RBCC

Full text data of F9

F9 [Confidence: low (only semi-automatic identification from reviews)]
Coagulation factor IX; 3.4.21.22 (Christmas factor; Plasma thromboplastin component; PTC; Coagulation factor IXa light chain; Coagulation factor IXa heavy chain; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P00740
ID FA9_HUMAN Reviewed; 461 AA.
AC P00740; A8K9N4; F2RM36; Q5FBE1; Q5JYJ8;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-JUN-2005, sequence version 2.
DT 22-JAN-2014, entry version 199.
DE RecName: Full=Coagulation factor IX;
DE EC=3.4.21.22;
DE AltName: Full=Christmas factor;
DE AltName: Full=Plasma thromboplastin component;
DE Short=PTC;
DE Contains:
DE RecName: Full=Coagulation factor IXa light chain;
DE Contains:
DE RecName: Full=Coagulation factor IXa heavy chain;
DE Flags: Precursor;
GN Name=F9;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=6959130; DOI=10.1073/pnas.79.21.6461;
RA Kurachi K., Davie E.W.;
RT "Isolation and characterization of a cDNA coding for human factor
RT IX.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:6461-6464(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=6687940; DOI=10.1093/nar/11.8.2325;
RA Jaye M., de la Salle H., Schamber F., Balland A., Kohli V.,
RA Findeli A., Tolstoshev P., Lecocq J.-P.;
RT "Isolation of a human anti-haemophilic factor IX cDNA clone using a
RT unique 52-base synthetic oligonucleotide probe deduced from the amino
RT acid sequence of bovine factor IX.";
RL Nucleic Acids Res. 11:2325-2335(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-194.
RX PubMed=6329734;
RA Anson D.S., Choo K.H., Rees D.J.G., Giannelli F., Gould K.G.,
RA Huddleston J.A., Brownlee G.G.;
RT "The gene structure of human anti-haemophilic factor IX.";
RL EMBO J. 3:1053-1060(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-194.
RX PubMed=2994716; DOI=10.1021/bi00335a049;
RA Yoshitake S., Schach B.G., Foster D.C., Davie E.W., Kurachi K.;
RT "Nucleotide sequence of the gene for human factor IX (antihemophilic
RT factor B).";
RL Biochemistry 24:3736-3750(1985).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-194.
RX PubMed=3857619; DOI=10.1073/pnas.82.9.2847;
RA McGraw R.A., Davis L.M., Noyes C.M., Lundblad R.L., Roberts H.R.,
RA Graham J.B., Stafford D.W.;
RT "Evidence for a prevalent dimorphism in the activation peptide of
RT human coagulation factor IX.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:2847-2851(1985).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RC TISSUE=Liver;
RA Sata S., Yonemitsu Y., Nakagawa K., Sueishi K.;
RT "Alternative splicing variant of Homo sapiens coagulation factor IX
RT lacking EGF like domain.";
RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PRO-461.
RG SeattleSNPs variation discovery resource;
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Nguyen D.T., Nguyen P.V., Nong H.V.;
RT "Homo sapiens coagulation factor IX (F9), mRNA.";
RL Submitted (MAR-2011) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 30-84, AND VARIANT HEMB GLN-43.
RX PubMed=8295821;
RA de la Salle C., Charmantier J.L., Ravanat C., Ohlmann P.,
RA Hartmann M.L., Schuhler S., Bischoff R., Ebel C., Roecklin D.,
RA Balland A.;
RT "The Arg-4 mutant factor IX Strasbourg 2 shows a delayed activation by
RT factor XIa.";
RL Nouv. Rev. Fr. Hematol. 35:473-480(1993).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 36-326 (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=6089357; DOI=10.1007/BF01534851;
RA Jagadeeswaran P., Lavelle D.E., Kaul R., Mohandas T., Warren S.T.;
RT "Isolation and characterization of human factor IX cDNA:
RT identification of Taq I polymorphism and regional assignment.";
RL Somat. Cell Mol. Genet. 10:465-473(1984).
RN [15]
RP PROTEIN SEQUENCE OF 47-461, AND VARIANT HEMB TRP-226.
RX PubMed=2592373;
RA Suehiro K., Kawabata S., Miyata T., Takeya H., Takamatsu J., Ogata K.,
RA Kamiya T., Saito H., Niho Y., Iwanaga S.;
RT "Blood clotting factor IX BM Nagoya. Substitution of arginine 180 by
RT tryptophan and its activation by alpha-chymotrypsin and rat mast cell
RT chymase.";
RL J. Biol. Chem. 264:21257-21265(1989).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 290-359.
