ࡱ> q objbjt+t+ "AAU]8  i2:""DDDDBXiiiiiii$jliFDDFFicDDcccF[DDiFicciiD hci Van Siboriboun F8C Gene April 1, 2002 VS-1 Introduction: Hemophilia A is correlated to defects in the F8C (also known as the F8) gene, which produces an antihemophilic globulin called factor VIII. Hemophilia A is an X-linked recessive disorder involving mutation in the bloods ability to coagulate. This disease affects one in 10,000 males and has variable expressivity. Severe hemophilia has been observed in 50% of patients. Moderate severe hemophilia affects 10% of patients and mild hemophilia affect 30-40% of patients (OMIM 2002). Expressivity of this disease depends upon the level at which factor VIII, product of F8C gene, is deficient. Factor VIII is a clotting factor. Clotting factors are proteins, that are changed from the inactive to active form, in the plasma of blood that aids in activating different parts of coagulation (Norris 1999). If this factor is present at levels lower than 1%, then this will result in severe hemorrhaging, deep-tissue bleeding, and is present within the first year of an individuals life. Moderate hemophilia is associated with factor VIII levels of 1%-5%. Moderate hemophilia is present during childhood and involves bleeding following trauma. Mild hemophilia results when factor VIII levels are between 5% and 25%. The symptoms may be mild enough to go undetected. Mild hemophilia is present during adulthood and is characterized by bleeding after severe trauma or surgery (Leung 2002). Children with hemophilia A display a wide array of coagulation problems. Deep muscle bleeding, joint bleeding, mouth bleeding (especially during teething), and nose bleeding. Some serious problems are throat bleeding, which is accompanied by tonsillitis or strep throat; neck bleeding can obstruct the airway; head injuries may lead to brain hemorrhaging and abdominal and chest wall injuries. The process of blood coagulation is very complex and a flaw in any step may lead to a disorder in the clotting ability of blood. Plasma carries numerous coagulation factors and proteins that function in the regulation of bleeding. Another component of blood is platelets, which helps in the contraction of blood vessels after an injury and aids in the clotting of blood vessels. The actions of both plasma and platelets help to speed up blood clotting (Norris 1999). Heredity and Mapping: The F8C gene of hemophilia is located on the X chromosome at locus Xq28. This is one of the largest known human gene consisting of a 300,000 dalton protein. This gene is located on the long arm of the X chromosome in region 28. The factor VIII gene is about 1.1 megabase (Mb) from the telomere (end of the chromosome). Transcription moves towards the centromere (middle of chromosome). About one third of hemophilia A patients have no family history of the disease indicating a new mutation (Leung 2002). Hemophilia A is characteristic of an X-linked gene because a large amount of males have this disease. If a father has the X-linked gene for hemophilia, he will pass it to all his daughters. This will result in heterozygous female progeny if the mother does not carry the F8C gene. A mother who is a carrier of the F8C gene will pass the gene on to half her sons and half her daughters. All her sons who have the F8C gene will have hemophilia A while heterozygous daughters will only be carriers (Leung 2002). Although cases involving females with hemophilia A are 3.1 times less frequent than cases involving male hemophiliacs, it is possible to observe a homozygous female. The level of VS-2 phenotypic expression of hemophilia is the same for males and females who have the genes. There have been numerous explanations for cases of severe hemophilia in females. A couple of explanations include biased X-inactivation and mating between closely related couples (OMIM 2002). Gene Structure and Gene Projects: The F8C gene contains 186kb, 26 exons, and codes for a 300,000 dalton protein. The factor VIII complex has a high molecular weight due to the polymerization of its two different components. The first component is a factor VIII named factor VIIIc or factor VIIIAg depending upon how the factor is measured. A mature factor VIII protein consists of 2,332 amino acids. The 26 exons of the F8C gene is found in Chart 2 and the amino acid sequence is found in Chart 1 (OMIM 2002). The F8C gene has two spliced transcripts consisting