LOCUS       NM_000132               9032 bp    mRNA    linear   PRI 12-OCT-2024
DEFINITION  Homo sapiens coagulation factor VIII (F8), transcript variant 1,
            mRNA.
ACCESSION   NM_000132
VERSION     NM_000132.4
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 9032)
  AUTHORS   de Vries,P.S., Reventun,P., Brown,M.R., Heath,A.S., Huffman,J.E.,
            Le,N.Q., Bebo,A., Brody,J.A., Temprano-Sagrera,G., Raffield,L.M.,
            Ozel,A.B., Thibord,F., Jain,D., Lewis,J.P., Rodriguez,B.A.T.,
            Pankratz,N., Taylor,K.D., Polasek,O., Chen,M.H., Yanek,L.R.,
            Carrasquilla,G.D., Marioni,R.E., Kleber,M.E., Tregouet,D.A.,
            Yao,J., Li-Gao,R., Joshi,P.K., Trompet,S., Martinez-Perez,A.,
            Ghanbari,M., Howard,T.E., Reiner,A.P., Arvanitis,M., Ryan,K.A.,
            Bartz,T.M., Rudan,I., Faraday,N., Linneberg,A., Ekunwe,L.,
            Davies,G., Delgado,G.E., Suchon,P., Guo,X., Rosendaal,F.R.,
            Klaric,L., Noordam,R., van Rooij,F., Curran,J.E., Wheeler,M.M.,
            Osburn,W.O., O'Connell,J.R., Boerwinkle,E., Beswick,A., Psaty,B.M.,
            Kolcic,I., Souto,J.C., Becker,L.C., Hansen,T., Doyle,M.F.,
            Harris,S.E., Moissl,A.P., Deleuze,J.F., Rich,S.S., van Hylckama
            Vlieg,A., Campbell,H., Stott,D.J., Soria,J.M., de Maat,M.P.M.,
            Almasy,L., Brody,L.C., Auer,P.L., Mitchell,B.D., Ben-Shlomo,Y.,
            Fornage,M., Hayward,C., Mathias,R.A., Kilpelainen,T.O., Lange,L.A.,
            Cox,S.R., Marz,W., Morange,P.E., Rotter,J.I., Mook-Kanamori,D.O.,
            Wilson,J.F., van der Harst,P., Jukema,J.W., Ikram,M.A.,
            Blangero,J., Kooperberg,C., Desch,K.C., Johnson,A.D.,
            Sabater-Lleal,M., Lowenstein,C.J., Smith,N.L. and Morrison,A.C.
  TITLE     A genetic association study of circulating coagulation factor VIII
            and von Willebrand factor levels
  JOURNAL   Blood 143 (18), 1845-1855 (2024)
   PUBMED   38320121
  REMARK    GeneRIF: A genetic association study of circulating coagulation
            factor VIII and von Willebrand factor levels.
REFERENCE   2  (bases 1 to 9032)
  AUTHORS   Hopp,M.T., Ugurlar,D., Pezeshkpoor,B., Biswas,A., Ramoji,A.,
            Neugebauer,U., Oldenburg,J. and Imhof,D.
  TITLE     In-depth structure-function profiling of the complex formation
            between clotting factor VIII and heme
  JOURNAL   Thromb Res 237, 184-195 (2024)
   PUBMED   38631156
  REMARK    GeneRIF: In-depth structure-function profiling of the complex
            formation between clotting factor VIII and heme.
REFERENCE   3  (bases 1 to 9032)
  AUTHORS   Symington,E., Rangarajan,S., Lester,W., Madan,B., Pierce,G.F.,
            Raheja,P., Robinson,T.M., Osmond,D., Russell,C.B., Vettermann,C.,
            Agarwal,S.K., Li,M., Wong,W.Y. and Laffan,M.
