sequence in the alignment. The weak (dotted) line is set to −0.05 when the sliding window contains human exon sequence and to −0.1 when the window is entirely composed of exon sequence. Regions containing local maxima or exceeding a conservation fraction of 0.7 are likely to be functional and are classified as “predicted regulatory regions”.  
         [0011]    [0011]FIG. 3 illustrates the predicted “enhancer” region in the human FOXC2 gene (HUMAN: nucleotides 200-475 of SEQ ID NO:1; MOUSE: nucleotides 174-461 of SEQ ID NO:5). Underlined sequences indicate likely transcription factor binding sites. Boxed sequence indicates exon sequence.  
         [0012]    Splice=sequence predicted as splice site in the alternatively spliced gene;  
         [0013]    E-box-like=sequence resembling the “E-box” motif CANNTG known as a target for DNA binding proteins containing a helix-loop-helix domain (often associated with the activation of cell-type specific gene transcription during tissue differentiation; see Massari &amp; Murre (2000) Mol. Cell. Biol. 20: 429-440)  
         [0014]    Forkhead-like=sequence resembling binding site for the winged helix/forkhead class of transcription factors;  
         [0015]    Ets-like=sequence resembling consensus binding site for ETS-domain transcription factor family (see Sharrocks et al. (1997) Int. J. Biochem. Cell Biol. 29, 1371-1387).  
         [0016]    [0016]FIG. 4 illustrates the predicted “promoter” region in the human FOXC2 gene (HUMAN: nucleotides 1251-1763 of SEQ ID NO:1; MOUSE: nucleotides 1126-1662 of SEQ ID NO:5). Underlined sequence indicates exon sequences. Boxed sequences indicate conserved block (potential transcription factor binding sites). 
     