of transcript variant 1 and transcript variant 2. Transcript variant 1 codes for isoform a, a glycoprotien that is found in plasma. Transcript variant 2 codes for isoform b, which is necessary for coagulation of the blood. Chart 1 (Information from SWISS-PROT) The amino acid sequence correlating to each exon is indifferent colors: 10 20 30 40 50 60 | | | | | | MQIELSTCFF LCLLRFCFSA TRRYYLGAVE LSWDYMQSDL GELPVDARFP PRVPKSFPFN 70 80 90 100 110 120 | | | | | | TSVVYKKTLF VEFTDHLFNI AKPRPPWMGL LGPTIQAEVY DTVVITLKNM ASHPVSLHAV 130 140 150 160 170 180 | | | | | | GVSYWKASEG AEYDDQTSQR EKEDDKVFPG GSHTYVWQVL KENGPMASDP LCLTYSYLSH 190 200 210 220 230 240 | | | | | | VDLVKDLNSG LIGALLVCRE GSLAKEKTQT LHKFILLFAV FDEGKSWHSE TKNSLMQDRD 250 260 270 280 290 300 | | | | | | AASARAWPKM HTVNGYVNRS LPGLIGCHRK SVYWHVIGMG TTPEVHSIFL EGHTFLVRNH 310 320 330 340 350 360 | | | | | | RQASLEISPI TFLTAQTLLM DLGQFLLFCH ISSHQHDGME AYVKVDSCPE EPQLRMKNNE 370 380 390 400 410 420 | | | | | | EAEDYDDDLT DSEMDVVRFD DDNSPSFIQI RSVAKKHPKT WVHYIAAEEE DWDYAPLVLA 430 440 450 460 470 480 VS-3 | | | | | | PDDRSYKSQY LNNGPQRIGR KYKKVRFMAY TDETFKTREA IQHESGILGP LLYGEVGDTL 490 500 510 520 530 540 | | | | | | LIIFKNQASR PYNIYPHGIT DVRPLYSRRL PKGVKHLKDF PILPGEIFKY KWTVTVEDGP 550 560 570 580 590 600 | | | | | | TKSDPRCLTR YYSSFVNMER DLASGLIGPL LICYKESVDQ RGNQIMSDKR NVILFSVFDE 610 620 630 640 650 660 | | | | | | NRSWYLTENI QRFLPNPAGV QLEDPEFQAS NIMHSINGYV FDSLQLSVCL HEVAYWYILS 670 680 690 700 710 720 | | | | | | IGAQTDFLSV FFSGYTFKHK MVYEDTLTLF PFSGETVFMS MENPGLWILG CHNSDFRNRG 730 740 750 760 770 780 | | | | | | MTALLKVSSC DKNTGDYYED SYEDISAYLL SKNNAIEPRS FSQNSRHPST RQKQFNATTI 790 800 810 820 830 840 | | | | | | PENDIEKTDP WFAHRTPMPK IQNVSSSDLL MLLRQSPTPH GLSLSDLQEA KYETFSDDPS 850 860 870 880 890 900 | | | | | | PGAIDSNNSL SEMTHFRPQL HHSGDMVFTP ESGLQLRLNE KLGTTAATEL KKLDFKVSST 910 920 930 940 950 960 | | | | | | SNNLISTIPS DNLAAGTDNT SSLGPPSMPV HYDSQLDTTL FGKKSSPLTE SGGPLSLSEE 970 980 990 1000 1010 1020 | | | | | | NNDSKLLESG LMNSQESSWG KNVSSTESGR LFKGKRAHGP ALLTKDNALF KVSISLLKTN 1030 1040 1050 1060 1070 1080 | | | | | | KTSNNSATNR KTHIDGPSLL IENSPSVWQN ILESDTEFKK VTPLIHDRML MDKNATALRL 1090 1100 1110 1120 1130 1140 | | | | | | NHMSNKTTSS KNMEMVQQKK EGPIPPDAQN PDMSFFKMLF LPESARWIQR THGKNSLNSG 1150 1160 1170 1180 1190 1200 | | | | | | QGPSPKQLVS LGPEKSVEGQ NFLSEKNKVV VGKGEFTKDV GLKEMVFPSS RNLFLTNLDN 1210 1220 1230 1240 1250 1260 | | | | | | LHENNTHNQE KKIQEEIEKK ETLIQENVVL PQIHTVTGTK NFMKNLFLLS TRQNVEGSYD 1270 1280 1290 1300 1310 1320 VS-4 | | | | | | GAYAPVLQDF RSLNDSTNRT KKHTAHFSKK GEEENLEGLG NQTKQIVEKY ACTTRISPNT 1330 1340 1350 1360 1370 1380 | | | | | | SQQNFVTQRS KRALKQFRLP LEETELEKRI IVDDTSTQWS KNMKHLTPST LTQIDYNEKE 1390 1400 1410 1420 1430 1440 | | | | | | KGAITQSPLS DCLTRSHSIP QANRSPLPIA KVSSFPSIRP IYLTRVLFQD NSSHLPAASY 1450 1460 1470 1480 1490 1500 | | | | | | RKKDSGVQES SHFLQGAKKN NLSLAILTLE MTGDQREVGS LGTSATNSVT YKKVENTVLP 1510 1520 1530 1540 1550 1560 | | | | | | KPDLPKTSGK VELLPKVHIY QKDLFPTETS NGSPGHLDLV EGSLLQGTEG AIKWNEANRP 1570 1580 1590 1600 1610 1620 | | | | | | GKVPFLRVAT ESSAKTPSKL LDPLAWDNHY GTQIPKEEWK SQEKSPEKTA FKKKDTILSL 1630 1640 1650 1660 1670 1680 | | | | | | NACESNHAIA AINEGQNKPE IEVTWAKQGR TERLCSQNPP VLKRHQREIT RTTLQSDQEE 1690 1700 1710 1720 1730 1740 | | | | | | IDYDDTISVE MKKEDFDIYD EDENQSPRSF QKKTRHYFIA AVERLWDYGM SSSPHVLRNR 1750 1760 1770 1780 1790 1800 | | | | | | AQSGSVPQFK KVVFQEFTDG SFTQPLYRGE LNEHLGLLGP YIRAEVEDNI MVTFRNQASR 1810 1820 1830 1840 1850 1860 | | | | | | PYSFYSSLIS YEEDQRQGAE PRKNFVKPNE TKTYFWKVQH HMAPTKDEFD CKAWAYFSDV 1870 1880 1890 1900 1910 1920 | | | | | | DLEKDVHSGL IGPLLVCHTN TLNPAHGRQV TVQEFALFFT IFDETKSWYF TENMERNCRA 1930 1940 1950 1960 1970 1980 | | | | | | PCNIQMEDPT FKENYRFHAI NGYIMDTLPG LVMAQDQRIR WYLLSMGSNE NIHSIHFSGH 1990 2000 2010 2020 2030 2040 | | | | | | VFTVRKKEEY KMALYNLYPG VFETVEMLPS KAGIWRVECL IGEHLHAGMS TLFLVYSNKC 2050 2060 2070 2080 2090 2100 | | | | | | QTPLGMASGH IRDFQITASG QYGQWAPKLA RLHYSGSINA WSTKEPFSWI KVDLLAPMII VS-5 2110 2120 2130 2140 2150 2160 | | | | | | HGIKTQGARQ KFSSLYISQF IIMYSLDGKK WQTYRGNSTG TLMVFFGNVD SSGIKHNIFN 2170 2180 2190 2200 2210 2220 | | | | | | PPIIARYIRL HPTHYSIRST LRMELMGCDL NSCSMPLGME SKAISDAQIT ASSYFTNMFA 2230 2240 2250 2260 2270 2280 | | | | | | TWSPSKARLH LQGRSNAWRP QVNNPKEWLQ VDFQKTMKVT GVTTQGVKSL LTSMYVKEFL 2290 2300 2310 2320 2330 2340 | | | | | | ISSSQDGHQW TLFFQNGKVK VFQGNQDSFT PVVNSLDPPL