RX PubMed=3340835; DOI=10.1126/science.3340835;
RA Stoflet E.S., Koeberl D.D., Sarkar G., Sommer S.S.;
RT "Genomic amplification with transcript sequencing.";
RL Science 239:491-494(1988).
RN [17]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 444-461.
RX PubMed=8236150;
RA de la Salle C., Charmantier J.L., Baas M.-J., Schwartz A.,
RA Wiesel M.L., Grunebaum L., Cazenave J.-P.;
RT "A deletion located in the 3' non translated part of the factor IX
RT gene responsible for mild haemophilia B.";
RL Thromb. Haemost. 70:370-371(1993).
RN [18]
RP HYDROXYLATION AT ASP-110.
RX PubMed=6688526; DOI=10.1016/0006-291X(83)90961-0;
RA McMullen B.A., Fujikawa K., Kisiel W.;
RT "The occurrence of beta-hydroxyaspartic acid in the vitamin K-
RT dependent blood coagulation zymogens.";
RL Biochem. Biophys. Res. Commun. 115:8-14(1983).
RN [19]
RP PROTEOLYTIC PROCESSING, AND ACTIVE SITE.
RX PubMed=659613; DOI=10.1172/JCI109073;
RA di Scipio R.G., Kurachi K., Davie E.W.;
RT "Activation of human factor IX (Christmas factor).";
RL J. Clin. Invest. 61:1528-1538(1978).
RN [20]
RP CALCIUM-BINDING.
RX PubMed=6425296;
RA Morita T., Isaacs B.S., Esmon C.T., Johnson A.E.;
RT "Derivatives of blood coagulation factor IX contain a high affinity
RT Ca2+-binding site that lacks gamma-carboxyglutamic acid.";
RL J. Biol. Chem. 259:5698-5704(1984).
RN [21]
RP ERRATUM.
RA Morita T., Isaacs B.S., Esmon C.T., Johnson A.E.;
RL J. Biol. Chem. 260:2583-2583(1985).
RN [22]
RP STRUCTURE OF CARBOHYDRATE ON SER-99.
RX PubMed=2511201;
RA Nishimura H., Kawabata S., Kisiel W., Hase S., Ikenaka T., Takao T.,
RA Shimonishi Y., Iwanaga S.;
RT "Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-
RT Glc) O-glycosidically linked to a serine residue in the first
RT epidermal growth factor-like domain of human factors VII and IX and
RT protein Z and bovine protein Z.";
RL J. Biol. Chem. 264:20320-20325(1989).
RN [23]
RP STRUCTURE OF CARBOHYDRATE ON SER-99.
RX PubMed=2129367;
RA Iwanaga S., Nishimura H., Kawabata S., Kisiel W., Hase S., Ikenaka T.;
RT "A new trisaccharide sugar chain linked to a serine residue in the
RT first EGF-like domain of clotting factors VII and IX and protein Z.";
RL Adv. Exp. Med. Biol. 281:121-131(1990).
RN [24]
RP STRUCTURE OF CARBOHYDRATE ON SER-107.
RX PubMed=1517205;
RA Nishimura H., Takao T., Hase S., Shimonishi Y., Iwanaga S.;
RT "Human factor IX has a tetrasaccharide O-glycosidically linked to
RT serine 61 through the fucose residue.";
RL J. Biol. Chem. 267:17520-17525(1992).
RN [25]
RP GLYCOSYLATION AT THR-205 AND THR-215.
RX PubMed=8172892; DOI=10.1021/bi00183a021;
RA Agarwala K.L., Kawabata S., Takao T., Murata H., Shimonishi Y.,
RA Nishimura H., Iwanaga S.;
RT "Activation peptide of human factor IX has oligosaccharides O-
RT glycosidically linked to threonine residues at 159 and 169.";
RL Biochemistry 33:5167-5171(1994).
RN [26]
RP PHOSPHORYLATION AT SER-114.
RA Harris R.J., Papac D.I., Truong L., Smith K.J.;
RT "Partial phosphorylation of serine-68 in EGF-1 of human factor IX.";
RL (In) Proceedings of XIth international conference on methods in
RL protein structure analysis, pp.50-50, Annecy (1996).
RN [27]
RP POST-TRANSLATIONAL MODIFICATIONS.