    
     DESCRIPTION OF THE INVENTION  
       [0017]    According to the present invention, the partially known sequence (SEQ ID NO: 8) of human FOXC2 gene has been extended. In the previously unknown region of the gene, differentially conserved regions, consistent with regulatory function, have been identified. Further, an alternative transcript has been identified, which includes the use of at least two exons. The putative regulatory enhancer is immediately adjacent to the newly discovered alternative exon, suggesting that it may play a role in the alternative selection of transcript classes.  
         [0018]    Modulation of the FOXC2 regulation is expected to have therapeutic value in type II diabetes; obesity, hypercholesterolemia, and other cardiovascular diseases or dyslipidemias.  
         [0019]    Consequently, in a first aspect this invention provides an isolated human FOXC2 promoter region comprising a sequence selected from:  
         [0020]    (a) the nucleotide sequence set forth as positions 1250 to 2235, such as positions 1250 to 1749 or positions 1692 to 1703, in SEQ ID NO:1, or a fragment thereof exhibiting FOXC2 promoter activity;  
         [0021]    (b) the complementary strand of (a); and  
         [0022]    (c) nucleotide sequences capable of hybridizing, under stringent hybridization conditions, to a nucleotide sequence as defined in (a) or (b).  
         [0023]    An “isolated” nucleic acid is a nucleic acid molecule the structure of which is not identical to that of a naturally occurring nucleic acid or to that of any fragment of a naturally occurring genomic nucleic acid spanning more than one gene.  
         [0024]    “Stringent” hybridization conditions are hybridization in 6× SSC at 45° C., followed by one or more washes in 0.2× SSC, 0.1% SDS at 65° C.  
         [0025]    “Promoter region” refers to a region of DNA that functions to control the transcription of one or more coding sequences, and is structurally identified by the presence of a binding site for DNA-dependent RNA polymerase and of other DNA sequences on the same molecule which interact to regulate promoter function.  
         [0026]    Another aspect of the invention is a recombinant construct comprising the human FOXC2 promoter region as defined above. In the said recombinant construct, the human FOXC2 promoter region can be operably linked to a gene encoding a detectable product, such as the human FOXC2 gene, or a reporter gene. The term “operably linked” as used herein means functionally fusing a promoter with a structural gene in the proper frame to express the structural gene under control of the promoter. As used herein, the term “reporter gene” means a gene encoding a gene product that can be identified using simple, inexpensive methods or reagents and that can be operably linked to the human FOXC2 promoter region or an active fragment thereof. Reporter genes such as, for example, a luciferase, β-galactosidase, alkaline phosphatase, or green fluorescent protein reporter gene, can be used to determine transcriptional activity in screening assays according to the invention (see, for example, Goeddel (ed.), Methods Enzymol., Vol. 185, San Diego: Academic Press, Inc. (1990); see also Sambrook, supra).  
         [0027]    The invention also provides a vector comprising the recombinant construct as defined above, as well as a host cell stably transformed with such a vector, or generally with the recombinant construct according to the invention. The term “vector” refers to any carrier of exogenous DNA that is useful for transferring the DNA to a host cell for replication and/or appropriate expression of the exogenous DNA by the host cell.  
         [0028]    In another aspect, the invention provides a method for identification of an agent regulating FOXC2 promoter activity, said method comprising the steps: (i) contacting a candidate agent with a human FOXC2 promoter region as defined above; and (ii) determining whether said candidate agent modulates expression of the FOXC2 gene, such modulation being indicative for an agent capable of regulating FOXC2 promoter activity. As used herein, the term “agent” means a biological or chemical compound such as a simple or complex organic molecule, a peptide, a protein or an oligonucleotide.  
         [0029]    A transfection assay can be a particularly useful screening assay for identifying an effective agent modulating and/or regulating FOXC2 promoter activity. In a transfection assay, a nucleic acid containing a gene, e.g. a reporter gene, operably linked to a human FOXC2 promoter or an active fragment thereof, is transfected into the desired cell type. A test level of reporter gene expression is assayed in the presence of a candidate agent and compared to a control level of expression. An effective agent is identified as an agent that results in a test level of expression that is different than a control level of reporter gene expression, which is the level of expression determined in the absence of the agent. Methods for transfecting cells and a variety of convenient reporter genes are well known in the art (see, for example, Goeddel (ed.), Methods Enzymol., Vol. 185, San Diego: Academic Press, Inc. (1990); see also Sambrook, supra). Consequently, the said method could e.g. comprising assaying reporter gene expression in a host cell, stably transformed with a recombinant construct comprising the human FOXC2 promoter, in the presence and absence of a candidate agent, wherein an effect on the test level of expression as compared to control level of expression is indicative of an agent capable of regulating FOXC2 promoter activity.  
         [0030]    Methods for identification of polypeptides regulating FOXC2 promoter activity could include various techniques known in the art, such as the yeast one-hybrid system (see: Li &amp; Herskowitz (1993) Science 262, 1870-1874) to identify proteins binding specific sequences from the FOXC2 regulatory region, biochemical purification of proteins which bind to the regulatory region, the use of a “southwestern” cloning strategy (see e.g. Hai et al. (1989) Genes &amp; Development 3: 2083-2090) in which a pool of bacteria infected with a “phage library” are induced to express the encoded protein and probed with radioactive DNA sequences from the FOXC2 regulatory regions to identify binding proteins.  
         [0031]    In a further aspect, the invention provides an isolated human FOXC2 enhancer region comprising a sequence selected from:  
         [0032]    (a) the nucleotide sequence set forth as positions 216 to 475, such as positions 223 to 231, positions 359 to 375, positions 378 to 402, or positions 403 to 423, in SEQ ID NO:1, or a fragment thereof exhibiting FOXC2 enhancer activity;  
         [0033]    (b) the complementary strand of (a); and  
         [0034]    (c) nucleotide sequences capable of hybridizing, under stringent hybridization conditions, to a nucleotide sequence as defined in (a) or (b).  
         [0035]    “Enhancer region” refers to a region of DNA that functions to control the transcription of one or more coding sequences.  
         [0036]    As described above for the human FOXC2 promoter region, the invention further provides a recombinant construct comprising a human FOXC2 enhancer region, a vector comprising the said recombinant construct, as well as a host cell stably transformed with said vector or with said recombinant construct.  
         [0037]    Further, the invention provides a method for identification of an agent regulating FOXC2 enhancer activity, said method comprising the steps: (i) contacting a candidate agent with the human FOXC2 enhancer region as defined above; and (ii) determining whether said candidate agent modulates expression of the FOXC2 gene, such modulation being indicative for an agent capable of regulating FOXC2 enhancer activity. It will be understood by the skilled person that known steps are available for performing such a method. For instance, a “panel” of constructs which include a variety of mutations and deletions can be used in order to associate a response with a specific alteration of a single base or subsegment of the regulatory apparatus. A simple panel might include: enhancer plus promoter, promoter only, enhancer plus a “minimal” promoter from a distinct gene. As mentioned above, a transfection assay, using a host cell stably transformed with a suitable recombinant construct, can be a particularly useful screening assay for identifying an effective agent.  
         [0038]    In yet a further aspect, the invention provides a method for identification of an agent capable of regulating a mammalian FOXC2 promoter activity, said method comprising the steps (i) contacting a candidate agent with a murine FoxC2 promoter nucleotide sequence shown as positions 216 to 2235, such as positions 216 to 475 or positions 1250 to 2235, in SEQ ID NO:5; and (ii) determining whether said candidate agent modulates expression of a mammalian FOXC2 gene, such modulation being indicative for an agent capable of regulating mammalian FOXC2 promoter activity.  
         [0039]    In another important aspect, the invention provides an isolated nucleic acid molecule selected from:  
         [0040]    (a) nucleic acid molecules comprising a nucleotide sequence as shown in SEQ ID NO:3;  
         [0041]    (b) nucleic acid molecules comprising a nucleotide sequence capable of hybridizing, under stringent hybridization conditions, to a nucleotide sequence complementary the polypeptide coding region of a nucleic acid molecule as defined in (a) and which codes for a variant form of the FOXC2 transcription factor; and  
         [0042]    (c) nucleic acid molecules comprising a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence as defined in (a) or (b) and which codes for a variant form of the FOXC2 transcription factor.  
         [0043]    In a preferred form of the invention, the said nucleic acid molecule has a nucleotide sequence identical with SEQ ID NO:3 of the Sequence Listing. However, the nucleic acid molecule according to the invention is not to be limited strictly to the sequence shown as SEQ ID NO:3. Rather the invention encompasses nucleic acid molecules carrying modifications like substitutions, small deletions, insertions or inversions, which nevertheless encode proteins having substantially the biochemical activity of the FOXC2 polypeptide according to the invention. Included in the invention are consequently nucleic acid molecules, the nucleotide sequence of which is at least 90% homologous, preferably at least 95% homologous, with the nucleotide sequence shown as SEQ ID NO:3 in the Sequence Listing.  
         [0044]    Included in the invention is also a nucleic acid molecule which nucleotide sequence is degenerate, because of the genetic code, to the nucleotide sequence shown as SEQ ID NO:3. A sequential grouping of three nucleotides, a “codon”, codes for one amino acid. Since there are 64 possible codons, but only 20 natural amino acids, most amino acids are coded for by more than one codon. This natural “degeneracy”, or “redundancy”, of the genetic code is well known in the art. It will thus be appreciated that the nucleotide sequence shown in the Sequence Listing is only an example within a large but definite group of sequences which will encode the variant FOXC2 polypeptide.  
         [0045]    The invention includes an isolated polypeptide encoded by the nucleic acid as defined above. In a preferred form, the said polypeptide has an amino acid sequence according to SEQ ID NO:4 of the Sequence Listing. However, the polypeptide according to the invention is not to be limited strictly to a polypeptide with an amino acid sequence identical with SEQ ID NO:4 in the Sequence Listing. Rather the invention encompasses polypeptides carrying modifications like substitutions, small deletions, insertions or inversions, which polypeptides nevertheless have substantially the biological activities of the variant FOXC2 polypeptide. In one embodiment, the polypeptide includes an amino acid sequence that is at least about 70%, 75%, 80%, 85%, 90%, 95%, 98% or more identical to the amino acid sequence of SEQ ID NO:4.  
         [0046]    An “isolated” polypeptide is substantially free of other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.  
         [0047]    A further aspect of the invention is a vector harboring the nucleic acid molecule according to the invention. The said vector can e.g. be a replicable expression vector, which carries and is capable of mediating the expression of a DNA molecule according to the invention. In the present context the term “replicable” means that the vector is able to replicate in a given type of host cell into which is has been introduced. Examples of vectors are viruses such as bacteriophages, cosmids, plasmids and other recombination vectors. Nucleic acid molecules are inserted into vector genomes by methods well known in the art.  
         [0048]    Included in the invention is also a cultured host cell harboring a vector according to the invention. Such a host cell can be a prokaryotic cell, a unicellular eukaryotic cell or a cell derived from a multicellular organism. The host cell can thus e.g. be a bacterial cell such as an  E. coli  cell; a cell from yeast such as  Saccharomyces cervisiae  or  Pichia pastoris,  or a mammalian cell. The methods employed to effect introduction of the vector into the host cell are standard methods well known to a person familiar with recombinant DNA methods.  
         [0049]    In yet another aspect, the invention includes a method for identifying an agent capable of regulating expression of the nucleic acid molecule as defined above, said method comprising the steps (i) contacting a candidate agent with the said nucleic acid molecule; and (ii) determining whether said candidate agent modulates expression of the said nucleic acid molecule.  
         [0050]    In another aspect the invention provides an antisense oligonucleotide having a sequence capable of specifically hybridizing to RNA transcribed by the alternatively spliced nucleic acid molecule shown as SEQ ID NO:3, so as to prevent translation of the said RNA. Antisense nucleic acids (preferably 10 to 20 base-pair oligonucleotides) capable of specifically binding to control sequences for the alternatively spliced FOXC2 gene are introduced into cells, e.g. by a viral vector or colloidal dispersion system such as a liposome. The antisense nucleic acid binds to the target nucleotide sequence in the cell and prevents transcription and/or translation of the target sequence. Phosphorothioate and methylphosphonate antisense oligonucleotides are specifically contemplated for therapeutic use by the invention. Suppression of expression of the alternatively spliced FOXC2 gene, at either the transcriptional or translational level, is useful to generate cellular or animal models for diseases/conditions related to lipid metabolism.  
         [0051]    In yet another aspect, the invention provides a method for the identification of polypeptides which bind to nucleotide sequences involved in the biological pathway regulating lipid metabolism and/or adipocyte differentiation, comprising the steps of:  
         [0052]    (a) transfecting a host cell line with a human FOXC2 nucleotide sequence linked to a reporter gene, such as a gene encoding Green Fluorescent Protein (GFP) (for a review, see e.g. Galbraith et al. (1999) Methods in Cell Biology 58: 315-341);  
         [0053]    (b) transfecting the said host cell line with a variety of human cDNA sequences, e.g. sequences included in a cDNA library;  
         [0054]    (c) identifying and isolating cells, e.g. by FACS cells sorting, having an altered level of expression of the said reporter gene, which is indicative that the polypeptide encoded by the added cDNA up- or downregulates at least one gene involved in the biological pathway regulating lipid metabolism and/or adipocyte differentiation;  
         [0055]    (d) recovering cDNA from the cells isolated in step (c), by standard procedures, e.g. PCR or a CRE-LOX mediated procedure (see e.g. Sauer (1998) Methods 14: 381-392); and  
         [0056]    (e) identifying the polypeptide expressed by the cDNA recovered in step (d), e.g. by sequencing the cDNA and comparing the obtained sequence against sequence databases.  
         [0057]    In yet another aspect, the invention includes a nucleic acid comprising a nucleotide sequence selected from the group consisting of nucleotides 1692 to 1703 of SEQ ID NO:1, nucleotides 223 to 231 of SEQ ID NO:1, nucleotides 359 to 375 of SEQ ID NO:1, nucleotides 378 to 402 of SEQ ID NO:1, and nucleotides 403 to 423 in SEQ ID NO:1, operably linked to a heterologous coding sequence. The nucleotide sequence can optionally comprise any of the promoter or enhancer sequences described herein. A “heterologous coding sequence” is any coding sequence other than one that encodes a naturally occurring FOXC2 protein.  
         [0058]    Throughout this description the terms “standard protocols” and “standard procedures”, when used in the context of molecular biology techniques, are to be understood as protocols and procedures found in an ordinary laboratory manual such as: Current Protocols in Molecular Biology, editors F. Ausubel et al., John Wiley and Sons, Inc. 1994, or Sambrook, J., Fritsch, E. F. and Maniatis, T., Molecular Cloning: A laboratory manual, 2 nd  Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 1989.  
       EXAMPLES  
     Example 1  
     Computational Identification of FOXC2 Genomic Sequences  
       [0059]    The sequences present in the GenBank database (http://www.ncbi.nlm.nih.gov) were screened for sequence similarity to the human FOXC2 cDNA sequence (GenBank accession number NM — 00521 (SEQ ID NO:9)). The BLAST algorithm (Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402) was used for determining sequence identity. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http.//www.ncbi.nlm.nih.gov). A working draft genomic sequence in 25 unordered pieces, from the  Homo sapiens  chromosome 16 clone RP11-463O9 (GenBank accession number AC009108; Version 6; GI:7689930; released May 4, 2000), was selected for further studies.  
         [0060]    Regions in sequence AC009108 matching portions of the FOXC2 cDNA sequence NM — 005251 were combined using the PHRAP software, developed at the University of Washington (http.//www.genome.washington.edu/UWGC/analysistools/phrap.htm). Two contigs of 9780 bp (positions 116445 to 126224 in GenBank AC009108.6) and 3784 bp (positions 42927 to 46710 in GenBank AC0091108.6), respectively, were assembled to generate a human FOXC2 genomic fragment of 13451 bp.  
         [0061]    The ClustalW multiple sequence alignment program, version 1.8 (Thompson et al. (1994) Nucleic Acids Research 22: 4673-4680), was then used to identify the human FOXC2 extended genomic DNA sequence of 6458 bp (SEQ ID NO:1) by comparison with the mouse cDNA sequence X74040 (SEQ ID NO:6). First, a 6459 bp sequence, corresponding to positions 1500-7958 in the 13451 bp sequence, was selected. Positions 1-2285 in this 6459 bp sequence corresponded to 44426-46710 in AC009108.6, while positions 2151-6459 corresponded to positions 126224-121916 (reverse complement taken) in AC009108.6. The overlap of positions 2151-2285 allowed for the contigs to be joined by the assembly program. The G residue in position 2655 was considered to be a sequencing error and was removed, which resulted in the 6458 bp sequence set forth as SEQ ID NO:1. The open reading frame in SEQ ID NO:1 encodes a polypeptide (SEQ ID NO:2) identical with the known human FOXC2 polypeptide shown as SEQ ID NO:10.  
       Example 2  
     Identification of Potential Regulatory Sequences in the Human and Mouse FOXC2 Genomic Sequences  
       [0062]    In phylogenetic footprinting (for a review, see Duret &amp; Bucher (1997) Current Opinion in Structural Biology 7(3): 399-406) sequences are aligned and a regional sequence identity is determined for each window of a fixed, arbitrary length. This allows the identification of potential regulatory regions in genomic sequences. Non-exon sequences that are conserved over the course of evolution are likely to perform regulatory roles. Phylogenetic footprinting was performed as described in Wasserman &amp; Fickett (1998) J. Mol. Biol. 278, 167-181, based on an alignment generated with the ClustalW multiple sequence alignment program, version 1.8 (Thompson et al. (1994) Nucleic Acids Research 22: 4673-4680), with default parameters adjusted to a gap opening penalty of 20 and a gap extension penalty of 0.2. The human (SEQ ID NO:1) and mouse (SEQ ID NO:5) genomic sequences were aligned. Percentage identity was plotted for each contiguous 200 bp segment of the human gene to identify segments differentially conserved (in comparison to adjoining sequences) (FIG. 2).  
         [0063]    In addition to segments of the published exon sequence, two differentially conserved regions or “footprints” were identified in the human gene. Both of these regions are local maxima and contain segments which exceed 70% nucleotide identity between the human and mouse genomic sequences. One region, shown as positions 1250 to 2235, in particular positions 1250 to 1749, in SEQ ID NO:1, immediately adjacent to the published exon region, is likely to contain the transcription start site and proximal promoter regulatory sequences (FIG. 4). Another region, shown as positions 216 to 475 in SEQ ID NO:1, approximately 1700 bp distal from the transcription start site, is likely to function as some form of regulatory region (either enhancer or repressor) (FIG. 3). (A schematic overview of the extended FOXC2 gene is shown in FIG. 1).  
         [0064]    Further analysis of these regulatory regions identified short segments of higher conservation between the mouse and human genes, suggesting that these specific segments function as transcription factor binding sites. The TRANSFAC transcription factor database (http://transfac.gbf.de) (see Wingender et al. (2000) Nucleic Acids Research 28(1): 316-319) was screened for matches to known transcription factors. Consensus sites (identifiers R05066; R05067; R05068; and R05069) were found to match sequences conserved between the human FOXC2 and mouse FoxC2 genes. This suggests the presence of multiple forkhead-like binding sites in the distal regulatory enhancer, and potential auto-regulation of FOXC2 by its protein product.  
         [0065]    The same analysis was performed with reference to 200 bp contiguous segments of the mouse FoxC2 genomic sequence (SEQ ID NO:5). The following conserved regions were identified: 190 to 420; 1070 to 1645; and 5580 to 5875. They correlate to the regions indicated above for the human sequence and should be considered orthologous regions.  
       Example 3  
     Identification of an Alternative Human FOXC2 cDNA Sequence  
       [0066]    BLASTN screening of the dbEST database from GenBank, using the human FOXC2 cDNA (SEQ ID NO:9) as a query sequence, revealed several ESTs overlapping containing portions of the available cDNA. A specialized tool, est_genome (http://www.sanger.ac.uk), for the prediction of exon boundaries using ESTs was applied to compare the EST sequences to the genomic sequences (See Mott, R. (1997) Computer Applications in the Biosciences 13(4): 477-478). Two classes of ESTs were observed: sequences extending into the 3′-untranslated region and sequences revealing an alternative first exon spliced to a junction internal to the previously described first exon.  
         [0067]    Specifically, it was found that the nucleotides in positions 33 to 182 in the EST with accession no. AW271272 (SEQ ID NO:11) were identical to positions 66 to 215 in the extended FOXC2 genomic sequence (SEQ ID NO:1), and that positions 183 to 327 in SEQ ID NO:11 were identical to positions 2516 to 2660 in SEQ ID NO:1. Similarly, positions 5 to 55 in the EST with accession no. AW793237 (SEQ ID NO:12) were identical to positions 165 to 215 in the extended FOXC2 genomic sequence (SEQ ID NO:1), and positions 56 to 157 in SEQ ID NO:12 were identical to positions 2516 to 2607 in SEQ ID NO:1. These results revealed an alternative splicing pattern in the human FOXC2 gene. According to this splicing pattern, an alternative gene sequence (SEQ ID NO:3) is derived by joining the regions shown as positions 1-215 and 2516-6458 in SEQ ID NO:1. Alternative splicing patterns are known to regulate the synthesis of a variety of peptides and proteins. It may result in proteins with an entirely different function or in dysfunctional or inhibitory splice products (for a review, see McKeown (1992) Annu. Rev. Cell. Biol. 8: 133-155).  
         [0068]    The amino acids corresponding to positions 1 to 94 in the published FOXC2 transcription factor (SEQ ID NO:10) are missing in protein encoded by the spliced variant generated from the alternative promoter (SEQ ID NO:4). Consequently, the entire region N-terminal of the DNA binding domain and a portion of the DNA-binding domain (corresponding to positions 72-94 in SEQ ID NO:2) are not present in the splice variant. It is postulated that this truncation leads to a protein which has a deficient “forkhead” DNA-binding region, and thus has a potential inhibitory function on the biological activities of the FOXC2 protein. This truncated FOXC2 protein may have a role in regulation of FOXC2, and an involvment in adipocyte differentiation and adipogenesis.  
       Example 4  
     Cloning and Sequencing of the FOXC2 Promoter  
       [0069]    The DNA region corresponding to nucleotide 176 to nucleotide 2233 (SEQ ID NO. 1 version 2) has been cloned using nested PCR on human genomic DNA. The PCR was performed according the Herculase™ protocol (Stratagene catalog #600260; http://www.stratagene.com/pcr/herculase.htm) and with the inclusion of 8-10% DMSO.  
         [0070]    In the initial reaction, the 5′-primer KRKX131 (CCATTGCCTTCTAGTCGC CTCC; SEQ ID NO:14) was used together with the 3′-primer KRKX133 (CGTTGGGG TCGGACACGGAGTA; SEQ ID NO:15) using 250 ng Clontech Genomic DNA #6550-1 as template. The nested reaction was performed on {fraction (1/100)} of the initial PCR reaction using the 5′-primer KRKX132 (GGTACCTACGCAGCCGATGAACAGCCA; SEQ ID NO:16) and the 3′-primer KRKX134 (GCTAGCGCTGCTTCCGAGACGGCTCG; SEQ ID NO:17). After the second PCR, the product was analyzed by electrophoresis in a 1.2% agarose gel, and a PCR product of the expected size was obtained and extracted for ligation into a TOPO PCR2.1 vector (Invitrogen, Carlsbad, Calif.) by standard cloning procedures and thereafter sequenced. The PCR reaction and cloning procedure was repeated in two parallel separate experiments, and sequence data from the two separate reactions were compared with the bioinformatically assembled sequence.  
         [0071]    A DNA region containing the promoter (FIG. 4) corresponding to nt1179 to 2233 (SEQ ID NO:1, version 2) was has been cloned using nested PCR in the same manner as described above. In the initial reaction, the 5′-primer KRKX136 (GGTACCCCCCGAGCC TGGAAACTCCCT; SEQ ID NO:18) was used together with the 3′-primer KRKX134 (GCTAGCGCTGCTTCCGAGACGGCTCG; SEQ ID NO:17) using 250 ng genomic DNA as a template. The PCR reaction and cloning procedure was repeated in four parallel separate experiments, and sequence data from the four separate reactions were compared with the bioinformatically assembled sequence.  
       Example 5  
     Tissue Expression Profiling of the Alternative Transcript  
       [0072]    A reverse transcriptase PCR (RT-PCR) approach was used in order to detect expression of the alternative transcript in human adipose tissue and human primary adipocytes. RNA samples from human adipose tissue (Invitrogen, D6005-01) and primary adipocytes (Zen-Bio, SA75, RNA prepared according to the Trizol protocol)) were analyzed. RT-PCR was performed according to SMART RACE protocol (Clontech). First strand cDNA synthesis was made using a oligo dT primer provided in the SMART RACE kit. For PCR amplification of the alternative transcript, nested 5′ primer specific for the alternative transcript was used (initial PCR step ROLX56 5′ATG AAC AGC CAG GAA GGG TGC AAG G3′ (SEQ ID NO:19) and nested primer ROLX58 5′ACA GCC AGG AAG GGT GCA AGG AAA C3′ (SEQ ID NO:20)) while the nested 3′ primers anneals to sequence common for both the alternative and the normal transcript (initial PCR step ROLX57 5′GAA GCT GCC GTT CTC GAA CAT GTT G 3′ (SEQ ID NO:21) and nested primer ROLX59 5′GTA GGA GTC CGG GTC CAG GGT CCA G 3′ (SEQ ID NO:22)). PCR was performed using the SMART RACE protocol. The primers anneal to sequence on either side of the suggested splice site. Thus a PCR product of the expected size of 223 bp was obtained when amplifying cDNA derived from the alternative transcript, while amplification of contaminating genomic DNA containing the intron sequence yielded a PCR product of much larger size. Using this approach, expression of the alternative transcript was detected in human adipose tissue and primary adipocytes. Expression of the alternative gene product (SEQ ID NO:4) in adipocytes and adipose tissue may be indicative of a regulatory function in this cell type.  
       Example 6  
     Mapping of the 5′-UTR of the Alternative Exon using cDNA Walking  
       [0073]    A cDNA walking method was used in order to map the 5′-UTR of the alternative exon. Human adipose total RNA was obtained from Invitrogen (D6005-01). First strand 5′ RACE cDNA was synthesized according to standard procedure as described in the Clontech manual. The cDNA was amplified according to the manual but using gene specific primers. The 3′-PCR primers used in all reactions anneals to a sequence at the 3′-end of the splice site. Amplification of contaminating genomic DNA yields a PCR product of a larger size, as this would contain the intron sequence. The 5′-PCR primers anneals to sequence upstream of the putative initiation codon of the alternative exon, with approximate 100 bp intervals. PCR products were subsequently cloned using TA cloning in a TOPO vector (Invitrogen) according to manual, and sequenced using standard procedure.  
         [0074]    In the PCR reaction yielding the longest PCR product nested 5′-primers were used (initial PCR step 5′-GCGTTCGGCTCACTGACTTACAAGGT-3′ (SEQ ID NO:23) and nested primer 5′-GGAAGTGTCTCTCTCACCTTTTCTGTCTTGA-3′ (SEQ ID NO:24)) together with nested 3′-primers (initial PCR step 5′-GAAGCTGCCGTTCTCGAACA TGTTG-3′ (SEQ ID NO:21) and nested primer 5′-GTAGGAGTCCGGGTCCAGGG TCCAG-3′ (SEQ ID NO:22)). This results in a PCR product of 878 bp (SEQ ID NO:13) containing the predicted sequence. PCR using primers annealing to sequence 5′ of GCGTTCGGCTCACTGACTTACAAGGT (SEQ ID NO:23) does not yield a detectable PCR product. These results suggest that the transcription initiation site for the alternative transcript is located at least 878 bp upstream of the suggested translational start. Position 692 in SEQ ID NO:13 corresponds to position 1 in SEQ ID NO:3.  
       Example 7  
     Functional Analysis  
       [0075]    The identified regulatory regions are analyzed to determine their impact on the transcription of the FOXC2 gene or a reporter gene substituted for FOXC2. A PCR reaction is performed to isolate the promoter region adjacent to the published exon sequence, possibly including the sequences extending to the beginning of the ATG encoding the first methionine. This PCR product is cloned into a reporter plasmid adjacent to a reporter gene (e.g. luciferase). The upstream regulatory region, i.e. regions containing both upstream and promoter proximal sequences, or these sequences bearing artificially induced differences, are cloned in a similar manner. These constructs are transfected into a cell culture model system and the level/activity of the protein encoded by the reporter gene is determined. This would provide information on the function of the identified regions, and used to assess the impact of the different regions on transcriptional regulation. Similarly, the upstream regulatory region, a region containing both upstream and promoter proximal sequences, or these sequences bearing artificially induced differences can be cloned and used to assess the impact of these regions on the transcription of the reporter gene.  
       Example 8  
     Reporter Gene Assay to Identify Modulating Compounds  
       [0076]    Reporter gene assays are well known as tools to signal transcriptional activity in cells. (For a review of chemiluminescent and bioluminescent reporter gene assays, see Bronstein et al. (1994) Analytical Biochemistry 219, 169-181.) For instance, the photoprotein luciferase provides a useful tool for assaying for modulators of promoter activity. Cells are transiently transfected with a reporter construct which includes a gene for the luciferase protein downstream from the FOXC2 promoter and enhancer region, or fragments thereof regulating the FOXC2 activity. Luciferase activity may be quantitatively measured using e.g. luciferase assay reagents that are commercially available from Promega (Madison, Wis.). Differences in luminescence in the presence versus the absence of a candidate modulator compound are indicative of modulatory activity.  
                                           TABLE I                           Summary of FOXC2 sequences            SEQ ID   GenBank           NO:   accession no.   Description                    1       Human FOXC2 extended genomic DNA sequence       2       Human FOXC2 polypeptide sequence               (Identical with SEQ ID NO:10)       3       Human FOXC2 DNA sequence               Alternative splicing       4       Human polypeptide sequence               Alternative open reading frame       5   Y08222   Mouse MHF-1 (FoxC2) genomic DNA sequence               (CDS 2070-3554)       6   X74040   Mouse MHF-1 (FoxC2) cDNA sequence       7       Mouse MHF-1 (FoxC2) polypeptide sequence       8   Y08223   Human FKHL14 (FOXC2) genomic DNA               sequence (CDS 1197-2702)       9   NM_005251   Human FKHL14 (FOXC2) cDNA sequence       10       Human FKHL14 (FOXC2) polypeptide sequence       11   AW 271272   Human EST       12   AW 793237   Human EST       13       5′-UTR of the alternative splice variant                  
 