LTRYLRIHPQ SWVHQIALRM 2350 | EVLGCEAQDL Y Chart 2(exons are colored; information from www.ncbi.nlm.nih.gov) 1 gcttagtgct gagcaatcca gtgggtaaag ttccttaaaa tgctctgcaa agaaattggg 61 acttttcatt aaatcagaaa ttttactttt ttcccctcct gggagctaaa gatattttag 121 agaagaatta accttttgct tctccagttg aacatttgta gcaataagtc atgcaaatag 181 agctctccac ctgcttcttt ctgtgccttt tgcgattctg ctttagtgcc accagaagat 241 actacctggg tgcagtggaa ctgtcatggg actatatgca aagtgatctc ggtgagctgc 301 ctgtggacgc aaggtaaagg catgtcctgt agggtctgat cggggccagg attgtgggga 361 tgtaagtctg cttggaggaa ggtgcagaca tcgggttagg atggttgtga tgctacctgg 421 gccccaaaga aacatttctg ggtaaggtgt gcacacatct gtgttattag cagaaatgct 481 aactgcccac gtgtatggtt attgatttta tgattcttat catatggcac ctaatgtatc 541 agttgagttg tgaaaacagt gtttcggttt aatggatgtt agggatttat atacaacttc 601 aaatttgcct ccttgctaat agtagaaaag agtagtatgg aagcattact tccagctgct 661 ttttgaagtg tccaccaaaa tgaacgactt tttcctttct tcacgcagat ttcctcctag 721 agtgccaaaa tcttttccat tcaacacctc agtcgtgtac aaaaagactc tgtttgtaga 781 attcacggat caccttttca acatcgctaa gccaaggcca ccctggatgg gtaatgaaaa 841 caatgttgaa tgctatttat gaaattgggt atcttatttt ctatcacaga ttccccaatc 901 ttgaggttgc agttaaaaag tgcagctgcc aaagagaatg tttccctaag catgcttctc 961 cactgtgacc ttgactctaa cttttggaat aacaggtttt ctggagtact atccccaagt 1021 aacctttggc ggacatctca ttcttacagg tctgctaggt cctaccatcc aggctgaggt 1081 ttatgataca gtggtcatta cacttaagaa catggcttcc catcctgtca gtcttcatgc 1141 tgttggtgta tcctactgga aagcttctga gggtgagtaa ataccctcct attgtcctgt 1201 cattctatga ataggtacag tggatataga aaggacaatt ttatttcttc ctgctatagg 1261 agctgaatat gatgatcaga ccagtcaaag ggagaaagaa gatgataaag tcttccctgg 1321 tggaagccat acatatgtct ggcaggtcct gaaagagaat ggtccaatgg cctctgaccc 1381 actgtgcctt acctactcat atctttctca tgtggacctg gtaaaagact tgaattcagg 1441 cctcattgga gccctactag tatgtagaga aggtaagtgt atgaaagcgt aggattgaga 1501 tgaaataagc agagaagtac aaacaactga atcttcttac tgtcaagtaa ctgatgaaga 1561 actgtctcct cctagtgaca atttcctaca atgagatttt ttaaatagaa gataaatgtt 1621 ctcacttctt tttcagggag tctggccaag gaaaagacac agaccttgca caaatttata 1681 ctactttttg ctgtatttga tgaaggttag tgagtcttaa tctgaatttt ggattcctga 1741 aagaaatcct ctgctactat taagaggagg tgattataga aagatcataa attacattac 1801 tgttcaggaa tgaaggagat ggggttaaaa atgaattcct acgattacag gtgtgagcca 1861 ccgcgcccgg cccctaggat gattttcata agctttcttt taaataattc agctaataaa 1921 aagaattgaa tcctgatgcc tcaagctaac caatattctg tcttctatta ttatccattc 1981 ccacttattg tcatggacaa atggagggag agaaaatcag tttgagcaag agatgtctgc 2041 ctttacataa ttatcttctc cctccctcac actgactttg agaggataag tgctgtgtgc 2101 ctactttgct gacaaaaatg cttaaggtgt gagcacactg ggagcaggga aggagaaagg 2161 ggaggcggtc attcatgaga caccatgctt agctgactct actctttgcc ttctctctca 2221 tcagggaaaa gttggcactc agaaacaaag aactccttga tgcaggatag ggatgctgca 2281 tctgctcggg cctggcctaa aatgcacaca gtcaatggtt atgtaaacag gtctctgcca 2341 ggtatgtaca cacctgctca acaatcctca gggtcttcca aattcagcac cagagttctg 2401 tactttcaga ttctctactt catagccata ggtgtcttat tcctacttta caggtctgat 2461 tggatgccac aggaaatcag tctattggca tgtgattgga atgggcacca ctcctgaagt 2521 gcactcaata ttcctcgaag gtcacacatt tcttgtgagg aaccatcgcc aggcgtcctt 2581 ggaaatctcg ccaataactt tccttactgc tcaaacactc ttgatggacc ttggacagtt 2641 tctactgttt tgtcatatct cttcccacca acatggtaat atcttggatc tttaaaatga 2701 atattataaa tatccagtcc tacttttaat aaaatttact ggacaatgtc cctcatggct 2761 tgatgctgtc ttcatgatat ttggtcattc agaagtgtgt ggcaacttgc actctctgtc 2821 ttgctcctgc tttcaccatg tgacatgtct cctccccctt cacctacccc catgattgta 2881 agcttcctga gacctccctg aagccaagca gatgccagca ccatgcttcc catatagcct 2941 gcagaacatg agccaattca atctcttttc tttataaatt acctagtctc tggtatagaa 3001 cagcctaata tagcaagaca ctctgacatt gtttggtttg tctgactcca gatggcatgg 3061 aagcttatgt caaagtagac agctgtccag aggaacccca actacgaatg aaaaataatg 3121 aagaagcgga agactatgat gatgatctta ctgattctga aatggatgtg gtcaggtttg 3181 atgatgacaa ctctccttcc tttatccaaa ttcgctcagt tgccaagaag catcctaaaa 3241 cttgggtaca ttacattgct gctgaagagg aggactggga ctatgctccc ttagtcctcg 3301 cccccgatga caggtaagca ctttttgact attggtactc tctcttcccc atactcaaaa 3361 agttcttacc agttattcaa accaacaaat cctgaagcca tgtttaaggt taggtacagg 3421 tatggaatca aatggcaagg gtattaacat ttggaaacta acatagctga gcatcagaga 3481 agcttgtatt tttctcactc cttgccttga ttgaatcata taagctgttt tagagttgga 3541 tttgagccta cctagaattt ttcttcccaa cctctcatct ttttttctct tatacagaag 3601 ttataaaagt caatatttga acaatggccc tcagcggatt ggtaggaagt acaaaaaagt 3661 ccgatttatg