RX PubMed=11133752; DOI=10.1182/blood.V97.1.130;
RA Arruda V.R., Hagstrom J.N., Deitch J., Heiman-Patterson T.,
RA Camire R.M., Chu K., Fields P.A., Herzog R.W., Couto L.B.,
RA Larson P.J., High K.A.;
RT "Posttranslational modifications of recombinant myotube-synthesized
RT human factor IX.";
RL Blood 97:130-138(2001).
RN [28]
RP STRUCTURE BY NMR OF 47-93.
RX PubMed=7713897; DOI=10.1074/jbc.270.14.7980;
RA Freedman S.J., Furie B.C., Furie B., Baleja J.D.;
RT "Structure of the metal-free gamma-carboxyglutamic acid-rich membrane
RT binding region of factor IX by two-dimensional NMR spectroscopy.";
RL J. Biol. Chem. 270:7980-7987(1995).
RN [29]
RP STRUCTURE BY NMR OF 47-93.
RX PubMed=7547952; DOI=10.1021/bi00038a005;
RA Freedman S.J., Furie B.C., Furie B., Baleja J.D.;
RT "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich
RT domain of factor IX.";
RL Biochemistry 34:12126-12137(1995).
RN [30]
RP STRUCTURE BY NMR OF 47-93.
RX PubMed=8663165; DOI=10.1074/jbc.271.27.16227;
RA Freedman S.J., Blostein M.D., Baleja J.D., Jacobs M., Furie B.C.,
RA Furie B.;
RT "Identification of the phospholipid binding site in the vitamin K-
RT dependent blood coagulation protein factor IX.";
RL J. Biol. Chem. 271:16227-16236(1996).
RN [31]
RP STRUCTURE BY NMR OF 47-93.
RX PubMed=9047312; DOI=10.1021/bi962250r;
RA Li L., Darden T.A., Freedman S.J., Furie B.C., Furie B., Baleja J.D.,
RA Smith H., Hiskey R.G., Pedersen L.G.;
RT "Refinement of the NMR solution structure of the gamma-carboxyglutamic
RT acid domain of coagulation factor IX using molecular dynamics
RT simulation with initial Ca2+ positions determined by a genetic
RT algorithm.";
RL Biochemistry 36:2132-2138(1997).
RN [32]
RP STRUCTURE BY NMR OF 91-133.
RX PubMed=1854745; DOI=10.1021/bi00244a006;
RA Huang L.H., Cheng H., Pardi A., Tam J.P., Sweeney W.V.;
RT "Sequence-specific 1H NMR assignments, secondary structure, and
RT location of the calcium binding site in the first epidermal growth
RT factor like domain of blood coagulation factor IX.";
RL Biochemistry 30:7402-7409(1991).
RN [33]
RP STRUCTURE BY NMR OF 92-130.
RX PubMed=1304885;
RA Baron M., Norman D.G., Harvey T.S., Handford P.A., Mayhew M.,
RA Tse A.G.D., Brownlee G.G., Campbell I.D.C.;
RT "The three-dimensional structure of the first EGF-like module of human
RT factor IX: comparison with EGF and TGF-alpha.";
RL Protein Sci. 1:81-90(1992).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 92-130.
RX PubMed=7606779; DOI=10.1016/0092-8674(95)90059-4;
RA Rao Z., Handford P., Mayhew M., Knott V., Brownlee G.G., Stuart D.;
RT "The structure of a Ca(2+)-binding epidermal growth factor-like
RT domain: its role in protein-protein interactions.";
RL Cell 82:131-141(1995).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 133-461.
RX PubMed=10467148; DOI=10.1016/S0969-2126(99)80125-7;
RA Hopfner K.-P., Lang A., Karcher A., Sichler K., Kopetzki E.,
RA Brandstetter H., Huber R., Bode W., Engh R.A.;
RT "Coagulation factor IXa: the relaxed conformation of Tyr99 blocks
RT substrate binding.";
RL Structure 7:989-996(1999).
RN [36]
RP MOLECULAR PATHOLOGY OF HEMB B.
RX PubMed=2743975;
RA Green P.M., Bentley D.R., Mibashan R.S., Nilsson I.M., Giannelli F.;
RT "Molecular pathology of haemophilia B.";
RL EMBO J. 8:1067-1072(1989).
RN [37]
RP REVIEW ON HEMB VARIANTS.
RX PubMed=1634040;
RA Sommer S.S.;
RT "Assessing the underlying pattern of human germline mutations: lessons
RT from the factor IX gene.";
RL FASEB J. 6:2767-2774(1992).