         [0077]    [0077]                                                         TABLE II                           Summary of features in human FOXC2 sequences       shown as SEQ ID NOs: 1 and 3            Feature   Positions                    SEQ ID NO:1            First exon according to the alternative transcript    1-215       Untranslated region    1-186       Region coding for 5′-part of alternative protein   187-215       Alternative first exon splice site   215-216       Predicted enhancer region   216-475       E-box-like region   223-231       Forkhead-like region   359-375       Forkhead-like region   378-402       Ets-like region   403-423       Predicted promoter region   1250-1749       Forkhead-like region   1692-1703       First exon according to the published form of the transcript   1746-4629       Untranslated region   1746-2234       Polypeptide coding region   2235-3740       Region coding for DNA-binding domain   2448-2735       Second exon according to the alternative transcript   2516-4629       Portion of polypeptide used in alternative transcript   2516-3740       Untranslated region   3741-4629            SEQ ID NO:3            Polypeptide coding region (5′ of splice site)   187-215       Polypeptide coding region (3′ of splice site)    216-1437       Region coding for truncated portion of protein   216-435                    
         [0078]    [0078] 
     
       
       
         1 
         
           
             24  
           
           
             1  
             6458  
             DNA  
             Homo sapiens  
             
               CDS  
               (2235)...(3737)  
             
           
            1 

cctttggctt tgaattgatc aggagacaaa gataatgcat ctacattttc gtcttctgtt     60 

cttttattgg aaataagtgg cacgccccat tgccttctag tcgcctcccc gaagcgaaga    120 

ggccgaagcg aagaggcctg gtgggttgtc tcaacatcct tttgctgaga atcgaatacg    180 

cagccgatga acagccagga agggtgcaag gaaacctgaa atacaaatgt tctccctgaa    240 

gccctcttcc ctgcccaacc agaccagcaa cttccaaaat tctgcccgtg tttagccttg    300 

ttaaaggggt gtctcactcc ttcagggaaa gtgggaaaag gggatctgat tattgaggtg    360 

tggaaggaat aaataatcag tccacaaata aacaaactgt ccgggattcc tagagggaag    420 

gagaaatcct tgaaggagat ccaagtcgct ccaggtctgc ctgccgaata atatcatccc    480 

gaagggatct tgaaccgttt gcaatcaacc gctcacccag tcttcccacg gagcgcgctc    540 

cctaactcac cctacccacc caacaaaaca aaaaaaaggc tgaaatatag aaaagcaact    600 

tggaggctcc cagggggacg ttgccaggag caggaggcag ggacagcgcc ctagggtcgg    660 

tgttagcggc cggcgccggc ctgggccacg ggaaacgtcc acgcttggtg cccgcggtgc    720 

gcggcgctca ttgcgcgcgc cttcgagcca agcccccgcg gaaaacaggc tcgggtttct    780 

cctcgcaggg cccaggaact cggctctgcc tggcccgggt gggtcgctgc attgtcccgg    840 

tcttctggga gtgcggggtc agcttgttag agggaatttc tacctgggaa aagggagacg    900 

agtttcgaag ctgaagttgg taggctgcga gtgtccacgc gggagacgaa agggggaaat    960 

agcagagtca cttcaccctt ttccccaaac cccacaaaac tgctcgcagc gacgcggatg   1020 

atctaccgaa ttccccgcga attcggagga ttaagttgtc agtcagcacg ttgctacctt   1080 

cccctctatg cactccgctg cctggctcct cggcggggag cgagggaaac tcagtttgta   1140 

gggtttacct ctaaaacctc gataggttat ccttgacgac cccgagcctg gaaactccct   1200 

gttgatgatt aattatttga ttaaataagt ataacatcca ggagaggccc tgccattcca   1260 

atccagcgcg tttgcttttg aatccattac acctgggccc ccataattag gaaatctaat   1320 

tattcgcttc atcactcatt aataagaaaa atgtcccagg atcattgcta cttacaaggt   1380 

ctttgggaga gatattttac tctattaatc cattctattt tatatttcaa attgattttt   1440 

tttaacagag gaaagtggct atctttttgt tttgggcatg tgggcccatt caccaaaatg   1500 

tgatcataaa ataaatttta ataagatata actttttaaa aagttttcaa gtgaagacgg   1560 

agtcgccgcg gaggccgggg cggcggggtc ttagagccga cggattcctg cgctcctcgc   1620 

cccgattggc gccggactcc tctcagctgc cgggtgattg gctcaaagtt ccgggagggg   1680 

gcgtggcccg aggaaagtaa aaactcgctt tcagcaagaa gacttttgaa acttttccca   1740 

atccctaaaa gggacttggc ctctttttct gggctcagcg gggcagccgc tcggaccccg   1800 

gcgcgctgac cctcggggct gccgattcgc tgggggcttg gagagcctcc tgcgcccctc   1860 

ctcgcgcggg ccgagggtcc accttggtcc ccaggccgcg gcgtctccgc tgggtccgcg   1920 

gccgcccgcc tgcccgcgct gccgccgccg ggtcctggag ccagcgagga gcggggccgg   1980 

cgctgcgctt gcccggggcg cgccctccag gatgccgatc cgcccggtcc gctgaaagcg   2040 

cgcgcccctg ctcggcccga gcgacgacga ccgcgcaccc tcgccccgga ggctgccagg   2100 

agaccggggc cgcccctccc gctcccctcc tctccccctc tggctctctc gcgctctctc   2160 

gctctcaggg cccccctcgc tcccccggcc gcagtccgtg cgcgagggcg ccggcgagcc   2220 

gtctcggaag cagc atg cag gcg cgc tac tcc gtg tcc gac ccc aac gcc     2270 
                Met Gln Ala Arg Tyr Ser Val Ser Asp Pro Asn Ala 
                 1               5                   10 

ctg gga gtg gtg ccc tac ctg agc gag cag aat tac tac cgg gct gcg     2318 
Leu Gly Val Val Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala 
         15                  20                  25 

ggc agc tac ggc ggc atg gcc agc ccc atg ggc gtc tat tcc ggc cac     2366 
Gly Ser Tyr Gly Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His 
     30                  35                  40 

ccg gag cag tac agc gcg ggg atg ggc cgc tcc tac gcg ccc tac cac     2414 
Pro Glu Gln Tyr Ser Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His 
 45                  50                  55                  60 

cac cac cag ccc gcg gcg cct aag gac ctg gtg aag ccg ccc tac agc     2462 
His His Gln Pro Ala Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser 
                 65                  70                  75 

tac atc gcg ctc atc acc atg gcc atc cag aac gcg ccc gag aag aag     2510 
Tyr Ile Ala Leu Ile Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys 
             80                  85                  90 

atc acc ttg aac ggc atc tac cag ttc atc atg gac cgc ttc ccc ttc     2558 
Ile Thr Leu Asn Gly Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe 
         95                 100                 105 

tac cgg gag aac aag cag ggc tgg cag aac agc atc cgc cac aac ctc     2606 
Tyr Arg Glu Asn Lys Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu 
    110                 115                 120 

tcg ctc aac gag tgc ttc gtc aag gtg ccc cgc gac gac aag aag ccc     2654 
Ser Leu Asn Glu Cys Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro 
125                 130                 135                 140 

ggc aag ggc agt tac tgg acc ctg gac ccg gac tcc tac aac atg ttc     2702 
Gly Lys Gly Ser Tyr Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe 
                145                 150                 155 

gag aac ggc agc ttc ctg cgg cgc cgg cgg cgc ttc aaa aag aag gac     2750 
Glu Asn Gly Ser Phe Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp 
            160                 165                 170 

gtg tcc aag gag aag gag gag cgg gcc cac ctc aag gag ccg ccc ccg     2798 
Val Ser Lys Glu Lys Glu Glu Arg Ala His Leu Lys Glu Pro Pro Pro 
        175                 180                 185 

gcg gcg tcc aag ggc gcc ccg gcc acc ccc cac cta gcg gac gcc ccc     2846 
Ala Ala Ser Lys Gly Ala Pro Ala Thr Pro His Leu Ala Asp Ala Pro 
    190                 195                 200 

aag gag gcc gag aag aag gtg gtg atc aag agc gag gcg gcg tcc ccg     2894 
Lys Glu Ala Glu Lys Lys Val Val Ile Lys Ser Glu Ala Ala Ser Pro 
205                 210                 215                 220 

gcg ctg ccg gtc atc acc aag gtg gag acg ctg agc ccc gag agc gcg     2942 
Ala Leu Pro Val Ile Thr Lys Val Glu Thr Leu Ser Pro Glu Ser Ala 
                225                 230                 235 

ctg cag ggc agc ccg cgc agc gcg gcc tcc acg ccc gcc ggc tcc ccc     2990 
Leu Gln Gly Ser Pro Arg Ser Ala Ala Ser Thr Pro Ala Gly Ser Pro 
            240                 245                 250 

gac ggt tcg ctg ccg gag cac cac gcc gcg gcg ccc aac ggg ctg cct     3038 
Asp Gly Ser Leu Pro Glu His His Ala Ala Ala Pro Asn Gly Leu Pro 
        255                 260                 265 