gcatacacag atgaaacctt taagactcgt gaagctattc agcatgaatc 3721 aggaatcttg ggacctttac tttatgggga agttggagac acactgttgg taagttgaag 3781 aaaagattta aggtcaggta agaagaaaaa gtctggagag ttttgagttt ctaaaatacc 3841 tcataattca gccttgtctc caatggacat atcttttaca tgagaggatg tgcatatgtt 3901 atatgcaaat actacatcat tttgagtaag agacttgagc atcacagatt gtggtatctg 3961 caggggtcct ggaaccaatc ctccatgcat gccaaggaac aatttcatga aaagaccaaa 4021 tattttgagt tttatctagc ctcaaattac tataatgtag gatagaggcc acttttattt 4081 atctggagtt agaccacagt tttcttgttg atcctagtcg ttttaggatt tgatcttaga 4141 tctcgcttat actttcagat tatatttaag aatcaagcaa gcagaccata taacatctac 4201 cctcacggaa tcactgatgt ccgtcctttg tattcaagga gattaccaaa aggtaaatat 4261 tccctcgttt atagctcact ctaattgagc tatttatggt tttgcttgtg ggtaggtgta 4321 aaacatttga aggattttcc aattctgcca ggagaaatat tcaaatataa atggacagtg 4381 actgtagaag atgggccaac taaatcagat cctcggtgcc tgacccgcta ttactctagt 4441 ttcgttaata tggagagaga tctagcttca ggactcattg gccctctcct catctgctac 4501 aaagaatctg tagatcaaag aggaaaccag gtgagttctt gcctttccaa gtgctgggtt 4561 tcattctcag tgtatgtccc cttataacct gaagaaaata taatggtttg caatataggt 4621 cagtaaagaa tgagcttagc ttttgcatgc catcgctttc atcatagact gctagctcct 4681 acctgacaac atcagtagca tttctttacc cctttcaata tatgtaatta acag gtgta 4321 aaacatttga aggattttcc aattctgcca ggagaaatat tcaaatataa atggacagtg 4381 actgtagaag atgggccaac taaatcagat cctcggtgcc tgacccgcta ttactctagt 4441 ttcgttaata tggagagaga tctagcttca ggactcattg gccctctcct catctgctac 4501 aaagaatctg tagatcaaag aggaaaccag gtgag taaagcagca cttaagtcca gtgggtggtg 4921 aataaagaaa aattgatgta atcaaagtga tgtccagata atgaatgaat tgtatgtgca 4981 cataaattta acaattatgt tacctataaa tgtataattt ttactcaaac acacgtgatc 5041 atataaccca tattttaaaa atccagccca actgattatt aacaatctac ttttttggaa 5101 gatataatat ctcttcctgg gaataagata atgggcataa catataataa ttcctaattg 5161 tatcatgaca atcacaatcc aaaatactaa atctgtgatg tgtctaaatc tcttttcccc 5221 attgtttttg caggcatcaa tggctatgtt tttgatagtt tgcagttgtc agtttgtttg 5281 catgaggtgg catactggta cattctaagc attggagcac agactgactt cctttctgtc 5341 ttcttctctg gatatacctt caaacacaaa atggtctatg aagacacact caccctattc 5401 ccattctcag gagaaactgt cttcatgtcg atggaaaacc caggttagtt attatatgga 5461 tcctagacct aaatgatcct tccttgtgct tacatattct gcaagtgggt gacagtggat 5521 gctaggtatt gtgttatgtg atttcaatgt attatatgat ggggtagata ctattagcct 5581 catttgaaaa ttagaaacct attgttcaga aagtttaagt gactttctca aagtcacaca 5641 gctggtaaat ggtagaactg ggatttgaat ccaggcaatc tgatggattt aagaggaacc 5701 tgtgccacta tgtgatatag caataacatc tagccaatat aaatactttc ctgaattaaa 5761 tcactgtcat attcagagag ttctgtgtca ctattaagac cctccattat tgtgtatatt 5821 aattacattt ccctatttta atcccaatat ctattcattt ttatcacagt cctttcttat 5881 ggtcacaaac aggcatagta caacagcagc aatgcaaaaa ccacttttat attacatgtt 5941 ccagggattt aacccaatga cctgtgatat aatgatactg actagtattt tttcatttat 6001 ctgggaatgg gagagaacct ctaacagaac gttttagaat ctgtgttatg agtaaccaga 6061 gtcttattct tcctcatctc caggtctatg gattctgggg tgccacaact cagactttcg 6121 gaacagaggc atgaccgcct tactgaaggt ttctagttgt gacaagaaca ctggtgatta 6181 ttacgaggac agttatgaag atatttcagc atacttgctg agtaaaaaca atgccattga 6241 accaagaagc ttctcccaga attcaagaca ccctagcact aggcaaaagc aatttaatgc 6301 caccacaatt ccagaaaatg acatagagaa gactgaccct tggtttgcac acagaacacc 6361 tatgcctaaa atacaaaatg tctcctctag tgatttgttg atgctcttgc gacagagtcc 6421 tactccacat gggctatcct tatctgatct ccaagaagcc aaatatgaga ctttttctga 6481 tgatccatca cctggagcaa tagacagtaa taacagcctg tctgaaatga cacacttcag 6541 gccacagctc catcacagtg gggacatggt atttacccct gagtcaggcc tccaattaag 6601 attaaatgag aaactgggga caactgcagc aacagagttg aagaaacttg atttcaaagt 6661 ttctagtaca tcaaataatc tgatttcaac aattccatca gacaatttgg cagcaggtac 6721 tgataataca agttccttag gacccccaag tatgccagtt cattatgata gtcaattaga 6781 taccactcta tttggcaaaa agtcatctcc ccttactgag tctggtggac ctctgagctt 6841 gagtgaagaa aataatgatt caaagttgtt agaatcaggt ttaatgaata gccaagaaag 6901 ttcatgggga aaaaatgtat cgtcaacaga gagtggtagg ttatttaaag ggaaaagagc 6961 tcatggacct gctttgttga ctaaagataa tgccttattc aaagttagca tctctttgtt 7021 aaagacaaac aaaacttcca ataattcagc aactaataga aagactcaca ttgatggccc 7081 atcattatta attgagaata gtccatcagt ctggcaaaat atattagaaa gtgacactga 7141 gtttaaaaaa gtgacacctt tgattcatga cagaatgctt atggacaaaa atgctacagc 7201 tttgaggcta aatcatatgt caaataaaac tacttcatca aaaaacatgg aaatggtcca 7261 acagaaaaaa gagggcccca ttccaccaga tgcacaaaat ccagatatgt cgttctttaa 7321 gatgctattc ttgccagaat cagcaaggtg