  TITLE     Long-term safety and efficacy outcomes of valoctocogene
            roxaparvovec gene transfer up to 6 years post-treatment
  JOURNAL   Haemophilia 30 (2), 320-330 (2024)
   PUBMED   38317480
  REMARK    GeneRIF: Long-term safety and efficacy outcomes of valoctocogene
            roxaparvovec gene transfer up to 6 years post-treatment.
REFERENCE   4  (bases 1 to 9032)
  AUTHORS   Tse,V., Chacaltana,G., Gutierrez,M., Forino,N.M., Jimenez,A.G.,
            Tao,H., Do,P.H., Oh,C., Chary,P., Quesada,I., Hamrick,A., Lee,S.,
            Stone,M.D. and Sanford,J.R.
  TITLE     An intronic RNA element modulates Factor VIII exon-16 splicing
  JOURNAL   Nucleic Acids Res 52 (1), 300-315 (2024)
   PUBMED   37962303
  REMARK    GeneRIF: An intronic RNA element modulates Factor VIII exon-16
            splicing.
REFERENCE   5  (bases 1 to 9032)
  AUTHORS   Nakajima,Y. and Nogami,K.
  TITLE     The role of proteolytic cleavage at Arg336 and Arg372 of the A1
            domain in factor VIIa/tissue factor-catalyzed reactions of B
            domain-deleted factor VIII
  JOURNAL   Biochim Biophys Acta Gen Subj 1868 (1), 130501 (2024)
   PUBMED   37925034
  REMARK    GeneRIF: The role of proteolytic cleavage at Arg[336] and Arg[372]
            of the A1 domain in factor VIIa/tissue factor-catalyzed reactions
            of B domain-deleted factor VIII.
REFERENCE   6  (bases 1 to 9032)
  AUTHORS   Konkle,B.A. and Nakaya Fletcher,S.
  TITLE     Hemophilia A
  JOURNAL   (in) Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and
            Amemiya A (Eds.);
            GENEREVIEWS(R);
            (1993)
   PUBMED   20301578
REFERENCE   7  (bases 1 to 9032)
  AUTHORS   Jonsdottir,S., Diamond,C., Levinson,B., Magnusson,S., Jensson,O.
            and Gitschier,J.
  TITLE     Missense mutations causing mild hemophilia A in Iceland detected by
            denaturing gradient gel electrophoresis
  JOURNAL   Hum Mutat 1 (6), 506-508 (1992)
   PUBMED   1301960
REFERENCE   8  (bases 1 to 9032)
  AUTHORS   Diamond,C., Kogan,S., Levinson,B. and Gitschier,J.
  TITLE     Amino acid substitutions in conserved domains of factor VIII and
            related proteins: study of patients with mild and moderately severe
            hemophilia A
  JOURNAL   Hum Mutat 1 (3), 248-257 (1992)
   PUBMED   1301932
REFERENCE   9  (bases 1 to 9032)
  AUTHORS   Nafa,K., Baudis,M., Deburgrave,N., Bardin,J.M., Sultan,Y.,
            Kaplan,J.C. and Delpech,M.
  TITLE     A novel mutation (Arg-->Leu in exon 18) in factor VIII gene
            responsible for moderate hemophilia A
  JOURNAL   Hum Mutat 1 (1), 77-78 (1992)
   PUBMED   1301194
REFERENCE   10 (bases 1 to 9032)
  AUTHORS   Zucker,M.B., Broekman,M.J. and Kaplan,K.L.
  TITLE     Factor VIII-related antigen in human blood platelets: localization
            and release by thrombin and collagen
  JOURNAL   J Lab Clin Med 94 (5), 675-682 (1979)
   PUBMED   501196
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from M14113.1, AC109993.4 and
            BC022513.1.
            This sequence is a reference standard in the RefSeqGene project.
            
            On Feb 24, 2020 this sequence version replaced NM_000132.3.