ggc ttc agc gtg gag aac atc atg acc ctg cga acg tcg ccg ccg ggc     3086 
Gly Phe Ser Val Glu Asn Ile Met Thr Leu Arg Thr Ser Pro Pro Gly 
    270                 275                 280 

gga gag ctg agc ccg ggg gcc gga cgc gcg ggc ctg gtg gtg ccg ccg     3134 
Gly Glu Leu Ser Pro Gly Ala Gly Arg Ala Gly Leu Val Val Pro Pro 
285                 290                 295                 300 

ctg gcg ctg cca tac gcc gcc gcg ccg ccc gcc gcc tac ggc cag ccg     3182 
Leu Ala Leu Pro Tyr Ala Ala Ala Pro Pro Ala Ala Tyr Gly Gln Pro 
                305                 310                 315 

tgc gct cag ggc ctg gag gcc ggg gcc gcc ggg ggc tac cag tgc agc     3230 
Cys Ala Gln Gly Leu Glu Ala Gly Ala Ala Gly Gly Tyr Gln Cys Ser 
            320                 325                 330 

atg cga gcg atg agc ctg tac acc ggg gcc gag cgg ccg gcg cac atg     3278 
Met Arg Ala Met Ser Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Met 
        335                 340                 345 

tgc gtc ccg ccc gcc ctg gac gag gcc ctc tcg gac cac ccg agc ggc     3326 
Cys Val Pro Pro Ala Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly 
    350                 355                 360 

ccc acg tcg ccc ctg agc gct ctc aac ctc gcc gcc ggc cag gag ggc     3374 
Pro Thr Ser Pro Leu Ser Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly 
365                 370                 375                 380 

gcg ctc gcc gcc acg ggc cac cac cac cag cac cac ggc cac cac cac     3422 
Ala Leu Ala Ala Thr Gly His His His Gln His His Gly His His His 
                385                 390                 395 

ccg cag gcg ccg ccg ccc ccg ccg gct ccc cag ccc cag ccg acg ccg     3470 
Pro Gln Ala Pro Pro Pro Pro Pro Ala Pro Gln Pro Gln Pro Thr Pro 
            400                 405                 410 

cag ccc ggg gcc gcc gcg gcg cag gcg gcc tcc tgg tat ctc aac cac     3518 
Gln Pro Gly Ala Ala Ala Ala Gln Ala Ala Ser Trp Tyr Leu Asn His 
        415                 420                 425 

agc ggg gac ctg aac cac ctc ccc ggc cac acg ttc gcg gcc cag cag     3566 
Ser Gly Asp Leu Asn His Leu Pro Gly His Thr Phe Ala Ala Gln Gln 
    430                 435                 440 

caa act ttc ccc aac gtg cgg gag atg ttc aac tcc cac cgg ctg ggg     3614 
Gln Thr Phe Pro Asn Val Arg Glu Met Phe Asn Ser His Arg Leu Gly 
445                 450                 455                 460 

att gag aac tcg acc ctc ggg gag tcc cag gtg agt ggc aat gcc agc     3662 
Ile Glu Asn Ser Thr Leu Gly Glu Ser Gln Val Ser Gly Asn Ala Ser 
                465                 470                 475 

tgc cag ctg ccc tac aga tcc acg ccg cct ctc tat cgc cac gca gcc     3710 
Cys Gln Leu Pro Tyr Arg Ser Thr Pro Pro Leu Tyr Arg His Ala Ala 
            480                 485                 490 

ccc tac tcc tac gac tgc acg aaa tac tgacgtgtcc cgggacctcc           3757 
Pro Tyr Ser Tyr Asp Cys Thr Lys Tyr 
        495                 500 

cctccccggc ccgctccggc ttcgcttccc agccccgacc caaccagaca attaaggggc   3817 

tgcagagacg caaaaaagaa acaaaacatg tccaccaacc ttttctcaga cccgggagca   3877 

gagagcgggc acgctagccc ccagccgtct gtgaagagcg caggtaactt taattcgccg   3937 

ccccgtttct gggatcccag gaaacccctc caaagggacg cagcccaaca aaatgagtat   3997 

tggtcttaaa atccccctcc cctaccagga cggctgtgct gtgctcgacc tgagctttca   4057 

aaagttaagt tatggaccca aatcccatag cgagccccta gtgactttct gtaggggtcc   4117 

ccataggtgt atgggggtct ctatagataa tatatgtgct gtgtgtaatt ttaaatttct   4177 

ccaaccgtgc tgtacaaatg tgtggatttg taatcaggct attttgttgt tgttgttgtt   4237 

gttcagagcc attaatataa tatttaaagt tgagttcact ggataagttt ttcatcttgc   4297 

ccaaccattt ctaactgcca aattgaattc aagaaaccga tgtgggtttt gtttcctgta   4357 

caattatgag atataattct ttttcccatt gtaggtcttt tacaaaacaa gaaaataatt   4417 

tatttttttg ttggtggata aagaagtcaa gtatctgata ctttttattt acaaagtgtg   4477 

atggttttgt atagtaggtt ccaccctgag tattcctaaa agaaaaaaaa aaaaaaagct   4537 

taaaaactct aacttcatct gtgtttgtct tacgtggtct taatcgttgt acttacctta   4597 

aaataaaccc atgttgtttt ttctgcccaa agtttggaca gtgtgtttgt gttgttgcat   4657 

tttttacaaa cgaggtgtgt ttgcaaaccc acctgctttg attatttttg ttacacaggt   4717 

gggtatatgt gtagacacat aaaaacgacc agagaatagg agcacacacc tgctgtcttg   4777 

tttagtgaca gaaaaaggct tttgattaat tttaaaatcc cactctagga ttttttcttt   4837 

tcgagaaacc gcccagttgg agggggctgc ctgaaggacc ggaccatgag tttgccgtga   4897 

tgcattttct taaatgcaca aaaacatgct aattgtcaaa acaaacagtg ccactccatc   4957 

tcagtgtcca gccgtcccca gtttaggagg tgaaggaagg gaagaataaa catttcccgt   5017 

ttgctaactg caacccaggg tgagtcctgc tttcccccga ttttataaaa tttgagcctc   5077 

tttgcctgct ttaatagttt tccagagaat ttgaactggg ccaatgaagg tctgaagggg   5137 

acggattttc tagcgtttga tatccatccc ccttagcggc cagatcagag gggaatttca   5197 

gactttatta cttctcaatg tcatgtctaa atctacaccc tcatcgcagt gaaaaatttt   5257 

aaaacctcat tacccttcaa aaataattta tgatattttt agagttctaa attcaagttt   5317 

ttcaatatgt taaataatag agattatttt ttgttttcaa tgttaatatc tcgtctttta   5377 

catttttaat agtaacatag tttttgtgaa atgtagctga cgaaatggct ttattatcta   5437 

tttcaatggc tgaagtccac cactcccctg ctggcctcta tgtgtgaatt tggggaccaa   5497 

agcttcatca attcccaccc cagcaggtga gctgtacctt gctaatgctg aagttctttg   5557 

tgagcttaac gtttcaagac cagatgattt tgctaaaggt gattttgctt gatgcagtgg   5617 

cgctgaacgt aacccgggtg tttttgtcgt gttgttttca acatggcact ttatctccac   5677 

gctatgttga aatagaatta ggggaagctt aaagcataat aattgtcccc acatgtgcaa   5737 

cacagactct ttcaatctgt ggccccagag gtggcacaca gttaagactt ggcggctgtc   5797 

tcattctttt tcataatgtg cgggttcccg ggtgtccggg tgctagactt tcagcaggcc   5857 

ccaggccaga cgggctttgg ttgagtgaac aggaggagga agttaaggag gtaggggtgg   5917 

ggagagaccc tctccaagct gcagaagaag gtggcccaag ctccttgcct gcgtctgccg   5977 

tgatggtttc attttacttc tgctcgcttc atgctatttg ccccaggaga agaggagagt   6037 

attccagacg gtaagcgagc tggctttttc ccttccctag acgttttaaa gaaatctttc   6097 

tgaaagcttg ccctcatcgt aagctttgaa accgttggtg tcctgttagt ggcgagggct   6157 

gagagacacg cggagaaata aaggagagcg acggtgtggc tgagagcccc caggtctgct   6217 

gttgaaacta agctgggctt ttgcaccttt aggaagcctt tttaaagaag tcctgctgtg   6277 

tgggggccgg aagcccaagt gagtgggcct tgtggaggtt atcgggaggg gtctttacca   6337 

ctccttgggg aacgtgggca acggggggat tgtatctgaa gctttattca ggtcttcggc   6397 

ggcagcagag tggagaacca ggcccttagt gtgtagcggc ctggggattt tgggactcat   6457 

c                                                                   6458 

 
           
             2  
             501  
             PRT  
             Homo sapiens  
           
            2 

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

Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala Gly Ser Tyr Gly 
            20                  25                  30 

Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His Pro Glu Gln Tyr 
        35                  40                  45 

Ser Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His His His Gln Pro 
    50                  55                  60 

Ala Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser Tyr Ile Ala Leu 
65                  70                  75                  80 

Ile Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys Ile Thr Leu Asn 
                85                  90                  95 

Gly Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn 
            100                 105                 110 

Lys Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu 
        115                 120                 125 

Cys Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser 
    130                 135                 140 

Tyr Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser 
145                 150                 155                 160 

Phe Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Ser Lys Glu 
                165                 170                 175 

Lys Glu Glu Arg Ala His Leu Lys Glu Pro Pro Pro Ala Ala Ser Lys 
            180                 185                 190 

Gly Ala Pro Ala Thr Pro His Leu Ala Asp Ala Pro Lys Glu Ala Glu 
        195                 200                 205 

Lys Lys Val Val Ile Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val 
    210                 215                 220 

Ile Thr Lys Val Glu Thr Leu Ser Pro Glu Ser Ala Leu Gln Gly Ser 
225                 230                 235                 240 

Pro Arg Ser Ala Ala Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu 
                245                 250                 255 

Pro Glu His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val 
            260                 265                 270 

Glu Asn Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Glu Leu Ser 
        275                 280                 285 

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

Tyr Ala Ala Ala Pro Pro Ala Ala Tyr Gly Gln Pro Cys Ala Gln Gly 
305                 310                 315                 320 

Leu Glu Ala Gly Ala Ala Gly Gly Tyr Gln Cys Ser Met Arg Ala Met 
                325                 330                 335 

Ser Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Met Cys Val Pro Pro 
            340                 345                 350 

Ala Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Thr Ser Pro 
        355                 360                 365 

Leu Ser Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Ala Ala 
    370                 375                 380 

Thr Gly His His His Gln His His Gly His His His Pro Gln Ala Pro 
385                 390                 395                 400 

Pro Pro Pro Pro Ala Pro Gln Pro Gln Pro Thr Pro Gln Pro Gly Ala 
                405                 410                 415 

Ala Ala Ala Gln Ala Ala Ser Trp Tyr Leu Asn His Ser Gly Asp Leu 
            420                 425                 430 

Asn His Leu Pro Gly His Thr Phe Ala Ala Gln Gln Gln Thr Phe Pro 
        435                 440                 445 

Asn Val Arg Glu Met Phe Asn Ser His Arg Leu Gly Ile Glu Asn Ser 
    450                 455                 460 

Thr Leu Gly Glu Ser Gln Val Ser Gly Asn Ala Ser Cys Gln Leu Pro 
465                 470                 475                 480 

Tyr Arg Ser Thr Pro Pro Leu Tyr Arg His Ala Ala Pro Tyr Ser Tyr 
                485                 490                 495 

Asp Cys Thr Lys Tyr 
            500 

 
           
             3  
             4158  
             DNA  
             Homo sapiens  
             
               CDS  
               (187)...(1437)  
             
           
            3 

cctttggctt tgaattgatc aggagacaaa gataatgcat ctacattttc gtcttctgtt     60 

cttttattgg aaataagtgg cacgccccat tgccttctag tcgcctcccc gaagcgaaga    120 

ggccgaagcg aagaggcctg gtgggttgtc tcaacatcct tttgctgaga atcgaatacg    180 

cagccg atg aac agc cag gaa ggg tgc aag gaa acc ttg aac ggc atc       228 
       Met Asn Ser Gln Glu Gly Cys Lys Glu Thr Leu Asn Gly Ile 
        1               5                   10 

tac cag ttc atc atg gac cgc ttc ccc ttc tac cgg gag aac aag cag      276 
Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn Lys Gln 
 15                  20                  25                  30 

ggc tgg cag aac agc atc cgc cac aac ctc tcg ctc aac gag tgc ttc      324 
Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu Cys Phe 
                 35                  40                  45 

gtc aag gtg ccc cgc gac gac aag aag ccc ggc aag ggc agt tac tgg      372 
Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser Tyr Trp 
             50                  55                  60 

acc ctg gac ccg gac tcc tac aac atg ttc gag aac ggc agc ttc ctg      420 
Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser Phe Leu 
         65                  70                  75 

cgg cgc cgg cgg cgc ttc aaa aag aag gac gtg tcc aag gag aag gag      468 
Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Ser Lys Glu Lys Glu 
     80                  85                  90 

gag cgg gcc cac ctc aag gag ccg ccc ccg gcg gcg tcc aag ggc gcc      516 
Glu Arg Ala His Leu Lys Glu Pro Pro Pro Ala Ala Ser Lys Gly Ala 
 95                 100                 105                 110 

ccg gcc acc ccc cac cta gcg gac gcc ccc aag gag gcc gag aag aag      564 
Pro Ala Thr Pro His Leu Ala Asp Ala Pro Lys Glu Ala Glu Lys Lys 
                115                 120                 125 

gtg gtg atc aag agc gag gcg gcg tcc ccg gcg ctg ccg gtc atc acc      612 
Val Val Ile Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val Ile Thr 
            130                 135                 140 