gatacaaagg actcatggaa agaactctct 7381 gaactctggg caaggcccca gtccaaagca attagtatcc ttaggaccag aaaaatctgt 7441 ggaaggtcag aatttcttgt ctgagaaaaa caaagtggta gtaggaaagg gtgaatttac 7501 aaaggacgta ggactcaaag agatggtttt tccaagcagc agaaacctat ttcttactaa 7561 cttggataat ttacatgaaa ataatacaca caatcaagaa aaaaaaattc aggaagaaat 7621 agaaaagaag gaaacattaa tccaagagaa tgtagttttg cctcagatac atacagtgac 7681 tggcactaag aatttcatga agaacctttt cttactgagc actaggcaaa atgtagaagg 7741 ttcatatgac ggggcatatg ctccagtact tcaagatttt aggtcattaa atgattcaac 7801 aaatagaaca aagaaacaca cagctcattt ctcaaaaaaa ggggaggaag aaaacttgga 7861 aggcttggga aatcaaacca agcaaattgt agagaaatat gcatgcacca caaggatatc 7921 tcctaataca agccagcaga attttgtcac gcaacgtagt aagagagctt tgaaacaatt 7981 cagactccca ctagaagaaa cagaacttga aaaaaggata attgtggatg acacctcaac 8041 ccagtggtcc aaaaacatga aacatttgac cccgagcacc ctcacacaga tagactacaa 8101 tgagaaggag aaaggggcca ttactcagtc tcccttatca gattgcctta cgaggagtca 8161 tagcatccct caagcaaata gatctccatt acccattgca aaggtatcat catttccatc 8221 tattagacct atatatctga ccagggtcct attccaagac aactcttctc atcttccagc 8281 agcatcttat agaaagaaag attctggggt ccaagaaagc agtcatttct tacaaggagc 8341 caaaaaaaat aacctttctt tagccattct aaccttggag atgactggtg atcaaagaga 8401 ggttggctcc ctggggacaa gtgccacaaa ttcagtcaca tacaagaaag ttgagaacac 8461 tgttctcccg aaaccagact tgcccaaaac atctggcaaa gttgaattgc ttccaaaagt 8521 tcacatttat cagaaggacc tattccctac ggaaactagc aatgggtctc ctggccatct 8581 ggatctcgtg gaagggagcc ttcttcaggg aacagaggga gcgattaagt ggaatgaagc 8641 aaacagacct ggaaaagttc cctttctgag agtagcaaca gaaagctctg caaagactcc 8701 ctccaagcta ttggatcctc ttgcttggga taaccactat ggtactcaga taccaaaaga 8761 agagtggaaa tcccaagaga agtcaccaga aaaaacagct tttaagaaaa aggataccat 8821 tttgtccctg aacgcttgtg aaagcaatca tgcaatagca gcaataaatg agggacaaaa 8881 taagcccgaa atagaagtca cctgggcaaa gcaaggtagg actgaaaggc tgtgctctca 8941 aaacccacca gtcttgaaac gccatcaacg ggaaataact cgtactactc ttcagtcaga 9001 tcaagaggaa attgactatg atgataccat atcagttgaa atgaagaagg aagattttga 9061 catttatgat gaggatgaaa atcagagccc ccgcagcttt caaaagaaaa cacgacacta 9121 ttttattgct gcagtggaga ggctctggga ttatgggatg agtagctccc cacatgttct 9181 aagaaacagg tatgaatgca ttggttattc ctttgctctg ctcttgtgac atttgacttt 9241 accagatgat gacaccaaca atgagagtta gaggatgaaa aatcaaggtg tcttgaaact 9301 cttactctgg tgagatagag agaagagagg tttacaagag ggtagaggaa tcagggacaa 9361 gaaggagcaa tggggagcag gaagaaagtc aacctcacct atcaacctta tgagctgcag 9421 gggaaatctt agtctcatca gagaacttta agcaaggcag aaggaagaag caagttcgtg 9481 ttaaagaggt taaggacttg gggaggattg gttttcatga tactggggat ccttacatgc 9541 taataaagct tggcaagagt atttcaagga agatgaagtg gttaactatg caaaatgctt 9601 ctcaggcacc taggaaaatg aggatgtgag gcatttctac ccacttggta cataaaatta 9661 ttgcttttcc tctgcttttt ttctccaggg ctcagagtgg cagtgtccct cagttcaaga 9721 aagttgtttt ccaggaattt actgatggct cctttactca gcccttatac cgtggagaac 9781 taaatgaaca tttgggactc ctggggccat atataagagc agaagttgaa gataatatca 9841 tggtgagtta aggacagtgg aattacaaga aaattaattt tatatattta ttttcttgct 9901 gactataatg tattcccact tttggaaatt tttaaagtat agaaaaataa ttccataatt 9961 atctttgtgt acgttctatt tttcctatgt atttttctcc ttatgtattc aaattatacc 10021 atgcagaatt caagctttta gacagtttct tttttcacta tataaataac gctgtaatca 10081 caacagtttt tctaagataa aattccagaa gtgcaatgta tttgagcatc ttaagagttt 10141 ttcttattaa ttatttggta atgtcccttg cacatttgtc tttcatggag gaagtgcttt 10201 tcttattgat tatgttacct tatatattag atagtaaacc actgaacatt ttaatgagag 10261 gtactttttc aagtttttgt tttctcttaa ttttataaat gatggttttt gaaataaaac 10321 aggttttaat ttttaggtag taacccatca atctttactt tttgacactt tcattgcttt 10381 tatgtttata aaaattcctg cctatccaga gattttttaa aaaacaccta tactttcctc 10441 agtttttctc ttacagttta attttttaca tttaactttt taatacttcc tgtagactaa 10501 agttattttg gtgcattgtg tgaaccaaga tcaagtagtt tattttttct gaaatatcta 10561 tgctgttcaa ttaattgatg gtgtatatta aggatgtaga aggatctaaa attatggaat 10621 gtgggcaatt ttgccttaca ttttatttta ctttccatta tattctatga taaatatgta 10681 taatttttaa tctggaaagt aagccttttt taaaagataa tatgcattca ttctagaatt 10741 tgtcatgaag aaccttaact tacatatcaa ctcctggcgt tatggtctct tataacccct 10801 gcagtaacat tttccctttt actctggaat ggcttttatg tgtttaggaa ttttctcctt 10861 tgcaactttg agttcatacc ttaaatttag aatacaaaac ctcctcagga ttaggtttga 10921 gttctaacag catccatctt ctgtaccact tcttccaggg tattaaaaac tttgataaag 10981 accaaaagac aggtatttct tttagggatg taaaccctaa ggaccttaag atcctagaag 11041 attattcttg cttttttttt tttgtcgtta ttgttctaca