RN [38]
RP REVIEW ON HEMB VARIANTS.
RX PubMed=8392713; DOI=10.1093/nar/21.13.3075;
RA Giannelli F., Green P.M., High K.A., Sommer S., Poon M.-C., Ludwig M.,
RA Schwaab R., Reitsma P.H., Goossens M., Yoshioka A., Brownlee G.G.;
RT "Haemophilia B: database of point mutations and short additions and
RT deletions -- fourth edition, 1993.";
RL Nucleic Acids Res. 21:3075-3087(1993).
RN [39]
RP VARIANT HEMB HIS-191.
RX PubMed=6603618; DOI=10.1073/pnas.80.14.4200;
RA Noyes C.M., Griffith M.J., Roberts H.R., Lundblad R.L.;
RT "Identification of the molecular defect in factor IX Chapel Hill:
RT substitution of histidine for arginine at position 145.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:4200-4202(1983).
RN [40]
RP VARIANT HEMB GLN-43.
RX PubMed=3009023; DOI=10.1016/0092-8674(86)90319-3;
RA Bentley A.K., Rees D.J., Rizza C., Brownlee G.G.;
RT "Defective propeptide processing of blood clotting factor IX caused by
RT mutation of arginine to glutamine at position -4.";
RL Cell 45:343-348(1986).
RN [41]
RP VARIANT HEMB GLY-93.
RX PubMed=3790720;
RA Davis L.M., McGraw R.A., Ware J.L., Roberts H.R., Stafford D.W.;
RT "Factor IXAlabama: a point mutation in a clotting protein results in
RT hemophilia B.";
RL Blood 69:140-143(1987).
RN [42]
RP VARIANT HEMB THR-443.
RX PubMed=3401602;
RA Ware J., Davis L., Frazier D., Bajaj S.P., Stafford D.W.;
RT "Genetic defect responsible for the dysfunctional protein: factor IX
RT (Long Beach).";
RL Blood 72:820-822(1988).
RN [43]
RP VARIANT HEMB VAL-436.
RX PubMed=3243764;
RA Sugimoto M., Miyata T., Kawabata S., Yoshioka A., Fukui H.,
RA Takahashi H., Iwanaga S.;
RT "Blood clotting factor IX Niigata: substitution of alanine-390 by
RT valine in the catalytic domain.";
RL J. Biochem. 104:878-880(1988).
RN [44]
RP VARIANT HEMB GLN-226.
RX PubMed=2713493;
RA Monroe D.M., McCord D.M., Huang M.N., High K.A., Lundblad R.L.,
RA Kasper C.K., Roberts H.R.;
RT "Functional consequences of an arginine180 to glutamine mutation in
RT factor IX Hilo.";
RL Blood 73:1540-1544(1989).
RN [45]
RP VARIANT HEMB ARG-442.
RX PubMed=2714791; DOI=10.1016/0888-7543(89)90330-3;
RA Attree O., Vidaud D., Vidaud M., Amselem S., Lavergne J.-M.,
RA Goossens M.;
RT "Mutations in the catalytic domain of human coagulation factor IX:
RT rapid characterization by direct genomic sequencing of DNA fragments
RT displaying an altered melting behavior.";
RL Genomics 4:266-272(1989).
RN [46]
RP VARIANTS HEMB GLN-75; ASP-79; TRP-268; THR-279; SER-306; MET-342;
RP ARG-357 AND ARG-453, AND VARIANT PHE-7.
RX PubMed=2773937;
RA Koeberl D.D., Bottema C.D., Buerstedde J.-M., Sommer S.S.;
RT "Functionally important regions of the factor IX gene have a low rate
RT of polymorphism and a high rate of mutation in the dinucleotide CpG.";
RL Am. J. Hum. Genet. 45:448-457(1989).
RN [47]
RP VARIANT HEMB CYS-191.
RX PubMed=2775660; DOI=10.1111/j.1365-2141.1989.tb04323.x;
RA Liddell M.B., Peake I.R., Taylor S.A., Lillicrap D.P., Giddings J.C.,
RA Bloom A.L.;
RT "Factor IX Cardiff: a variant factor IX protein that shows abnormal
RT activation is caused by an arginine to cysteine substitution at
RT position 145.";
RL Br. J. Haematol. 72:556-560(1989).
RN [48]
RP VARIANT HEMB PHE-228.