            
            Summary: This gene encodes coagulation factor VIII, which
            participates in the intrinsic pathway of blood coagulation; factor
            VIII is a cofactor for factor IXa which, in the presence of Ca+2
            and phospholipids, converts factor X to the activated form Xa.
            This gene produces two alternatively spliced transcripts.
            Transcript variant 1 encodes a large glycoprotein, isoform a, which
            circulates in plasma and associates with von Willebrand factor in a
            noncovalent complex. This protein undergoes multiple cleavage
            events. Transcript variant 2 encodes a putative small protein,
            isoform b, which consists primarily of the phospholipid binding
            domain of factor VIIIc. This binding domain is essential for
            coagulant activity. Defects in this gene results in hemophilia A, a
            common recessive X-linked coagulation disorder. [provided by
            RefSeq, Jul 2008].
            
            Transcript Variant: This variant (1) consists of 26 exons and
            encodes the full-length isoform (a).
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: M14113.1, X01179.1 [ECO:0000332]
            RNAseq introns              :: mixed sample support SAMEA1965299,
                                           SAMEA1966682 [ECO:0006172]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000360256.9/ ENSP00000353393.4
            RefSeq Select criteria :: based on manual assertion, conservation,
                                      expression, longest protein
            ##RefSeq-Attributes-END##
            COMPLETENESS: complete on the 3' end.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-8518              M14113.1           1-8518
            8519-8519           AC109993.4         150288-150288       c
            8520-9029           M14113.1           8520-9029
            9030-9032           BC022513.1         2518-2520
FEATURES             Location/Qualifiers
     source          1..9032
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="X"
                     /map="Xq28"
     gene            1..9032
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /note="coagulation factor VIII"
                     /db_xref="GeneID:2157"
                     /db_xref="HGNC:HGNC:3546"
                     /db_xref="MIM:300841"
     exon            1..314
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     CDS             172..7227
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /note="isoform a preproprotein is encoded by transcript
                     variant 1; factor VIII F8B; coagulation factor VIIIc;
                     antihemophilic factor; coagulation factor VIII,
                     procoagulant component; coagulation factor VIII C2 domain;
                     coagulation factor VIII A1 domain"
                     /codon_start=1
                     /product="coagulation factor VIII isoform a preproprotein"
                     /protein_id="NP_000123.1"
                     /db_xref="CCDS:CCDS35457.1"
                     /db_xref="GeneID:2157"
                     /db_xref="HGNC:HGNC:3546"
                     /db_xref="MIM:300841"
                     /translation="MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSDLGELP
                     VDARFPPRVPKSFPFNTSVVYKKTLFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDT
                     VVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVL
                     KENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLF
                     AVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHV
                     IGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSH
                     QHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRS
                     VAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIGRKYKKVRFMAY
                     TDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGITDVRPLYSR
                     RLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNMERDLASGL
                     IGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAGVQLED
                     PEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKHKMV
                     YEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYED
                     SYEDISAYLLSKNNAIEPRSFSQNSRHPSTRQKQFNATTIPENDIEKTDPWFAHRTPM
                     PKIQNVSSSDLLMLLRQSPTPHGLSLSDLQEAKYETFSDDPSPGAIDSNNSLSEMTHF
                     RPQLHHSGDMVFTPESGLQLRLNEKLGTTAATELKKLDFKVSSTSNNLISTIPSDNLA
                     AGTDNTSSLGPPSMPVHYDSQLDTTLFGKKSSPLTESGGPLSLSEENNDSKLLESGLM
                     NSQESSWGKNVSSTESGRLFKGKRAHGPALLTKDNALFKVSISLLKTNKTSNNSATNR
                     KTHIDGPSLLIENSPSVWQNILESDTEFKKVTPLIHDRMLMDKNATALRLNHMSNKTT
                     SSKNMEMVQQKKEGPIPPDAQNPDMSFFKMLFLPESARWIQRTHGKNSLNSGQGPSPK
                     QLVSLGPEKSVEGQNFLSEKNKVVVGKGEFTKDVGLKEMVFPSSRNLFLTNLDNLHEN
                     NTHNQEKKIQEEIEKKETLIQENVVLPQIHTVTGTKNFMKNLFLLSTRQNVEGSYDGA
                     YAPVLQDFRSLNDSTNRTKKHTAHFSKKGEEENLEGLGNQTKQIVEKYACTTRISPNT
                     SQQNFVTQRSKRALKQFRLPLEETELEKRIIVDDTSTQWSKNMKHLTPSTLTQIDYNE
                     KEKGAITQSPLSDCLTRSHSIPQANRSPLPIAKVSSFPSIRPIYLTRVLFQDNSSHLP
                     AASYRKKDSGVQESSHFLQGAKKNNLSLAILTLEMTGDQREVGSLGTSATNSVTYKKV
                     ENTVLPKPDLPKTSGKVELLPKVHIYQKDLFPTETSNGSPGHLDLVEGSLLQGTEGAI
                     KWNEANRPGKVPFLRVATESSAKTPSKLLDPLAWDNHYGTQIPKEEWKSQEKSPEKTA
                     FKKKDTILSLNACESNHAIAAINEGQNKPEIEVTWAKQGRTERLCSQNPPVLKRHQRE
                     ITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLW
                     DYGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRA
                     EVEDNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHM
                     APTKDEFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFT
                     IFDETKSWYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQR
                     IRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWR
                     VECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLARLHY
                     SGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKWQ
                     TYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDL
                     NSCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEW
                     LQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQ
                     DSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLY"
     exon            315..436
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            437..559
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            560..772