aag gtg gag acg ctg agc ccc gag agc gcg ctg cag ggc agc ccg cgc      660 
Lys Val Glu Thr Leu Ser Pro Glu Ser Ala Leu Gln Gly Ser Pro Arg 
        145                 150                 155 

agc gcg gcc tcc acg ccc gcc ggc tcc ccc gac ggt tcg ctg ccg gag      708 
Ser Ala Ala Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu Pro Glu 
    160                 165                 170 

cac cac gcc gcg gcg ccc aac ggg ctg cct ggc ttc agc gtg gag aac      756 
His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val Glu Asn 
175                 180                 185                 190 

atc atg acc ctg cga acg tcg ccg ccg ggc gga gag ctg agc ccg ggg      804 
Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Glu Leu Ser Pro Gly 
                195                 200                 205 

gcc gga cgc gcg ggc ctg gtg gtg ccg ccg ctg gcg ctg cca tac gcc      852 
Ala Gly Arg Ala Gly Leu Val Val Pro Pro Leu Ala Leu Pro Tyr Ala 
            210                 215                 220 

gcc gcg ccg ccc gcc gcc tac ggc cag ccg tgc gct cag ggc ctg gag      900 
Ala Ala Pro Pro Ala Ala Tyr Gly Gln Pro Cys Ala Gln Gly Leu Glu 
        225                 230                 235 

gcc ggg gcc gcc ggg ggc tac cag tgc agc atg cga gcg atg agc ctg      948 
Ala Gly Ala Ala Gly Gly Tyr Gln Cys Ser Met Arg Ala Met Ser Leu 
    240                 245                 250 

tac acc ggg gcc gag cgg ccg gcg cac atg tgc gtc ccg ccc gcc ctg      996 
Tyr Thr Gly Ala Glu Arg Pro Ala His Met Cys Val Pro Pro Ala Leu 
255                 260                 265                 270 

gac gag gcc ctc tcg gac cac ccg agc ggc ccc acg tcg ccc ctg agc     1044 
Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Thr Ser Pro Leu Ser 
                275                 280                 285 

gct ctc aac ctc gcc gcc ggc cag gag ggc gcg ctc gcc gcc acg ggc     1092 
Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Ala Ala Thr Gly 
            290                 295                 300 

cac cac cac cag cac cac ggc cac cac cac ccg cag gcg ccg ccg ccc     1140 
His His His Gln His His Gly His His His Pro Gln Ala Pro Pro Pro 
        305                 310                 315 

ccg ccg gct ccc cag ccc cag ccg acg ccg cag ccc ggg gcc gcc gcg     1188 
Pro Pro Ala Pro Gln Pro Gln Pro Thr Pro Gln Pro Gly Ala Ala Ala 
    320                 325                 330 

gcg cag gcg gcc tcc tgg tat ctc aac cac agc ggg gac ctg aac cac     1236 
Ala Gln Ala Ala Ser Trp Tyr Leu Asn His Ser Gly Asp Leu Asn His 
335                 340                 345                 350 

ctc ccc ggc cac acg ttc gcg gcc cag cag caa act ttc ccc aac gtg     1284 
Leu Pro Gly His Thr Phe Ala Ala Gln Gln Gln Thr Phe Pro Asn Val 
                355                 360                 365 

cgg gag atg ttc aac tcc cac cgg ctg ggg att gag aac tcg acc ctc     1332 
Arg Glu Met Phe Asn Ser His Arg Leu Gly Ile Glu Asn Ser Thr Leu 
            370                 375                 380 

ggg gag tcc cag gtg agt ggc aat gcc agc tgc cag ctg ccc tac aga     1380 
Gly Glu Ser Gln Val Ser Gly Asn Ala Ser Cys Gln Leu Pro Tyr Arg 
        385                 390                 395 

tcc acg ccg cct ctc tat cgc cac gca gcc ccc tac tcc tac gac tgc     1428 
Ser Thr Pro Pro Leu Tyr Arg His Ala Ala Pro Tyr Ser Tyr Asp Cys 
    400                 405                 410 

acg aaa tac tgacgtgtcc cgggacctcc cctccccggc ccgctccggc             1477 
Thr Lys Tyr 
415 

ttcgcttccc agccccgacc caaccagaca attaaggggc tgcagagacg caaaaaagaa   1537 

acaaaacatg tccaccaacc ttttctcaga cccgggagca gagagcgggc acgctagccc   1597 

ccagccgtct gtgaagagcg caggtaactt taattcgccg ccccgtttct gggatcccag   1657 

gaaacccctc caaagggacg cagcccaaca aaatgagtat tggtcttaaa atccccctcc   1717 

cctaccagga cggctgtgct gtgctcgacc tgagctttca aaagttaagt tatggaccca   1777 

aatcccatag cgagccccta gtgactttct gtaggggtcc ccataggtgt atgggggtct   1837 

ctatagataa tatatgtgct gtgtgtaatt ttaaatttct ccaaccgtgc tgtacaaatg   1897 

tgtggatttg taatcaggct attttgttgt tgttgttgtt gttcagagcc attaatataa   1957 

tatttaaagt tgagttcact ggataagttt ttcatcttgc ccaaccattt ctaactgcca   2017 

aattgaattc aagaaaccga tgtgggtttt gtttcctgta caattatgag atataattct   2077 

ttttcccatt gtaggtcttt tacaaaacaa gaaaataatt tatttttttg ttggtggata   2137 

aagaagtcaa gtatctgata ctttttattt acaaagtgtg atggttttgt atagtaggtt   2197 

ccaccctgag tattcctaaa agaaaaaaaa aaaaaaagct taaaaactct aacttcatct   2257 

gtgtttgtct tacgtggtct taatcgttgt acttacctta aaataaaccc atgttgtttt   2317 

ttctgcccaa agtttggaca gtgtgtttgt gttgttgcat tttttacaaa cgaggtgtgt   2377 

ttgcaaaccc acctgctttg attatttttg ttacacaggt gggtatatgt gtagacacat   2437 

aaaaacgacc agagaatagg agcacacacc tgctgtcttg tttagtgaca gaaaaaggct   2497 

tttgattaat tttaaaatcc cactctagga ttttttcttt tcgagaaacc gcccagttgg   2557 

agggggctgc ctgaaggacc ggaccatgag tttgccgtga tgcattttct taaatgcaca   2617 

aaaacatgct aattgtcaaa acaaacagtg ccactccatc tcagtgtcca gccgtcccca   2677 

gtttaggagg tgaaggaagg gaagaataaa catttcccgt ttgctaactg caacccaggg   2737 

tgagtcctgc tttcccccga ttttataaaa tttgagcctc tttgcctgct ttaatagttt   2797 

tccagagaat ttgaactggg ccaatgaagg tctgaagggg acggattttc tagcgtttga   2857 

tatccatccc ccttagcggc cagatcagag gggaatttca gactttatta cttctcaatg   2917 

tcatgtctaa atctacaccc tcatcgcagt gaaaaatttt aaaacctcat tacccttcaa   2977 

aaataattta tgatattttt agagttctaa attcaagttt ttcaatatgt taaataatag   3037 

agattatttt ttgttttcaa tgttaatatc tcgtctttta catttttaat agtaacatag   3097 

tttttgtgaa atgtagctga cgaaatggct ttattatcta tttcaatggc tgaagtccac   3157 

cactcccctg ctggcctcta tgtgtgaatt tggggaccaa agcttcatca attcccaccc   3217 

cagcaggtga gctgtacctt gctaatgctg aagttctttg tgagcttaac gtttcaagac   3277 

cagatgattt tgctaaaggt gattttgctt gatgcagtgg cgctgaacgt aacccgggtg   3337 

tttttgtcgt gttgttttca acatggcact ttatctccac gctatgttga aatagaatta   3397 

ggggaagctt aaagcataat aattgtcccc acatgtgcaa cacagactct ttcaatctgt   3457 

ggccccagag gtggcacaca gttaagactt ggcggctgtc tcattctttt tcataatgtg   3517 

cgggttcccg ggtgtccggg tgctagactt tcagcaggcc ccaggccaga cgggctttgg   3577 

ttgagtgaac aggaggagga agttaaggag gtaggggtgg ggagagaccc tctccaagct   3637 

gcagaagaag gtggcccaag ctccttgcct gcgtctgccg tgatggtttc attttacttc   3697 

tgctcgcttc atgctatttg ccccaggaga agaggagagt attccagacg gtaagcgagc   3757 

tggctttttc ccttccctag acgttttaaa gaaatctttc tgaaagcttg ccctcatcgt   3817 

aagctttgaa accgttggtg tcctgttagt ggcgagggct gagagacacg cggagaaata   3877 

aaggagagcg acggtgtggc tgagagcccc caggtctgct gttgaaacta agctgggctt   3937 

ttgcaccttt aggaagcctt tttaaagaag tcctgctgtg tgggggccgg aagcccaagt   3997 

gagtgggcct tgtggaggtt atcgggaggg gtctttacca ctccttgggg aacgtgggca   4057 

acggggggat tgtatctgaa gctttattca ggtcttcggc ggcagcagag tggagaacca   4117 

ggcccttagt gtgtagcggc ctggggattt tgggactcat c                       4158 

 
           
             4  
             417  
             PRT  
             Homo sapiens  
           
            4 

Met Asn Ser Gln Glu Gly Cys Lys Glu Thr Leu Asn Gly Ile Tyr Gln 
 1               5                  10                  15 

Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn Lys Gln Gly Trp 
            20                  25                  30 

Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu Cys Phe Val Lys 
        35                  40                  45 

Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser Tyr Trp Thr Leu 
    50                  55                  60 

Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser Phe Leu Arg Arg 
65                  70                  75                  80 

Arg Arg Arg Phe Lys Lys Lys Asp Val Ser Lys Glu Lys Glu Glu Arg 
                85                  90                  95 

Ala His Leu Lys Glu Pro Pro Pro Ala Ala Ser Lys Gly Ala Pro Ala 
            100                 105                 110 

Thr Pro His Leu Ala Asp Ala Pro Lys Glu Ala Glu Lys Lys Val Val 
        115                 120                 125 

Ile Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val Ile Thr Lys Val 
    130                 135                 140 

Glu Thr Leu Ser Pro Glu Ser Ala Leu Gln Gly Ser Pro Arg Ser Ala 
145                 150                 155                 160 

Ala Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu Pro Glu His His 
                165                 170                 175 

Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val Glu Asn Ile Met 
            180                 185                 190 

Thr Leu Arg Thr Ser Pro Pro Gly Gly Glu Leu Ser Pro Gly Ala Gly 
        195                 200                 205 

Arg Ala Gly Leu Val Val Pro Pro Leu Ala Leu Pro Tyr Ala Ala Ala 
    210                 215                 220 

Pro Pro Ala Ala Tyr Gly Gln Pro Cys Ala Gln Gly Leu Glu Ala Gly 
225                 230                 235                 240 

Ala Ala Gly Gly Tyr Gln Cys Ser Met Arg Ala Met Ser Leu Tyr Thr 
                245                 250                 255 

Gly Ala Glu Arg Pro Ala His Met Cys Val Pro Pro Ala Leu Asp Glu 
            260                 265                 270 

Ala Leu Ser Asp His Pro Ser Gly Pro Thr Ser Pro Leu Ser Ala Leu 
        275                 280                 285 

Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Ala Ala Thr Gly His His 
    290                 295                 300 

His Gln His His Gly His His His Pro Gln Ala Pro Pro Pro Pro Pro 
305                 310                 315                 320 

Ala Pro Gln Pro Gln Pro Thr Pro Gln Pro Gly Ala Ala Ala Ala Gln 
                325                 330                 335 

Ala Ala Ser Trp Tyr Leu Asn His Ser Gly Asp Leu Asn His Leu Pro 
            340                 345                 350 

Gly His Thr Phe Ala Ala Gln Gln Gln Thr Phe Pro Asn Val Arg Glu 
        355                 360                 365 

Met Phe Asn Ser His Arg Leu Gly Ile Glu Asn Ser Thr Leu Gly Glu 
    370                 375                 380 

Ser Gln Val Ser Gly Asn Ala Ser Cys Gln Leu Pro Tyr Arg Ser Thr 
385                 390                 395                 400 

Pro Pro Leu Tyr Arg His Ala Ala Pro Tyr Ser Tyr Asp Cys Thr Lys 
                405                 410                 415 

Tyr  
           
             5  
             6021  
             DNA  
             Mus musculus  
             
               exon  
               (1649)...(438)  
             