RX PubMed=2753873;
RA Sakai T., Yoshioka A., Yamamoto K., Niinomi K., Fujimura Y., Fukui H.,
RA Miyata T., Iwanaga S.;
RT "Blood clotting factor IX Kashihara: amino acid substitution of
RT valine-182 by phenylalanine.";
RL J. Biochem. 105:756-759(1989).
RN [49]
RP VARIANT HEMB GLN-43.
RX PubMed=2738071;
RA Ware J., Diuguid D.L., Liebman H.A., Rabiet M.J., Kasper C.K.,
RA Furie B.C., Furie B., Stafford D.W.;
RT "Factor IX San Dimas. Substitution of glutamine for Arg-4 in the
RT propeptide leads to incomplete gamma-carboxylation and altered
RT phospholipid binding properties.";
RL J. Biol. Chem. 264:11401-11406(1989).
RN [50]
RP VARIANTS HEMB LYS-73; SER-106 AND GLN-294.
RX PubMed=2472424; DOI=10.1172/JCI114130;
RA Chen S.H., Thompson A.R., Zhang M., Scott C.R.;
RT "Three point mutations in the factor IX genes of five hemophilia B
RT patients. Identification strategy using localization by altered
RT epitopes in their hemophilic proteins.";
RL J. Clin. Invest. 84:113-118(1989).
RN [51]
RP VARIANT HEMB VAL-73.
RX PubMed=2339358;
RA Wang N.S., Zhang M., Thompson A.R., Chen S.H.;
RT "Factor IX Chongqing: a new mutation in the calcium-binding domain of
RT factor IX resulting in severe hemophilia B.";
RL Thromb. Haemost. 63:24-26(1990).
RN [52]
RP VARIANT HEMB LEU-228.
RX PubMed=2372509; DOI=10.1111/j.1365-2141.1990.tb02652.x;
RA Taylor S.A., Liddell M.B., Peake I.R., Bloom A.L., Lillicrap D.P.;
RT "A mutation adjacent to the beta cleavage site of factor IX (valine
RT 182 to leucine) results in mild haemophilia Bm.";
RL Br. J. Haematol. 75:217-221(1990).
RN [53]
RP VARIANTS HEMB GLN-226; TRP-226; PHE-227 AND THR-414.
RX PubMed=2162822;
RA Bertina R.M., van der Linden I.K., Mannucci P.M., Reinalda-Poot H.H.,
RA Cupers R., Poort S.R., Reitsma P.H.;
RT "Mutations in hemophilia Bm occur at the Arg180-Val activation site or
RT in the catalytic domain of factor IX.";
RL J. Biol. Chem. 265:10876-10883(1990).
RN [54]
RP VARIANT HEMB GLU-357.
RX PubMed=1958666; DOI=10.1021/bi00111a014;
RA Miyata T., Sakai T., Sugimoto M., Naka H., Yamamoto K., Yoshioka A.,
RA Fukui H., Mitsui K., Kamiya K., Umeyama H., Iwanaga S.;
RT "Factor IX Amagasaki: a new mutation in the catalytic domain resulting
RT in the loss of both coagulant and esterase activities.";
RL Biochemistry 30:11286-11291(1991).
RN [55]
RP VARIANT HEMB THR-443.
RX PubMed=1902289; DOI=10.1093/nar/19.5.1165;
RA Sarkar G., Cassady J.D., Pyeritz R.E., Gilchrist G.S., Sommer S.S.;
RT "Isoleucine-397 is changed to threonine in two females with hemophilia
RT B.";
RL Nucleic Acids Res. 19:1165-1165(1991).
RN [56]
RP VARIANTS HEMB VAL-291; GLN-294; HIS-410; GLY-411 AND ILE-411.
RX PubMed=1346975;
RA Ludwig M., Sabharwal A.K., Brackmann H.H., Olek K., Smith K.J.,
RA Birktoft J.J., Bajaj S.P.;
RT "Hemophilia B caused by five different nondeletion mutations in the
RT protease domain of factor IX.";
RL Blood 79:1225-1232(1992).
RN [57]
RP VARIANT HEMB SER-252.
RX PubMed=1615485;
RA Taylor S.A., Duffin J., Cameron C., Teitel J., Garvey B.,
RA Lillicrap D.P.;
RT "Characterization of the original Christmas disease mutation (cysteine
RT 206-->serine): from clinical recognition to molecular pathogenesis.";
RL Thromb. Haemost. 67:63-65(1992).
RN [58]
RP VARIANTS HEMB ARG-253; GLN-294; GLN-379; PRO-426 AND ILE-TYR-THR-445
RP INS.