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            773..841
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            842..958
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            959..1180
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            1181..1442
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            1443..1614
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            1615..1708
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            1709..1923
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            1924..2074
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            2075..2284
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            2285..5390
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            5391..5544
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            5545..5757
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            5758..5986
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            5987..6169
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6170..6286
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6287..6358
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6359..6444
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6445..6600
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6601..6745
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6746..6894
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            6895..7071
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     exon            7072..9032
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /inference="alignment:Splign:2.1.0"
     regulatory      9010..9015
                     /regulatory_class="polyA_signal_sequence"
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /note="hexamer: AATAAA"
     polyA_site      9032
                     /gene="F8"
                     /gene_synonym="AHF; DXS1253E; F8B; F8C; FVIII; HEMA;
                     THPH13"
                     /note="major polyA site"
ORIGIN      
        1 gcttagtgct gagcacatcc agtgggtaaa gttccttaaa atgctctgca aagaaattgg
       61 gacttttcat taaatcagaa attttacttt tttcccctcc tgggagctaa agatatttta
      121 gagaagaatt aaccttttgc ttctccagtt gaacatttgt agcaataagt catgcaaata
      181 gagctctcca cctgcttctt tctgtgcctt ttgcgattct gctttagtgc caccagaaga
      241 tactacctgg gtgcagtgga actgtcatgg gactatatgc aaagtgatct cggtgagctg
      301 cctgtggacg caagatttcc tcctagagtg ccaaaatctt ttccattcaa cacctcagtc
      361 gtgtacaaaa agactctgtt tgtagaattc acggatcacc ttttcaacat cgctaagcca
      421 aggccaccct ggatgggtct gctaggtcct accatccagg ctgaggttta tgatacagtg
      481 gtcattacac ttaagaacat ggcttcccat cctgtcagtc ttcatgctgt tggtgtatcc
      541 tactggaaag cttctgaggg agctgaatat gatgatcaga ccagtcaaag ggagaaagaa
      601 gatgataaag tcttccctgg tggaagccat acatatgtct ggcaggtcct gaaagagaat
      661 ggtccaatgg cctctgaccc actgtgcctt acctactcat atctttctca tgtggacctg
      721 gtaaaagact tgaattcagg cctcattgga gccctactag tatgtagaga agggagtctg
      781 gccaaggaaa agacacagac cttgcacaaa tttatactac tttttgctgt atttgatgaa
      841 gggaaaagtt ggcactcaga aacaaagaac tccttgatgc aggataggga tgctgcatct
      901 gctcgggcct ggcctaaaat gcacacagtc aatggttatg taaacaggtc tctgccaggt
      961 ctgattggat gccacaggaa atcagtctat tggcatgtga ttggaatggg caccactcct