ggtaactttc agaaatcagg 11101 cctctcgtcc ctattccttc tattctagcc ttatttctta tgaggaagat cagaggcaag 11161 gagcagaacc tagaaaaaac tttgtcaagc ctaatgaaac caaaacttac ttttggaaag 11221 tgcaacatca tatggcaccc actaaagatg agtttgactg caaagcctgg gcttatttct 11281 ctgatgttga cctggtaagc aggtgtctat tgtgctgacc actttttggt ttaaaagaaa 11341 tggtctttgt gtactaagaa ttttgatatt tatcctacgt gcaataagaa gctttaaata 11401 ggagagttga tcattatatt tgtgttttag aaatgtcatt ctggaatcta ctgaagagga 11461 tggattatat ttttggaagg tgggaggcag gttggactgg cataaaaatt gatgagaaat 11521 ccactctggt tcataggtga gagagcttat actcatagga ttgatgtctt ccctccctag 11581 gaaaaagatg tgcactcagg cctgattgga ccccttctgg tctgccacac taacacactg 11641 aaccctgctc atgggagaca agtgacagta caggaatttg ctctgttttt caccatcttt 11701 gatgagacca aaagctggta cttcactgaa aatatggaaa gaaactgcag ggctccctcg 11761 aatatccaga tggaagatcc cacttttaaa gagaattatc gcttccatgg taatatattc 11821 cacatccaaa cattatcact gtgaaatgca gattgcactt tgacaaatga gacttgatcc 11881 agggacttga acattgtatt tatttagagt atatctgtgg gagtggaatc ctcatagatg 11941 tcagtttttt tggtggagtg gagagaaaga aacttatata atagatttta acaggcttct 12001 ctgtgtcctt ctccagcaat caatggctac ataatggata cactacctgg cttagtaatg 12061 gctcaggatc aaaggattcg atggtatctg ctcagcatgg gcagcaatga aaacatccat 12121 tctattcatt tcagtggaca tgtgttcact gtacgaaaaa aagaggagta taaaatggca 12181 ctgtacaatc tctatccagg tatgagcttg tttgtgctct ttcttctacc tactctattt 12241 gttgagtact tactttaaat ggtctaggca ctgggaacac aatcagtgat caaagcagac 12301 aagctccatg ctcttaagta atactttttc aaatgctttt taaaccattt gttcaaagca 12361 aatgaacaag ataatttcag atatagaaaa attgctaaaa aggaaataga acagaataaa 12421 tggataatta atgtcacagt actttcctag ggaaaaggaa tttattcctt tatcatttac 12481 catctcaaat cccatagggc accagtagtc atccaaagag tcatttgttt atgtatgtaa 12541 ccagtatatt gattaagcac tactcataat gttgatcaca acacaatttt attttggttc 12601 ttcactgtcc ctttaaaata gatttggcca ggtgcgatgg ctcacacttg taatcccagc 12661 actttgggag gccaaggttg gaggattgct tgaggccagg agttcaagac cagcctgggt 12721 gacaaagcaa gacccccatc tctacaaaaa ataattagcc agacatgtgg tatatacctg 12781 tagtcccagc tacttcacct acttgggtgg ctgaagtgga aggattgctt gagcccagga 12841 ggttgatgct gcagtgagct atgaaagtgc cactgcatca aacttggaca acagagcaag 12901 accctgtctc taaaaaaaaa aaaccatcca gtttaatagc gggggtaaac tttccttatt 12961 tcttcgtaaa aattctgata agccctgtaa cttttctgct cacccttaag taataaacag 13021 gactaaagtc actttatgtc acaaatacag ttcaaatcag aaattacaat gtccatccca 13081 agatattaat caaaattgta aacttgattt aacttcaatc tcccctcctc caacttgagc 13141 ctgcatcagg ctggaagtct gcattggaaa agggagacat ggttgagtcc tctgtttctg 13201 taccttgtga tgatcgtgct tccccacaac ccctttatag ctgctgtttt gaactccaac 13261 atggataggt taaaggtaag gggataagat agttcttacc tatttacagc tggcaccatt 13321 gttgtaaact agcttaacac tgtttgtgcc tggcaatact tgttgactct ttctcctgca 13381 gggcactttc agggaactct ttagagactc ccttacgtga ctgtcatgaa atccccttga 13441 catgatttct tccaccttta ctctgggtgg tcacttgtga ctcatttctc agccctcagt 13501 gttcacctgc agcttcttgt tgctggggta actttaccct tgtaggcagc tctagtggac 13561 tggatccaga gggaactcac cctgacttat ctgtttcaca gagtccacat ctggccaatg 13621 ggaaacacac cttttgctca gaaagaccct gggaatgtag gtcaatcata atgagtagca 13681 ttctccttcc caaccatcaa agaattcact caccctgttt ctcatctgct ggggggaggg 13741 gagtggtcag aactcaatct ccacaacccc caactgtaag ggtcacgtag caagcacttt 13801 gcatttgagg ggtccaaaag tagtggaact accaaatttg gtaggtctac tctgatattt 13861 cgcataaacc aatgtatctc atgctcattt tttagtgaaa agaaataatt tctgttcctg 13921 ttggttttta taaggtgttt ttgagacagt ggaaatgtta ccatccaaag ctggaatttg 13981 gcgggtggaa tgccttattg gcgagcatct acatgctggg atgagcacac tttttctggt 14041 gtacagcaat agtgagtagc aatgtgggca gaggttccct acctactcag cctacttctt 14101 tacagctttc ttcctttctg gaatggttgc ttgtgtcagg aaataaatac aagtttacat 14161 cattatcaaa tttaaaatga atattgctgg tagaaatcat cagagttctc agagtagggc 14221 agatatactt gaagctttga acactttgta cctgaagctc taaataattg acaaaaaaaa 14281 aataccacct catttttcac aacttggtaa agctcgaaga tctccagtag cagatttttg 14341 gaatttaatg ttgatttagt taccagataa cttagaaata ctacttggaa gagtttggag 14401 attaacccta aacaagtaag agagccactg gtctattatg tatggacccc agtttcttca 14461 gctgtaaaat gtgaatcatt ctagcacctg ttaggattaa ttaaatgaac taatacagta 14521 aaacgttgag tacagttctt ggcacattta aacactaaaa atagcatttg ttgacgttct 14581 cccattttca ttgacttaca tttgagaagc tgaattttgt gcactctagt tactgtgttc 14641 cacccgtttc atttcagagt gtcagactcc cctgggaatg gcttctggac acattagaga 14701 ttttcagatt acagcttcag gacaatatgg taaatactat tatttttgct ccaagaacct 14761 gggctgatta