           
            5 

ctcgagtcaa aggtagcaca cataaaacct attttgctgc ttcggtacgt caagcaatgc     60 

cactaaagtt tcctcacccg ccaaagctga aacagtgagt tctaatctct caaagccttt    120 

tgccgaaaat ctaaaggggg tggggggcta tggtggtggc gtgggggggg ggtcggagaa    180 

gaagaaagac tgagacaaat gttttatctg tcgccttctt ccctacccaa ccggaccaac    240 

aacttccaga aggttctgcg aggcatagag ccattccgta gggacatctc ggtgcttctg    300 

aggaagcgga ccgagcaggg atccgatgac gactggagat gttgaaggaa taaataccag    360 

tccacaaata aacaaactgt ccccgggatt cctagaggga aggagcacgc ttgaaggtcg    420 

gggaactccg agtcgctgtg cgtcaaggtt ggcataaaat taaaaaaaaa aaaagtcctt    480 

cagttaccag gccctctaag gagcccctgg tcctcagctc accttatcaa aactcagtaa    540 

aacaaacagc ctgaaataca gtcaatttac aggatcccaa agatgctgac cgcggagtgg    600 

gacccacgcc gggccccggc aacagctagg gaagcgggtc cgaggctaca cagtgccgcg    660 

ctcctttgcg tttccagtga cgaagccggc gatggagtgc aggcttggag ctccccacgc    720 

cgaacgggga caccagctcc cgggggctgg ctgccttgtc ctaacctcca gacagcgctt    780 

tcataggtgg ggagaaggga gaggccggga tggatggcag ggaaagctag ccctcgtcta    840 

tgcgggagag gagaccagga aagcaacagt tgggttcacg cgcttccctg aaccccacga    900 

aattgtttgg aggactcaga tggatcacct aagtagcagc gaagacgaag gaccaatggt    960 

tccttaggtg ttaccttccc agtttggcat tcccactaag ccttccctcc cagcccgacc   1020 

ccgtcgtgaa ggggagagga accgaattct ccaacccggc ctcctttgtg ggctcttcct   1080 

caacctggaa gcgtcctgtg aattatccat cactgcattc aacaggccct acacgctcag   1140 

tccgtttgct ctgaacccat tacaactagg ccccgataat taagaaatct aattattcgc   1200 

ctcttcatcc attaataata ataaaaaaaa aatctccagg ctctttccta cttacaaggt   1260 

cttgggggca aatctctgcc caacttcatc aattcgatgt tatatttcaa actaaacttc   1320 

tttttatttt ccaaaggaac agggttttta atttttgctc tggacacgtg gtctcgttaa   1380 

acaaaatgtg ataataaaat aaaattttat aagatgtaac tcatttttaa aagtcctcaa   1440 

gttaacttga gctggggggg ggggagatct ggctaagagc atctgggtct tagagccgac   1500 

ggattcaggc gctcctcgtt ttgattggtg ccatccttct cgcagctgcc agatgattgg   1560 

tgcaaacttc ctggaggggg cgcggcctga agaaagtaaa aactcgcttt gagccagaag   1620 

acttttgaaa cttttcccaa tccctaaaag ggactttgct tctttttccg ggctcggccg   1680 

cgcagcctct ccggacccta gctcgctgac gctgcgggct gcagttctcc tggcggggcc   1740 

cgagagccgc tgtctccttt tctagcactc ggaagggctg gtgtcgctcc acggtcgcgc   1800 

gtggcgtctg tgccgccagc tcagggctgc cacccgccaa gccgagagtg cgcggccagc   1860 

ggggccgcct gccgtgcacc cttcaggatg ccgatccgcc cggtcggctg aacccgagcg   1920 

ccggcgtctt ccgcgcgtgg accgcgaggc tgccccgagt cggggctgcc tgcatcgctc   1980 

cgtcccttcc tgctctcctg ctccgggcct cgctcgccgc gggccgcagt cggtgcgcgc   2040 

aggcggcgac cgggcgtctg ggacgcagca tgcaggcgcg ttactcggta tcggacccca   2100 

acgccctggg agtggtaccc tatttgagtg agcaaaacta ctaccgggcg gccggcagct   2160 

acggcggcat ggccagcccc atgggcgtct actccggcca cccggagcag tacggcgccg   2220 

gcatgggccg ctcctacgcg ccctaccacc accagcccgc ggcgcccaag gacctggtga   2280 

agccgcccta cagctatata gcgctcatca ccatggcgat ccagaacgcg ccagagaaga   2340 

agatcactct gaacggcatc taccagttca tcatggaccg tttccccttc taccgcgaga   2400 

acaagcaggg ctggcagaac agcatccgcc acaacctgtc actcaatgag tgcttcgtga   2460 

aagtgccgcg cgacgacaag aagccgggca agggcagcta ctggacgctc gacccggact   2520 

cctacaacat gttcgagaat ggcagcttcc tgcggcggcg gcggcgcttc aagaagaagg   2580 

atgtgcccaa ggacaaggag gagcgggccc acctcaagga gccgccctcg accacggcca   2640 

agggcgctcc gacagggacc ccggtagctg acgggcccaa ggaggccgag aagaaagtcg   2700 

tggttaagag cgaggcggcg tcccccgcgc tgccggtcat caccaaggtg gagacgctga   2760 

gccccgaggg agcgctgcag gccagtccgc gcagcgcatc ctccacgccc gcaggttccc   2820 

cagacggctc gctgccggag caccacgccg cggcgcctaa cgggctgccc ggcttcagcg   2880 

tggagaccat catgacgctg cgcacgtcgc ctccgggcgg cgatctgagc ccagcggccg   2940 

cgcgcgccgg cctggtggtg ccaccgctgg cactgccata cgccgcagcg ccacccgccg   3000 

cttacacgca gccgtgcgcg cagggcctgg aggctgcggg ctccgcgggc taccagtgca   3060 

gtatgcgggc tatgagtctg tacaccgggg ccgagcggcc cgcgcacgtg tgcgttccgc   3120 

ccgcgctgga cgaggctctg tcggaccacc cgagcggccc cggctccccg ctcggcgccc   3180 

tcaacctcgc agcgggtcag gagggcgcgt tgggggcctc gggtcaccac caccagcatc   3240 

acggccacct ccacccgcag gcgccaccgc ccgccccgca gccccctccc gcgccgcagc   3300 

ccgccaccca ggccacctcc tggtatctga accacggcgg ggacctgagc cacctccccg   3360 

gccacacgtt tgcaacccaa cagcaaactt tccccaacgt ccgggagatg ttcaactcgc   3420 

accggctagg actggacaac tcgtccctcg gggagtccca ggtgagcaat gcgagctgtc   3480 

agctgcccta tcgagctacg ccgtccctct accgccacgc agccccctac tcttacgact   3540 

gcaccaaata ctgaggctgt ccagtccgct ccagccccag gaccgcaccg gcttcgcctc   3600 

ctccatggga accttcttcg acggagccgc agaaagcgac ggaaagcgcc cctctctcag   3660 

aaccaggagc agagagctcc gtgcaactcg caggtaactt atccgcagct cagtttgaga   3720 

tctcagcgag tccctctaag ggggatgcag cccagcaaaa cgaaatacag attttttttt   3780 

taattccttc ccctacccag atgctgcgcc tgctcccttg gggcttcata gattagctta   3840 

tggaccaaac ccatagggac ccctaatgac ttctgtggag attctccacg ggcgcaagag   3900 

gtctctccgg ataaggtgcc ttctgtaaac gagtgcggat ttgtaaccag gctattttgt   3960 

tcttgcccag agcctttaat ataatattta aagttgtgtc cactggataa ggtttcgtct   4020 

tgcccaactg ttactgccaa attgaattca agaaacgtgt gtgggtcttt tctccccacg   4080 

tcaccatgat aaaataggtc cctccccaaa ctgtaggtct tttacaaaac aagaaaataa   4140 

tttatttttt tgttgttgtt ggataacgaa attaagtatc ggatactttt aatttaggaa   4200 

gtgcatggct ttgtacagta gatgccatct ggggtattcc aaaaacacac caaaagactt   4260 

taaaatttca atctcacctg tgtttgtctt atgtgatctc agtgttgtat ttaccttaaa   4320 

ataaacccgt gttgtttttc tgcccaaagt tcggacagag tctttgtgtt cttgaatttt   4380 

aaaagggaaa ttgtagtaag ccagttgtga ttgatttttg tgatgcaggt tggcctggta   4440 

acgtggatgc atatacaggt tacaggacga tggagctctc gattagtaat agaaggggct   4500 

cttgatttgt tgaactatcc cgtcctgaga tatttttgtt ttctgctcga ggtaatctga   4560 

gaaactgttc tccatccaca cacggacagg gctgcctgag ggcaacgtcc tgctggcctg   4620 

ttaacgaaat gctttgcggg atgcagaaaa ctgttgccaa ttgtcaaaac aaaatggtgt   4680 

caccctgtct cggtgtccag ctgtcctctg ttagagggga gaaaccgaga aaggacaaac   4740 

ggcctgcagc ttgctaacct cagcgtagca ggagcctggg tgagtgctcg gctccctcca   4800 

tttccttaga tgcggacttg ttgcccctgt tggcgtttta agagtgccag caagaagcaa   4860 

agagggttgg taggtctctg gtatttaact gccggctttg ggatcagatt agaagtgaat   4920 

ttcagtctga tttatttctt aatttgggct ttaaatattt tactccggcg tggtggaaaa   4980 

agaagccact gtgcgcctcc agcatgatat tttagcgctg aaatggctct ggttttcagc   5040 

atgctaagta acaggagatt atttttcttt tgattcttgt atttcatttc tttaaaaaaa   5100 

aaaaaggaaa tagatcggga caaactctct aaaatgtacc tggctggctg gggtggggtc   5160 

cttaccaatc tgctgcctga aagatacagc ttcagcacag gcctgcgtgt tggactttag   5220 

gcatatcatg gattcccacg ccagttggta acctggactg tgctaatgga agttctttct   5280 

gcacagaaca tgtaggccag gaggaggcag ggacccggga ggggggtgga ctttgcaggt   5340 

catctgctta gcttagtggt ggccacgggt taacacgtat atagtgttac tgtttgaaac   5400 

tccaagtttt atatctgtgc tgttttgatg tagaatttgg ggaggttcct gatgatacta   5460 

ccctacccgt gtatgtaaga cagtctttca acctgcagtg ccagaatgtg acccacactt   5520 

cagtatcttc cataaagtgg ggggactaag aactggacag gggtgctgtg gaggggggca   5580 

ggccaggtgt atcttggttc ctgagcagag cagagagctt aggaaggggt cgggagatct   5640 

ctggttcctc ccaacactgg tttcattttg catggctctc ttcaaacctc ttgccccagg   5700 

agaagcgagc tttgtccaag ccagctggct cgctcctttc ccagatgttt taggggcctc   5760 

cctgaaagct tgccctcctc ttaagattca gaactcctga cccagggaaa gataggaggc   5820 

tttgtggatg ggagcttttt tttaaagagg accgttctcg ttctcaagta ggtagctaga   5880 

gagaagcccc ctggagcagg ccctacttgt gactgtcagg gaacccaggt tgtgttgtag   5940 

gcttttccca ggcctcccag agcagcggtg tgaaaaaatg cggtcctggg aaaagttggt   6000 

ctggggtgtt gcttcctcga g                                             6021 

 
           
             6  
             2712  
             DNA  
             Mus musculus  
             
               CDS  
               (422)...(1903)  
             
           
            6 

agggactttg cttctttttc cgggctcggc cgcgcagcct ctccggaccc tagctcgctg     60 

acgctgcggg ctgcagttct cctggcgggg cccgagagcc gctgtctcct tttctagcac    120 

tcggaagggc tggtgtcgct ccacggtcgc gcgtggcgtc tgtgccgcca gctcagggct    180 

gccacccgcc aagccgagag tgcgcggcca gcggggccgc ctgccgtgca cccttcagga    240 

tgccgatccg cccggtcggc tgaacccgag cgccggcgtc ttccgcgcgt ggaccgcgag    300 

gctgccccga gtcggggctg cctgcatcgc tccgtccctt cctgctctcc tgctccgggc    360 

ctcgctcgcc gcgggccgca gtcggtgcgc gcaggcggcg accgggcgtc tgggacgcag    420 

c atg cag gcg cgt tac tcg gta tcg gac ccc aac gcc ctg gga gtg gta    469 
  Met Gln Ala Arg Tyr Ser Val Ser Asp Pro Asn Ala Leu Gly Val Val 
   1               5                   10                  15 

ccc tat ttg agt gag caa aac tac tac cgg gcg gcc ggc agc tac ggc      517 
Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala Gly Ser Tyr Gly 
             20                  25                  30 

ggc atg gcc agc ccc atg ggc gtc tac tcc ggc cac ccg gag cag tac      565 
Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His Pro Glu Gln Tyr 
         35                  40                  45 

ggc gcc ggc atg ggc cgc tcc tac gcg ccc tac cac cac cag ccc gcg      613 
Gly Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His His Gln Pro Ala 
     50                  55                  60 

gcg ccc aag gac ctg gtg aag ccg ccc tac agc tat ata gcg ctc atc      661 
Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser Tyr Ile Ala Leu Ile 
 65                  70                  75                  80 

acc atg gcg atc cag aac gcg cca gag aag aag atc act ctg aac ggc      709 
Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys Ile Thr Leu Asn Gly 
                 85                  90                  95 

atc tac cag ttc atc atg gac cgt ttc ccc ttc tac cgc gag aac aag      757 
Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn Lys 
            100                 105                 110 

cag ggc tgg cag aac agc atc cgc cac aac ctg tca ctc aat gag tgc      805 
Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu Cys 
        115                 120                 125 

ttc gtg aaa gtg ccg cgc gac gac aag aag ccg ggc aag ggc agc tac      853 
Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser Tyr 
    130                 135                 140 

tgg acg ctc gac ccg gac tcc tac aac atg ttc gag aat ggc agc ttc      901 
Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser Phe 
145                 150                 155                 160 

ctg cgg cgg cgg cgg cgc ttc aag aag aag gat gtg ccc aag gac aag      949 
Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Pro Lys Asp Lys 
                165                 170                 175 

gag gag cgg gcc cac ctc aag gag ccg ccc tcg acc acg gcc aag ggc      997 
Glu Glu Arg Ala His Leu Lys Glu Pro Pro Ser Thr Thr Ala Lys Gly 
            180                 185                 190 

gct ccg aca ggg acc ccg gta gct gac ggg ccc aag gag gcc gag aag     1045 
Ala Pro Thr Gly Thr Pro Val Ala Asp Gly Pro Lys Glu Ala Glu Lys 
        195                 200                 205 

aaa gtc gtg gtt aag agc gag gcg gcg tcc ccc gcg ctg ccg gtc atc     1093 
Lys Val Val Val Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val Ile 
    210                 215                 220 

acc aag gtg gag acg ctg agc ccc gag gga gcg ctg cag gcc agt ccg     1141 
Thr Lys Val Glu Thr Leu Ser Pro Glu Gly Ala Leu Gln Ala Ser Pro 
225                 230                 235                 240 