     1021 gaagtgcact caatattcct cgaaggtcac acatttcttg tgaggaacca tcgccaggcg
     1081 tccttggaaa tctcgccaat aactttcctt actgctcaaa cactcttgat ggaccttgga
     1141 cagtttctac tgttttgtca tatctcttcc caccaacatg atggcatgga agcttatgtc
     1201 aaagtagaca gctgtccaga ggaaccccaa ctacgaatga aaaataatga agaagcggaa
     1261 gactatgatg atgatcttac tgattctgaa atggatgtgg tcaggtttga tgatgacaac
     1321 tctccttcct ttatccaaat tcgctcagtt gccaagaagc atcctaaaac ttgggtacat
     1381 tacattgctg ctgaagagga ggactgggac tatgctccct tagtcctcgc ccccgatgac
     1441 agaagttata aaagtcaata tttgaacaat ggccctcagc ggattggtag gaagtacaaa
     1501 aaagtccgat ttatggcata cacagatgaa acctttaaga ctcgtgaagc tattcagcat
     1561 gaatcaggaa tcttgggacc tttactttat ggggaagttg gagacacact gttgattata
     1621 tttaagaatc aagcaagcag accatataac atctaccctc acggaatcac tgatgtccgt
     1681 cctttgtatt caaggagatt accaaaaggt gtaaaacatt tgaaggattt tccaattctg
     1741 ccaggagaaa tattcaaata taaatggaca gtgactgtag aagatgggcc aactaaatca
     1801 gatcctcggt gcctgacccg ctattactct agtttcgtta atatggagag agatctagct
     1861 tcaggactca ttggccctct cctcatctgc tacaaagaat ctgtagatca aagaggaaac
     1921 cagataatgt cagacaagag gaatgtcatc ctgttttctg tatttgatga gaaccgaagc
     1981 tggtacctca cagagaatat acaacgcttt ctccccaatc cagctggagt gcagcttgag
     2041 gatccagagt tccaagcctc caacatcatg cacagcatca atggctatgt ttttgatagt
     2101 ttgcagttgt cagtttgttt gcatgaggtg gcatactggt acattctaag cattggagca
     2161 cagactgact tcctttctgt cttcttctct ggatatacct tcaaacacaa aatggtctat
     2221 gaagacacac tcaccctatt cccattctca ggagaaactg tcttcatgtc gatggaaaac
     2281 ccaggtctat ggattctggg gtgccacaac tcagactttc ggaacagagg catgaccgcc
     2341 ttactgaagg tttctagttg tgacaagaac actggtgatt attacgagga cagttatgaa
     2401 gatatttcag catacttgct gagtaaaaac aatgccattg aaccaagaag cttctcccag
     2461 aattcaagac accctagcac taggcaaaag caatttaatg ccaccacaat tccagaaaat
     2521 gacatagaga agactgaccc ttggtttgca cacagaacac ctatgcctaa aatacaaaat
     2581 gtctcctcta gtgatttgtt gatgctcttg cgacagagtc ctactccaca tgggctatcc
     2641 ttatctgatc tccaagaagc caaatatgag actttttctg atgatccatc acctggagca
     2701 atagacagta ataacagcct gtctgaaatg acacacttca ggccacagct ccatcacagt
     2761 ggggacatgg tatttacccc tgagtcaggc ctccaattaa gattaaatga gaaactgggg
     2821 acaactgcag caacagagtt gaagaaactt gatttcaaag tttctagtac atcaaataat
     2881 ctgatttcaa caattccatc agacaatttg gcagcaggta ctgataatac aagttcctta
     2941 ggacccccaa gtatgccagt tcattatgat agtcaattag ataccactct atttggcaaa
     3001 aagtcatctc cccttactga gtctggtgga cctctgagct tgagtgaaga aaataatgat
     3061 tcaaagttgt tagaatcagg tttaatgaat agccaagaaa gttcatgggg aaaaaatgta
     3121 tcgtcaacag agagtggtag gttatttaaa gggaaaagag ctcatggacc tgctttgttg
     3181 actaaagata atgccttatt caaagttagc atctctttgt taaagacaaa caaaacttcc
     3241 aataattcag caactaatag aaagactcac attgatggcc catcattatt aattgagaat
     3301 agtccatcag tctggcaaaa tatattagaa agtgacactg agtttaaaaa agtgacacct
     3361 ttgattcatg acagaatgct tatggacaaa aatgctacag ctttgaggct aaatcatatg
     3421 tcaaataaaa ctacttcatc aaaaaacatg gaaatggtcc aacagaaaaa agagggcccc
     3481 attccaccag atgcacaaaa tccagatatg tcgttcttta agatgctatt cttgccagaa
     3541 tcagcaaggt ggatacaaag gactcatgga aagaactctc tgaactctgg gcaaggcccc
     3601 agtccaaagc aattagtatc cttaggacca gaaaaatctg tggaaggtca gaatttcttg