tatctttttt taataatctg gtggagaatc tcagataatg aatccatctc 14821 catgcttcta ttagttctat tccataagtg cctctcaaat acatctcctc ctctccactt 14881 cccactgtgg ccatcttaac tcaggtcacc atcatttctt acctgggcaa tgacactgcc 14941 tcttaaatat cctccctacc ttcagtattt cttccttgag tcaattcttt tcagtgcagc 15001 aggaagctat actttcctat gagcagtaat ggtaaagttt gactagggtc tatagagaat 15061 tcgaatttaa tctctgattt ctctacttac ttgggcaaag gacagtgggc cccaaagctg 15121 gccagacttc attattccgg atcaatcaat gcctggagca ccaaggagcc cttttcttgg 15181 atcaaggtta gaaaatgtaa tcaatgatgg gaaatgtatc acattcactc tttaaaaata 15241 ggttaaaata aagtgttatt ttaattggta ggtggatctg ttggcaccaa tgattattca 15301 cggcatcaag acccagggtg cccgtcagaa gttctccagc ctctacatct ctcagtttat 15361 catcatgtat agtcttgatg ggaagaagtg gcagacttat cgaggaaatt ccactggaac 15421 cttaatggta tgtaattagt catttaaacc tgccttatta aagtattgat ctttgttctt 15481 gagctctacc agggtttctc aacctcctac ctgaatccca aggctcccac aaagacactt 15541 ttgtccatag atcattgtca aattattgtt cctgtggggg aacaagagct agggacctcc 15601 tatccccatc aactcactga taccgttctc ctgatgctgc attttgaatt gccctcaggt 15661 gatgctgcct actcctggtc tgtggaccat gctggagtag cagagcccaa atggcttcct 15721 caacttttat gagcctttta caggaactca aagtagaaaa taacttcact tgccccagac 15781 ctaataattt cctttgttcc cacttcttct tggtgctttc ctcctttgtg tctaccatcg 15841 taacatccat ctaaccatag ttgtcttatg tagatgttgg atgctgttga gaaacgcaca 15901 aagcaaatta gaaggaagat atgattgaca gaaattgctt tttactctgt attcactttc 15961 catgtatttg tgctaatctc tccatacagg tcttctttgg caatgtggat tcatctggga 16021 taaaacacaa tatttttaac cctccaatta ttgctcgata catccgtttg cacccaactc 16081 attatagcat tcgcagcact cttcgcatgg agttgatggg ctgtgattta aatagtaagt 16141 gccaagtcat cccatatcct tcttccctca accatgggta gggtgactaa ctgttctagt 16201 tatcctgaga ctgggggagg ggttcccggt atcaggacac aaaatcagtg gaagctgctc 16261 agtataactg aggctgaagc atgtccttgt gataaccttc ttttttcttt tctttgaggt 16321 tgcagcatgc cattgggaat ggagagtaaa gcaatatcag atgcacagat tactgcttca 16381 tcctacttta ccaatatgtt tgccacctgg tctccttcaa aagctcgact tcacctccaa 16441 gggaggagta atgcctggag acctcaggta agaggcaaca gatttactgt ttaactgact 16501 cagagaaaaa gaaagtagag tgagaagtgc tgtggtatgg ttaagaggga tttgggaatt 16561 tctgggagta aatggtgacc aagaggctac tagtccaact ctattgccct caggtgaata 16621 atccaaaaga gtggctgcaa gtggacttcc agaagacaat gaaagtcaca ggagtaacta 16681 ctcagggagt aaaatctctg cttaccagca tgtatgtgaa ggagttcctc atctccagca 16741 gtcaagatgg ccatcagtgg actctctttt ttcagaatgg caaagtaaag gtaagctggc 16801 acttaatgtc actgaggttt gggaagtggg tgagaacact gtagatataa ggcctagcta 16861 gagtgaaggc ctccaaagca gggtgctctt aattctagat gtcccagatg cgtaggacag 16921 agtcatctag tcatcttcca gggtttaatc ctggactact ggaaacaact agaagtgaga 16981 aaagcgtctg tgctttgcag tgaccattgt cctgtcagac aaccaataaa tgctatcttt 17041 cctctttcag gtttttcagg gaaatcaaga ctccttcaca cctgtggtga actctctaga 17101 cccaccgtta ctgactcgct accttcgaat tcacccccag agttgggtgc accagattgc 17161 cctgaggatg gaggttctgg gctgcgaggc acaggacctc tactgagggt ggccactgca 17221 gcacctgcca ctgccgtcac ctctccctcc tcagctccag ggcagtgtcc ctccctggct 17281 tgccttctac ctttgtgcta aatcctagca gacactgcct tgaagcctcc tgaattaact 17341 atcatcagtc ctgcatttct ttggtggggg gccaggaggg tgcatccaat ttaacttaac 17401 tcttacctat tttctgcagc tgctcccaga ttactccttc cttccaatat aactaggcaa 17461 aaagaagtga ggagaaacct gcatgaaagc attcttccct gaaaagttag gcctctcaga 17521 gtcaccactt cctctgttgt agaaaaacta tgtgatgaaa ctttgaaaaa gatatttatg 17581 atgttaacat ttcaggttaa gcctcatacg tttaaaataa aactctcagt tgtttattat 17641 cctgatcaag catggaacaa agcatgtttc aggatcagat caatacaatc ttggagtcaa 17701 aaggcaaatc atttggacaa tctgcaaaat ggagagaata caataactac tacagtaaag 17761 tctgtttctg cttccttaca catagatata attatgttat ttagtcatta tgaggggcac 17821 attcttatct ccaaaactag cattcttaaa ctgagaatta tagatggggt tcaagaatcc 17881 ctaagtcccc tgaaattata taaggcattc tgtataaatg caaatgtgca tttttctgac 17941 gagtgtccat agatataaag ccatttggtc ttaattctga ccaataaaaa aataagtcag 18001 gaggatgcaa ttgttgaaag ctttgaaata aaataacaat gtcttcttga aatttgtgat 18061 ggccaagaaa gaaaatgatg atgacattag gcttctaaag gacatacatt taatatttct 18121 gtggaaatat gaggaaaatc catggttatc tgagatagga gatacaaact ttgtaattct 18181 aataatgcac tcagtttact ctctccctct actaatttcc tgctgaaaat aacacaacaa 18241 aaatgtaaca ggggaaatta tataccgtga ctgaaaacta gagtcctact tacatagttg 18301 aaatatcaag gaggtcagaa gaaaattgga ctggtgaaaa cagaaaaaac actccagtct 18361 gccatatcac cacacaatag gatccccctt cttgccctcc acccccataa gattgtgaag 18421 ggtttactgc tccttccatc tgcctgaccc cttcactatg actacacaga