cgc agc gca tcc tcc acg ccc gca ggt tcc cca gac ggc tcg ctg ccg     1189 
Arg Ser Ala Ser Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu Pro 
                245                 250                 255 

gag cac cac gcc gcg gcg cct aac ggg ctg ccc ggc ttc agc gtg gag     1237 
Glu His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val Glu 
            260                 265                 270 

acc atc atg acg ctg cgc acg tcg cct ccg ggc ggc gat ctg agc cca     1285 
Thr Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Asp Leu Ser Pro 
        275                 280                 285 

gcg gcc gcg cgc gcc ggc ctg gtg gtg cca ccg ctg gca ctg cca tac     1333 
Ala Ala Ala Arg Ala Gly Leu Val Val Pro Pro Leu Ala Leu Pro Tyr 
    290                 295                 300 

gcc gca gcg cca ccc gcc gct tac acg cag ccg tgc gcg cag ggc ctg     1381 
Ala Ala Ala Pro Pro Ala Ala Tyr Thr Gln Pro Cys Ala Gln Gly Leu 
305                 310                 315                 320 

gag gct gcg ggc tcc gcg ggc tac cag tgc agt atg cgg gct atg agt     1429 
Glu Ala Ala Gly Ser Ala Gly Tyr Gln Cys Ser Met Arg Ala Met Ser 
                325                 330                 335 

ctg tac acc ggg gcc gag cgg ccc gcg cac gtg tgc gtt ccg ccc gcg     1477 
Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Val Cys Val Pro Pro Ala 
            340                 345                 350 

ctg gac gag gct ctg tcg gac cac ccg agc ggc ccc ggc tcc ccg ctc     1525 
Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Gly Ser Pro Leu 
        355                 360                 365 

ggc gcc ctc aac ctc gca gcg ggt cag gag ggc gcg ttg ggg gcc tcg     1573 
Gly Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Gly Ala Ser 
    370                 375                 380 

ggt cac cac cac cag cat cac ggc cac ctc cac ccg cag gcg cca ccg     1621 
Gly His His His Gln His His Gly His Leu His Pro Gln Ala Pro Pro 
385                 390                 395                 400 

ccc gcc ccg cag ccc cct ccc gcg ccg cag ccc gcc acc cag gcc acc     1669 
Pro Ala Pro Gln Pro Pro Pro Ala Pro Gln Pro Ala Thr Gln Ala Thr 
                405                 410                 415 

tcc tgg tat ctg aac cac ggc ggg gac ctg agc cac ctc ccc ggc cac     1717 
Ser Trp Tyr Leu Asn His Gly Gly Asp Leu Ser His Leu Pro Gly His 
            420                 425                 430 

acg ttt gca acc caa cag caa act ttc ccc aac gtc cgg gag atg ttc     1765 
Thr Phe Ala Thr Gln Gln Gln Thr Phe Pro Asn Val Arg Glu Met Phe 
        435                 440                 445 

aac tcg cac cgg cta gga ctg gac aac tcg tcc ctc ggg gag tcc cag     1813 
Asn Ser His Arg Leu Gly Leu Asp Asn Ser Ser Leu Gly Glu Ser Gln 
    450                 455                 460 

gtg agc aat gcg agc tgt cag ctg ccc tat cga gct acg ccg tcc ctc     1861 
Val Ser Asn Ala Ser Cys Gln Leu Pro Tyr Arg Ala Thr Pro Ser Leu 
465                 470                 475                 480 

tac cgc cac gca gcc ccc tac tct tac gac tgc acc aaa tac             1903 
Tyr Arg His Ala Ala Pro Tyr Ser Tyr Asp Cys Thr Lys Tyr 
                485                 490 

tgaggctgtc cagtccgctc cagccccagg accgcaccgg cttcgcctcc tccatgggaa   1963 

ccttcttcga cggagccgca gaaagcgacg gaaagcgccc ctctctcaga accaggagca   2023 

gagagctccg tgcaactcgc aggtaactta tccgcagctc agtttgagat ctcagcgagt   2083 

ccctctaagg gggatgcagc ccagcaaaac gaaatacaga tttttttttt aattccttcc   2143 

cctacccaga tgctgcgcct gctcccttgg ggcttcatag attagcttat ggaccaaacc   2203 

catagggacc cctaatgact tctgtggaga ttctccacgg gcgcaagagg tctctccgga   2263 

taaggtgcct tctgtaaacg agtgcggatt tgtaaccagg ctattttgtt cttgcccaga   2323 

gcctttaata taatatttaa agttgtgtcc actggataag gtttcgtctt gcccaactgt   2383 

tactgccaaa ttgaattcaa gaaacgtgtg tgggtctttt ctccccacgt caccatgata   2443 

aaataggtcc ctccccaaac tgtaggtctt ttacaaaaca agaaaataat ttattttttt   2503 

gttgttgttg gataacgaaa ttaagtatcg gatactttta atttaggaag tgcatggctt   2563 

tgtacagtag atgccatctg gggtattcca aaaacacacc aaaagacttt aaaatttcaa   2623 

tctcacctgt gtttgtctta tgtgatctca gtgttgtatt taccttaaaa taaacccgtg   2683 

ttgtttttct gcccaaaaaa aaaaaaaaa                                     2712 

 
           
             7  
             494  
             PRT  
             Mus musculus  
           
            7 

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

Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala Gly Ser Tyr Gly 
            20                  25                  30 

Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His Pro Glu Gln Tyr 
        35                  40                  45 

Gly Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His His Gln Pro Ala 
    50                  55                  60 

Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser Tyr Ile Ala Leu Ile 
65                  70                  75                  80 

Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys Ile Thr Leu Asn Gly 
                85                  90                  95 

Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn Lys 
            100                 105                 110 

Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu Cys 
        115                 120                 125 

Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser Tyr 
    130                 135                 140 

Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser Phe 
145                 150                 155                 160 

Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Pro Lys Asp Lys 
                165                 170                 175 

Glu Glu Arg Ala His Leu Lys Glu Pro Pro Ser Thr Thr Ala Lys Gly 
            180                 185                 190 

Ala Pro Thr Gly Thr Pro Val Ala Asp Gly Pro Lys Glu Ala Glu Lys 
        195                 200                 205 

Lys Val Val Val Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val Ile 
    210                 215                 220 

Thr Lys Val Glu Thr Leu Ser Pro Glu Gly Ala Leu Gln Ala Ser Pro 
225                 230                 235                 240 

Arg Ser Ala Ser Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu Pro 
                245                 250                 255 

Glu His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val Glu 
            260                 265                 270 

Thr Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Asp Leu Ser Pro 
        275                 280                 285 

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

Ala Ala Ala Pro Pro Ala Ala Tyr Thr Gln Pro Cys Ala Gln Gly Leu 
305                 310                 315                 320 

Glu Ala Ala Gly Ser Ala Gly Tyr Gln Cys Ser Met Arg Ala Met Ser 
                325                 330                 335 

Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Val Cys Val Pro Pro Ala 
            340                 345                 350 

Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Gly Ser Pro Leu 
        355                 360                 365 

Gly Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Gly Ala Ser 
    370                 375                 380 

Gly His His His Gln His His Gly His Leu His Pro Gln Ala Pro Pro 
385                 390                 395                 400 

Pro Ala Pro Gln Pro Pro Pro Ala Pro Gln Pro Ala Thr Gln Ala Thr 
                405                 410                 415 

Ser Trp Tyr Leu Asn His Gly Gly Asp Leu Ser His Leu Pro Gly His 
            420                 425                 430 

Thr Phe Ala Thr Gln Gln Gln Thr Phe Pro Asn Val Arg Glu Met Phe 
        435                 440                 445 

Asn Ser His Arg Leu Gly Leu Asp Asn Ser Ser Leu Gly Glu Ser Gln 
    450                 455                 460 

Val Ser Asn Ala Ser Cys Gln Leu Pro Tyr Arg Ala Thr Pro Ser Leu 
465                 470                 475                 480 

Tyr Arg His Ala Ala Pro Tyr Ser Tyr Asp Cys Thr Lys Tyr 
                485                 490 

 
           
             8  
             3289  
             DNA  
             Homo sapiens  
           
            8 

gaattcggag gattaagttg tcagtcagca cgttgctacc ttcccctcta tgcactccgc     60 

tgcctggctc ctcggcgggg agcgagggaa actcagtttg tagggtttac ctctaaaacc    120 

tcgataggtt atccttgacg accccgagcc tggaaactcc ctgttgatga ttaattattt    180 

gattaaataa gtataacatc caggagaggc cctgccattc caatccagcg cgtttgcttt    240 

tgaatccatt acacctgggc ccccataatt aggaaatcta attattcgct tcatcactca    300 

ttaataagaa aaatgtccca ggatcattgc tacttacaag gtctttggga gagatatttt    360 

actctattaa tccattctat tttatatttc aaattgattt tttttaacag aggaaagtgg    420 

ctatcttttt gttttgggca tgtgggccca ttcaccaaaa tgtgatcata aaataaattt    480 

taataagata taacttttta aaaagttttc aagtgaagac ggagtcgccg cggaggccgg    540 

ggcggcgggg tcttagagcc gacggattcc tgcgctcctc gccccgattg gcgccggact    600 

cctctcagct gccgggtgat tggctcaaag ttccgggagg gggcgtggcc cgaggaaagt    660 

aaaaactcgc tttcagcaag aagacttttg aaacttttcc caatccctaa aagggacttg    720 

gcctcttttt ctgggctcag cggggcagcc gctcggaccc cggcgcgctg accctcgggg    780 

ctgccgattc gctgggggct tggagagcct cctgcgcccc tcctcgcgcg ggccgagggt    840 

ccaccttggt ccccaggccg cggcgtctcc gctgggtccg cggccgcccg cctgcccgcg    900 

ctgccgccgc cgggtcctgg agccagcgag gagcggggcc ggcgctgcgc ttgcccgggg    960 

cgcgccctcc aggatgccga tccgcccggt ccgctgaaag cgcgcgcccc tgctcggccc   1020 

gagcgacgac gaccgcgcac cctcgccccg gaggctgcca ggagaccggg gccgcccctc   1080 

ccgctcccct cctctccccc tctggctctc tcgcgctctc tcgctctcag ggcccccctc   1140 

gctcccccgg ccgcagtccg tgcgcgaggg cgccggcgag ccgtctcgga agcagcatgc   1200 

aggcgcgcta ctccgtgtcc gaccccaacg ccctgggagt ggtgccctac ctgagcgagc   1260 

agaattacta ccgggctgcg ggcagctacg gcggcatggc cagccccatg ggcgtctatt   1320 

ccggccaccc ggagcagtac agcgcgggga tgggccgctc ctacgcgccc taccaccacc   1380 

accagcccgc ggcgcctaag gacctggtga agccgcccta cagctacatc gcgctcatca   1440 

ccatggccat ccagaacgcg cccgagaaga agatcacctt gaacggcatc taccagttca   1500 

tcatggaccg cttccccttc taccgggaga acaagcaggg ctggcagaac agcatccgcc   1560 

acaacctctc gctcaacgag tgcttcgtca aggtgccccg cgacgacaag aagcccggca   1620 

agggcagtta ctggaccctg gacccggact cctacaacat gttcgagaac ggcagcttcc   1680 

tgcggcgccg gcggcgcttc aaaaagaagg acgtgtccaa ggagaaggag gagcgggccc   1740 

acctcaagga gccgcccccg gcggcgtcca agggcgcccc ggccaccccc cacctagcgg   1800 

acgcccccaa ggaggccgag aagaaggtgg tgatcaagag cgaggcggcg tccccggcgc   1860 

tgccggtcat caccaaggtg gagacgctga gccccgagag cgcgctgcag ggcagcccgc   1920 

gcagcgcggc ctccacgccc gccggctccc ccgacggttc gctgccggag caccacgccg   1980 

cggcgcccaa cgggctgcct ggcttcagcg tggagaacat catgaccctg cgaacgtcgc   2040 

cgccgggcgg agagctgagc ccgggggccg gacgcgcggg cctggtggtg ccgccgctgg   2100 

cgctgccata cgccgccgcg ccgcccgccg cctacggcca gccgtgcgct cagggcctgg   2160 

aggccggggc cgccgggggc taccagtgca gcatgcgagc gatgagcctg tacaccgggg   2220 

ccgagcggcc ggcgcacatg tgcgtcccgc ccgccctgga cgaggccctc tcggaccacc   2280 

cgagcggccc cacgtcgccc ctgagcgctc tcaacctcgc cgccggccag gagggcgcgc   2340 

tcgccgccac gggccaccac caccagcacc acggccacca ccacccgcag gcgccgccgc   2400 

ccccgccggc tccccagccc cagccgacgc cgcagcccgg ggccgccgcg gcgcaggcgg   2460 

cctcctggta tctcaaccac agcggggacc tgaaccacct ccccggccac acgttcgcgg   2520 

cccagcagca aactttcccc aacgtgcggg agatgttcaa ctcccaccgg ctggggattg   2580 

agaactcgac cctcggggag tcccaggtga gtggcaatgc cagctgccag ctgccctaca   2640 

gatccacgcc gcctctctat cgccacgcag ccccctactc ctacgactgc acgaaatact   2700 

gacgtgtccc gggacctccc ctccccggcc cgctccggct tcgcttccca gccccgaccc   2760 

aaccagacaa ttaaggggct gcagagacgc aaaaaagaaa caaaacatgt ccaccaacct   2820 

tttctcagac ccgggagcag agagcgggca cgctagcccc cagccgtctg tgaagagcgc   2880 

aggtaacttt aattcgccgc cccgtttctg ggatcccagg aaacccctcc aaagggacgc   2940 

agcccaacaa aatgagtatt ggtcttaaaa tccccctccc ctaccaggac ggctgtgctg   3000 

tgctcgacct gagctttcaa aagttaagtt atggacccaa atcccatagc gagcccctag   3060 

tgactttctg taggggtccc cataggtgta tgggggtctc tatagataat atatgtgctg   3120 

tgtgtaattt taaatttctc caaccgtgct gtacaaatgt gtggatttgt aatcaggcta   3180 

ttttgttgtt gttgttgttg ttcagagcca ttaatataat atttaaagtt gagttcactg   3240 

gataagtttt tcatcttgcc caaccatttc taactgccaa attgaattc               3289 

 
           