     3661 tctgagaaaa acaaagtggt agtaggaaag ggtgaattta caaaggacgt aggactcaaa
     3721 gagatggttt ttccaagcag cagaaaccta tttcttacta acttggataa tttacatgaa
     3781 aataatacac acaatcaaga aaaaaaaatt caggaagaaa tagaaaagaa ggaaacatta
     3841 atccaagaga atgtagtttt gcctcagata catacagtga ctggcactaa gaatttcatg
     3901 aagaaccttt tcttactgag cactaggcaa aatgtagaag gttcatatga cggggcatat
     3961 gctccagtac ttcaagattt taggtcatta aatgattcaa caaatagaac aaagaaacac
     4021 acagctcatt tctcaaaaaa aggggaggaa gaaaacttgg aaggcttggg aaatcaaacc
     4081 aagcaaattg tagagaaata tgcatgcacc acaaggatat ctcctaatac aagccagcag
     4141 aattttgtca cgcaacgtag taagagagct ttgaaacaat tcagactccc actagaagaa
     4201 acagaacttg aaaaaaggat aattgtggat gacacctcaa cccagtggtc caaaaacatg
     4261 aaacatttga ccccgagcac cctcacacag atagactaca atgagaagga gaaaggggcc
     4321 attactcagt ctcccttatc agattgcctt acgaggagtc atagcatccc tcaagcaaat
     4381 agatctccat tacccattgc aaaggtatca tcatttccat ctattagacc tatatatctg
     4441 accagggtcc tattccaaga caactcttct catcttccag cagcatctta tagaaagaaa
     4501 gattctgggg tccaagaaag cagtcatttc ttacaaggag ccaaaaaaaa taacctttct
     4561 ttagccattc taaccttgga gatgactggt gatcaaagag aggttggctc cctggggaca
     4621 agtgccacaa attcagtcac atacaagaaa gttgagaaca ctgttctccc gaaaccagac
     4681 ttgcccaaaa catctggcaa agttgaattg cttccaaaag ttcacattta tcagaaggac
     4741 ctattcccta cggaaactag caatgggtct cctggccatc tggatctcgt ggaagggagc
     4801 cttcttcagg gaacagaggg agcgattaag tggaatgaag caaacagacc tggaaaagtt
     4861 ccctttctga gagtagcaac agaaagctct gcaaagactc cctccaagct attggatcct
     4921 cttgcttggg ataaccacta tggtactcag ataccaaaag aagagtggaa atcccaagag
     4981 aagtcaccag aaaaaacagc ttttaagaaa aaggatacca ttttgtccct gaacgcttgt
     5041 gaaagcaatc atgcaatagc agcaataaat gagggacaaa ataagcccga aatagaagtc
     5101 acctgggcaa agcaaggtag gactgaaagg ctgtgctctc aaaacccacc agtcttgaaa
     5161 cgccatcaac gggaaataac tcgtactact cttcagtcag atcaagagga aattgactat
     5221 gatgatacca tatcagttga aatgaagaag gaagattttg acatttatga tgaggatgaa
     5281 aatcagagcc cccgcagctt tcaaaagaaa acacgacact attttattgc tgcagtggag
     5341 aggctctggg attatgggat gagtagctcc ccacatgttc taagaaacag ggctcagagt
     5401 ggcagtgtcc ctcagttcaa gaaagttgtt ttccaggaat ttactgatgg ctcctttact
     5461 cagcccttat accgtggaga actaaatgaa catttgggac tcctggggcc atatataaga
     5521 gcagaagttg aagataatat catggtaact ttcagaaatc aggcctctcg tccctattcc
     5581 ttctattcta gccttatttc ttatgaggaa gatcagaggc aaggagcaga acctagaaaa
     5641 aactttgtca agcctaatga aaccaaaact tacttttgga aagtgcaaca tcatatggca
     5701 cccactaaag atgagtttga ctgcaaagcc tgggcttatt tctctgatgt tgacctggaa
     5761 aaagatgtgc actcaggcct gattggaccc cttctggtct gccacactaa cacactgaac
     5821 cctgctcatg ggagacaagt gacagtacag gaatttgctc tgtttttcac catctttgat
     5881 gagaccaaaa gctggtactt cactgaaaat atggaaagaa actgcagggc tccctgcaat
     5941 atccagatgg aagatcccac ttttaaagag aattatcgct tccatgcaat caatggctac
     6001 ataatggata cactacctgg cttagtaatg gctcaggatc aaaggattcg atggtatctg
     6061 ctcagcatgg gcagcaatga aaacatccat tctattcatt tcagtggaca tgtgttcact
     6121 gtacgaaaaa aagaggagta taaaatggca ctgtacaatc tctatccagg tgtttttgag
     6181 acagtggaaa tgttaccatc caaagctgga atttggcggg tggaatgcct tattggcgag
     6241 catctacatg ctgggatgag cacacttttt ctggtgtaca gcaataagtg tcagactccc
     6301 ctgggaatgg cttctggaca cattagagat tttcagatta cagcttcagg acaatatgga