atctcctgat 18481 agtaaagggg gctggaggca aggataagtt atagagcagt tggaggaagc atccaaagat 18541 tgcaacccag ggcaaatgga aaacaggaga tcctaatatg aaagaaaaat ggatcccaat 18601 ctgagaaaag gcaaaagaat ggctactttt ttctatgctg gagtattttc taataatcct 18661 gcttgaccct tatctgacct ctttggaaac tataacatag ctgtcacagt atagtcacaa 18721 tccacaaatg atgcaggtgc aaatggttta tagccctgtg aagttcttaa agtttagagg 18781 ctaacttaca gaaatgaata agttgttttg ttttatagcc cggtagagga gttaacccca 18841 aaggtgatat ggttttattt cctgttatgt ttaacttaat aatcttattt tggcattctt 18901 ttcccattga ctatatacat ctctatttct caaatgttca tggaactagc tcttttattt 18961 tcctgctggt ttcttcagta atgagttaaa taaaacattg acacataca Nature and Effect of Mutations/Variants: A large number of hemophilia A is caused by point mutations. Two point mutations were discovered in a study of 83 patients by Yussoufian (OMIM 2002). One mutation was in exon 18 while the other was in exon 22. These two mutations are point mutations that changes CG to TG resulting in a nonsense codon. Nonsense codons have been linked to the termination of the synthesis of factor VIII (OMIM 2002). The normal arginine codon number 2307 is converted to a stop codon in some severe hemophiliacs. This results in the coding for arginine (CGA) to be converted to a stop condon (TGA). Individuals with mild hemophilia showed a mutation in the normal CGA codon to a CAA (glutamine) to a stop (TGA) codon (OMIM 2002). Other types of mutations are also observed in hemophilia A including missense, gene insertions, and gene deletions. The location of deletions in the factor VIII gene cannot be precisely located. A total of 300 mutations of the factor VIII gene have been discovered. Many of the mutations result in a nonfunctional factor VIII or the production of sufficient factor VIII. Around 45% of patients with severe hemophilia have an inversion in intron 22 of the F8C gene (Leung 2002). VS-13 Additional Comments: The first report of hemophilia A was in 1792. Hemophilia A inflicted the last Tsar of Russia and many have heard of the numerous cases of hemophilia in the family line of Queen Victoria. Queen Victoria was a carrier of the mutant allele. None of the ancestors of Queen Victoria had hemophilia A indicating that the mutant allele was first present in her. Today the pedigree of Queen Victorias family is observed in many text books (OMIM 2002). Queen Victoria passed the recessive X-linked hemophilia A gene to her daughters. Her carrier daughters married royalty Russian and Spanish men. The recessive gene was passed from the Russian czars family to the Germans (Couric 1984). Many medical procedures have been used throughout the ages as medical doctors attempted to treat hemophilia A. Transfusion of blood from beef and pork was used in hemophilia patients in the early nineteenth century. During the twentieth century, normal human serum was used to treat patients. Around the 1860s, fresh frozen plasma was put to use in patients (Pacheco 1998). Although there is no current cure for hemophilia A, the use of recombinant DNA technology may prove to be beneficial in the future. A modern method of treatment for hemophilia A in mild patients is the use of drugs that help to stimulate the release of the factor VIII clotting factor. In patients with mild to severe hemophilia, bleeding may be stopped by infusion of blood plasma (Norris 1999). Hemophilia A can be detected in infants by performing an amniocentesis, which is a procedure that extracts fluid surrounding the fetus. Hemophilia A can also be detected using procedures that tests for the presence of clotting factor VIII and other factors (Couric 1984). VS-14 References: Couric, John M. InfoTrac Web: Health Reference Center-Academic. Hemophilia has outlasted the czars. Leung, Lawrence L.K. . Hematology:Hemophilia A. Scientific American Medicine 1: 14-15, 2002. NCBI. F8C: Hemophilia A.  HYPERLINK "http://www.ncbi.nlm.nih.gov/cgi- bin/Entrez/getfeat?gi=182380&id=3&entity=1" http://www.ncbi.nlm.nih.gov/cgi- bin/Entrez/getfeat?gi=182380&id=3&entity=1 Norris, Teresa G. InfoTrac Web: Health Reference Center-Academic. Coagulation disorders. OMIM. Hemophilia A.  HYPERLINK "http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?306700" http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?306700 Pacheco, Maria. Hemophilia A. Magills Medical Guide II: 813-816, 1998. SWISS-PROT. Hemophilia A.  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