             9  
             1506  
             DNA  
             Homo sapiens  
             
               CDS  
               (1)...(1503)  
             
           
            9 

atg cag gcg cgc tac tcc gtg tcc gac ccc aac gcc ctg gga gtg gtg       48 
Met Gln Ala Arg Tyr Ser Val Ser Asp Pro Asn Ala Leu Gly Val Val 
 1               5                   10                  15 

ccc tac ctg agc gag cag aat tac tac cgg gct gcg ggc agc tac ggc       96 
Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala Gly Ser Tyr Gly 
             20                  25                  30 

ggc atg gcc agc ccc atg ggc gtc tat tcc ggc cac ccg gag cag tac      144 
Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His Pro Glu Gln Tyr 
         35                  40                  45 

agc gcg ggg atg ggc cgc tcc tac gcg ccc tac cac cac cac cag ccc      192 
Ser Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His His His Gln Pro 
     50                  55                  60 

gcg gcg cct aag gac ctg gtg aag ccg ccc tac agc tac atc gcg ctc      240 
Ala Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser Tyr Ile Ala Leu 
 65                  70                  75                  80 

atc acc atg gcc atc cag aac gcg ccc gag aag aag atc acc ttg aac      288 
Ile Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys Ile Thr Leu Asn 
                 85                  90                  95 

ggc atc tac cag ttc atc atg gac cgc ttc ccc ttc tac cgg gag aac      336 
Gly Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn 
            100                 105                 110 

aag cag ggc tgg cag aac agc atc cgc cac aac ctc tcg ctc aac gag      384 
Lys Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu 
        115                 120                 125 

tgc ttc gtc aag gtg ccc cgc gac gac aag aag ccc ggc aag ggc agt      432 
Cys Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser 
    130                 135                 140 

tac tgg acc ctg gac ccg gac tcc tac aac atg ttc gag aac ggc agc      480 
Tyr Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser 
145                 150                 155                 160 

ttc ctg cgg cgc cgg cgg cgc ttc aaa aag aag gac gtg tcc aag gag      528 
Phe Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Ser Lys Glu 
                165                 170                 175 

aag gag gag cgg gcc cac ctc aag gag ccg ccc ccg gcg gcg tcc aag      576 
Lys Glu Glu Arg Ala His Leu Lys Glu Pro Pro Pro Ala Ala Ser Lys 
            180                 185                 190 

ggc gcc ccg gcc acc ccc cac cta gcg gac gcc ccc aag gag gcc gag      624 
Gly Ala Pro Ala Thr Pro His Leu Ala Asp Ala Pro Lys Glu Ala Glu 
        195                 200                 205 

aag aag gtg gtg atc aag agc gag gcg gcg tcc ccg gcg ctg ccg gtc      672 
Lys Lys Val Val Ile Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val 
    210                 215                 220 

atc acc aag gtg gag acg ctg agc ccc gag agc gcg ctg cag ggc agc      720 
Ile Thr Lys Val Glu Thr Leu Ser Pro Glu Ser Ala Leu Gln Gly Ser 
225                 230                 235                 240 

ccg cgc agc gcg gcc tcc acg ccc gcc ggc tcc ccc gac ggt tcg ctg      768 
Pro Arg Ser Ala Ala Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu 
                245                 250                 255 

ccg gag cac cac gcc gcg gcg ccc aac ggg ctg cct ggc ttc agc gtg      816 
Pro Glu His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val 
            260                 265                 270 

gag aac atc atg acc ctg cga acg tcg ccg ccg ggc gga gag ctg agc      864 
Glu Asn Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Glu Leu Ser 
        275                 280                 285 

ccg ggg gcc gga cgc gcg ggc ctg gtg gtg ccg ccg ctg gcg ctg cca      912 
Pro Gly Ala Gly Arg Ala Gly Leu Val Val Pro Pro Leu Ala Leu Pro 
    290                 295                 300 

tac gcc gcc gcg ccg ccc gcc gcc tac ggc cag ccg tgc gct cag ggc      960 
Tyr Ala Ala Ala Pro Pro Ala Ala Tyr Gly Gln Pro Cys Ala Gln Gly 
305                 310                 315                 320 

ctg gag gcc ggg gcc gcc ggg ggc tac cag tgc agc atg cga gcg atg     1008 
Leu Glu Ala Gly Ala Ala Gly Gly Tyr Gln Cys Ser Met Arg Ala Met 
                325                 330                 335 

agc ctg tac acc ggg gcc gag cgg ccg gcg cac atg tgc gtc ccg ccc     1056 
Ser Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Met Cys Val Pro Pro 
            340                 345                 350 

gcc ctg gac gag gcc ctc tcg gac cac ccg agc ggc ccc acg tcg ccc     1104 
Ala Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Thr Ser Pro 
        355                 360                 365 

ctg agc gct ctc aac ctc gcc gcc ggc cag gag ggc gcg ctc gcc gcc     1152 
Leu Ser Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Ala Ala 
    370                 375                 380 

acg ggc cac cac cac cag cac cac ggc cac cac cac ccg cag gcg ccg     1200 
Thr Gly His His His Gln His His Gly His His His Pro Gln Ala Pro 
385                 390                 395                 400 

ccg ccc ccg ccg gct ccc cag ccc cag ccg acg ccg cag ccc ggg gcc     1248 
Pro Pro Pro Pro Ala Pro Gln Pro Gln Pro Thr Pro Gln Pro Gly Ala 
                405                 410                 415 

gcc gcg gcg cag gcg gcc tcc tgg tat ctc aac cac agc ggg gac ctg     1296 
Ala Ala Ala Gln Ala Ala Ser Trp Tyr Leu Asn His Ser Gly Asp Leu 
            420                 425                 430 

aac cac ctc ccc ggc cac acg ttc gcg gcc cag cag caa act ttc ccc     1344 
Asn His Leu Pro Gly His Thr Phe Ala Ala Gln Gln Gln Thr Phe Pro 
        435                 440                 445 

aac gtg cgg gag atg ttc aac tcc cac cgg ctg ggg att gag aac tcg     1392 
Asn Val Arg Glu Met Phe Asn Ser His Arg Leu Gly Ile Glu Asn Ser 
    450                 455                 460 

acc ctc ggg gag tcc cag gtg agt ggc aat gcc agc tgc cag ctg ccc     1440 
Thr Leu Gly Glu Ser Gln Val Ser Gly Asn Ala Ser Cys Gln Leu Pro 
465                 470                 475                 480 

tac aga tcc acg ccg cct ctc tat cgc cac gca gcc ccc tac tcc tac     1488 
Tyr Arg Ser Thr Pro Pro Leu Tyr Arg His Ala Ala Pro Tyr Ser Tyr 
                485                 490                 495 

gac tgc acg aaa tac tga                                             1506 
Asp Cys Thr Lys Tyr 
            500 

 
           
             10  
             501  
             PRT  
             Homo sapiens  
           
            10 

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

Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala Gly Ser Tyr Gly 
            20                  25                  30 

Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His Pro Glu Gln Tyr 
        35                  40                  45 

Ser Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His His His Gln Pro 
    50                  55                  60 

Ala Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser Tyr Ile Ala Leu 
65                  70                  75                  80 

Ile Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys Ile Thr Leu Asn 
                85                  90                  95 

Gly Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn 
            100                 105                 110 

Lys Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu 
        115                 120                 125 

Cys Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser 
    130                 135                 140 

Tyr Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser 
145                 150                 155                 160 

Phe Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Ser Lys Glu 
                165                 170                 175 

Lys Glu Glu Arg Ala His Leu Lys Glu Pro Pro Pro Ala Ala Ser Lys 
            180                 185                 190 

Gly Ala Pro Ala Thr Pro His Leu Ala Asp Ala Pro Lys Glu Ala Glu 
        195                 200                 205 

Lys Lys Val Val Ile Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val 
    210                 215                 220 

Ile Thr Lys Val Glu Thr Leu Ser Pro Glu Ser Ala Leu Gln Gly Ser 
225                 230                 235                 240 

Pro Arg Ser Ala Ala Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu 
                245                 250                 255 

Pro Glu His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val 
            260                 265                 270 

Glu Asn Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Glu Leu Ser 
        275                 280                 285 

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

Tyr Ala Ala Ala Pro Pro Ala Ala Tyr Gly Gln Pro Cys Ala Gln Gly 
305                 310                 315                 320 

Leu Glu Ala Gly Ala Ala Gly Gly Tyr Gln Cys Ser Met Arg Ala Met 
                325                 330                 335 

Ser Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Met Cys Val Pro Pro 
            340                 345                 350 

Ala Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Thr Ser Pro 
        355                 360                 365 

Leu Ser Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Ala Ala 
    370                 375                 380 

Thr Gly His His His Gln His His Gly His His His Pro Gln Ala Pro 
385                 390                 395                 400 

Pro Pro Pro Pro Ala Pro Gln Pro Gln Pro Thr Pro Gln Pro Gly Ala 
                405                 410                 415 

Ala Ala Ala Gln Ala Ala Ser Trp Tyr Leu Asn His Ser Gly Asp Leu 
            420                 425                 430 

Asn His Leu Pro Gly His Thr Phe Ala Ala Gln Gln Gln Thr Phe Pro 
        435                 440                 445 

Asn Val Arg Glu Met Phe Asn Ser His Arg Leu Gly Ile Glu Asn Ser 
    450                 455                 460 

Thr Leu Gly Glu Ser Gln Val Ser Gly Asn Ala Ser Cys Gln Leu Pro 
465                 470                 475                 480 

Tyr Arg Ser Thr Pro Pro Leu Tyr Arg His Ala Ala Pro Tyr Ser Tyr 
                485                 490                 495 

Asp Cys Thr Lys Tyr 
            500 

 
           
             11  
             327  
             DNA  
             Homo sapiens  
           
            11 

ttttttttac attttcgtct tctgttcttg tgattggaaa taagtggcac gccccattgc     60 

cttctagtcg cctccccgaa gcgaagaggc cgaagcgaag aggcctggtg ggttgtctca    120 

acatcctttt gctgagaatc gaatacgcag ccgatgaaca gccaggaagg gtgcaaggaa    180 

accttgaacg gcatctacca gttcatcatg gaccgcttcc ccttctaccg ggagaacaag    240 

cagggctggc agaacagcat ccgccacaac ctctcgctca acgagtgctt cgtcaaggtg    300 

ccccgcgacg acaagaagcc cggcaag                                        327 

 
           
             12  
             147  
             DNA  
             Homo sapiens  
           
            12 

ccgtctgaga atcgaatacg cagccgatga acagccagga agggtgcaag gaaaccttga     60 

acggcatcta ccagttcatc atggaccgct tccccttcta ccgggagaac aagcagggct    120 

ggcagaacag catccgccac aacctct                                        147 

 
           
             13  
             878  
             DNA  
             Homo sapiens  
           
            13 

gtctctctca ccttttctgt cttgatgaga cgaatttctt tcccctcccc ttttcctttc     60 

tttggggcgg gggagggtgg ataatatatt gggcgactcg atttaggtgt ttgtttgttt    120 

gtttgtttgt ttccccagat gacattggtt taaaccggga cacccttgtg aatacaaacg    180 

taggcagcaa ctgccatttt ggaatttatt ttttcatagt ccttagctat tttaggtttt    240 

gctgtgataa agctgtttct ctctctctct ctctctcaca cacacacaca cacccctcgt    300 

aaaagcagag taaataatat tcctccagga agcctacagg ctgaggagtg tttcttgatc    360 

aatagtttgc atttccagta aaatcgtgac acgaactcag tgtgcctgtc atgcgctgca    420 

ggagaagggc actttttgct agtccttttt tttttttaag ctagatgcgg aaatactagc    480 

ttattaaaaa taataaagtc atggtgggag tttagggttg gggcagaaag ctcaaatcat    540 

ttgcctgtga gctgagaact gggcagcttt attttacttt gtttcaaaga aagaagaaaa    600 

aggatcaggt tagaaaaaga gcccagaata ctcataaaaa caatgtttca gaagtggaat    660 

attcaaggta aaggaacctg atttgtagct tccctttggc tttgaattga tcaggagaca    720 

aagataatgc atctacattt tcgtcttctg ttcttttatt ggaaataagt ggcacgcccc    780 

attgccttct agtcgcctcc ccgaagcgaa gaggccgaag cgaagaggcc tggtgggttg    840 

tctcaacatc cttttgctga gaatcgaata cgcagccg                            878 

 
           
             14  
             22  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            14 

ccattgcctt ctagtcgcct cc                                              22 

 
           
             15  
             22  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            15 

cgttggggtc ggacacggag ta                                              22 

 
           
             16  
             27  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            16 

ggtacctacg cagccgatga acagcca                                         27 

 
           
             17  
             26  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            17 

gctagcgctg cttccgagac ggctcg                                          26 

 
           
             18  
             27  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            18 

ggtacccccc gagcctggaa actccct                                         27 

 
           
             19  
             25  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            19 

atgaacagcc aggaagggtg caagg                                           25 

 
           
             20  
             24  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            20 

acagccagga agggtgcaag gaaa                                            24 

 
           
             21  
             25  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            21 

gaagctgccg ttctcgaaca tgttg                                           25 

 
           
             22  
             25  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            22 

gtaggagtcc gggtccaggg tccag                                           25 

 
           
             23  
             26  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            23 

gcgttcggct cactgactta caaggt                                          26 

 
           
             24  
             31  
             DNA  
             Artificial Sequence  
             
               primer for PCR  
             
           
            24 

ggaagtgtct ctctcacctt ttctgtcttg a                                    31