     6361 cagtgggccc caaagctggc cagacttcat tattccggat caatcaatgc ctggagcacc
     6421 aaggagccct tttcttggat caaggtggat ctgttggcac caatgattat tcacggcatc
     6481 aagacccagg gtgcccgtca gaagttctcc agcctctaca tctctcagtt tatcatcatg
     6541 tatagtcttg atgggaagaa gtggcagact tatcgaggaa attccactgg aaccttaatg
     6601 gtcttctttg gcaatgtgga ttcatctggg ataaaacaca atatttttaa ccctccaatt
     6661 attgctcgat acatccgttt gcacccaact cattatagca ttcgcagcac tcttcgcatg
     6721 gagttgatgg gctgtgattt aaatagttgc agcatgccat tgggaatgga gagtaaagca
     6781 atatcagatg cacagattac tgcttcatcc tactttacca atatgtttgc cacctggtct
     6841 ccttcaaaag ctcgacttca cctccaaggg aggagtaatg cctggagacc tcaggtgaat
     6901 aatccaaaag agtggctgca agtggacttc cagaagacaa tgaaagtcac aggagtaact
     6961 actcagggag taaaatctct gcttaccagc atgtatgtga aggagttcct catctccagc
     7021 agtcaagatg gccatcagtg gactctcttt tttcagaatg gcaaagtaaa ggtttttcag
     7081 ggaaatcaag actccttcac acctgtggtg aactctctag acccaccgtt actgactcgc
     7141 taccttcgaa ttcaccccca gagttgggtg caccagattg ccctgaggat ggaggttctg
     7201 ggctgcgagg cacaggacct ctactgaggg tggccactgc agcacctgcc actgccgtca
     7261 cctctccctc ctcagctcca gggcagtgtc cctccctggc ttgccttcta cctttgtgct
     7321 aaatcctagc agacactgcc ttgaagcctc ctgaattaac tatcatcagt cctgcatttc
     7381 tttggtgggg ggccaggagg gtgcatccaa tttaacttaa ctcttaccta ttttctgcag
     7441 ctgctcccag attactcctt ccttccaata taactaggca aaaagaagtg aggagaaacc
     7501 tgcatgaaag cattcttccc tgaaaagtta ggcctctcag agtcaccact tcctctgttg
     7561 tagaaaaact atgtgatgaa actttgaaaa agatatttat gatgttaaca tttcaggtta
     7621 agcctcatac gtttaaaata aaactctcag ttgtttatta tcctgatcaa gcatggaaca
     7681 aagcatgttt caggatcaga tcaatacaat cttggagtca aaaggcaaat catttggaca
     7741 atctgcaaaa tggagagaat acaataacta ctacagtaaa gtctgtttct gcttccttac
     7801 acatagatat aattatgtta tttagtcatt atgaggggca cattcttatc tccaaaacta
     7861 gcattcttaa actgagaatt atagatgggg ttcaagaatc cctaagtccc ctgaaattat
     7921 ataaggcatt ctgtataaat gcaaatgtgc atttttctga cgagtgtcca tagatataaa
     7981 gccatttggt cttaattctg accaataaaa aaataagtca ggaggatgca attgttgaaa
     8041 gctttgaaat aaaataacaa tgtcttcttg aaatttgtga tggccaagaa agaaaatgat
     8101 gatgacatta ggcttctaaa ggacatacat ttaatatttc tgtggaaata tgaggaaaat
     8161 ccatggttat ctgagatagg agatacaaac tttgtaattc taataatgca ctcagtttac
     8221 tctctccctc tactaatttc ctgctgaaaa taacacaaca aaaatgtaac aggggaaatt
     8281 atataccgtg actgaaaact agagtcctac ttacatagtt gaaatatcaa ggaggtcaga
     8341 agaaaattgg actggtgaaa acagaaaaaa cactccagtc tgccatatca ccacacaata
     8401 ggatccccct tcttgccctc cacccccata agattgtgaa gggtttactg ctccttccat
     8461 ctgcctgacc ccttcactat gactacacag aatctcctga tagtaaaggg ggctggagac
     8521 aaggataagt tatagagcag ttggaggaag catccaaaga ttgcaaccca gggcaaatgg
     8581 aaaacaggag atcctaatat gaaagaaaaa tggatcccaa tctgagaaaa ggcaaaagaa
     8641 tggctacttt tttctatgct ggagtatttt ctaataatcc tgcttgaccc ttatctgacc
     8701 tctttggaaa ctataacata gctgtcacag tatagtcaca atccacaaat gatgcaggtg
     8761 caaatggttt atagccctgt gaagttctta aagtttagag gctaacttac agaaatgaat
     8821 aagttgtttt gttttatagc ccggtagagg agttaacccc aaaggtgata tggttttatt
     8881 tcctgttatg tttaacttga taatcttatt ttggcattct tttcccattg actatataca
     8941 tctctatttc tcaaatgttc atggaactag ctcttttatt ttcctgctgg tttcttcagt
     9001 aatgagttaa ataaaacatt gacacataca aa
//