RX PubMed=8257988; DOI=10.1002/humu.1380020506;
RA David D., Rosa H.A.V., Pemberton S., Diniz M.J., Campos M.,
RA Lavinha J.;
RT "Single-strand conformation polymorphism (SSCP) analysis of the
RT molecular pathology of hemophilia B.";
RL Hum. Mutat. 2:355-361(1993).
RN [59]
RP VARIANTS HEMB HIS-191; GLY-226; THR-279; GLN-379; GLU-419 AND GLN-449.
RX PubMed=8076946; DOI=10.1007/BF00208285;
RA Aguilar-Martinez P., Romey M.-C., Schved J.-F., Gris J.-C.,
RA Demaille J., Claustres M.;
RT "Factor IX gene mutations causing haemophilia B: comparison of SSC
RT screening versus systematic DNA sequencing and diagnostic
RT applications.";
RL Hum. Genet. 94:287-290(1994).
RN [60]
RP VARIANT HEMB GLU-419.
RX PubMed=8199596; DOI=10.1002/humu.1380030211;
RA Aguilar-Martinez P., Romey M.-C., Gris J.-C., Schved J.-F.,
RA Demaille J., Claustres M.;
RT "A novel mutation (Val-373 to Glu) in the catalytic domain of factor
RT IX, resulting in moderately/severe hemophilia B in a southern French
RT patient.";
RL Hum. Mutat. 3:156-158(1994).
RN [61]
RP VARIANTS HEMB GLN-294 AND ARG-413.
RX PubMed=7981722; DOI=10.1002/humu.1380040214;
RA Caglayan S.H., Vielhaber E., Guersel T., Aktuglu G., Sommer S.S.;
RT "Identification of mutations in four hemophilia B patients of Turkish
RT origin, including a novel deletion of base 6411.";
RL Hum. Mutat. 4:163-165(1994).
RN [62]
RP VARIANTS HEMB.
RX PubMed=8680410; DOI=10.1002/humu.1380060410;
RA Wulff K., Schroeder W., Wehnert M., Herrmann F.H.;
RT "Twenty-five novel mutations of the factor IX gene in haemophilia B.";
RL Hum. Mutat. 6:346-348(1995).
RN [63]
RP VARIANT WARFARIN SENSITIVITY THR-37.
RX PubMed=8833911; DOI=10.1172/JCI118956;
RA Chu K., Wu S.M., Stanley T., Stafford D.W., High K.A.;
RT "A mutation in the propeptide of factor IX leads to warfarin
RT sensitivity by a novel mechanism.";
RL J. Clin. Invest. 98:1619-1625(1996).
RN [64]
RP VARIANTS HEMB LYS-113; MET-342; ARG-413 AND VAL-424.
RX PubMed=9222764;
RX DOI=10.1002/(SICI)1098-1004(1997)10:1<76::AID-HUMU11>3.3.CO;2-0;
RA Caglayan S.H., Goekmen Y., Aktuglu G., Guergey A., Sommer S.S.;
RT "Mutations associated with hemophilia B in Turkish patients.";
RL Hum. Mutat. 10:76-79(1997).
RN [65]
RP VARIANT HEMB PRO-397.
RX PubMed=9590153;
RX DOI=10.1002/(SICI)1096-8652(199805)58:1<72::AID-AJH13>3.0.CO;2-7;
RA Chan V., Chan V.W.Y., Yip B., Chim C.S., Chan T.K.;
RT "Hemophilia B in a female carrier due to skewed inactivation of the
RT normal X-chromosome.";
RL Am. J. Hematol. 58:72-76(1998).
RN [66]
RP VARIANTS HEMB ARG-119 AND THR-454.
RX PubMed=9452115;
RA David D., Moreira I., Morais S., de Deus G.;
RT "Five novel factor IX mutations in unrelated hemophilia B patients.";
RL Hum. Mutat. Suppl. 1:S301-S303(1998).
RN [67]
RP VARIANTS HEMB GLN-43; TRP-43; THR-46; SER-106; CYS-115; PHE-155;
RP GLN-379; GLU-387; VAL-432 AND CYS-450.
RX PubMed=9600455;
RX DOI=10.1002/(SICI)1098-1004(1998)11:5<372::AID-HUMU4>3.3.CO;2-D;
RA Heit J.A., Thorland E.C., Ketterling R.P., Lind T.J., Daniels T.M.,
RA Zapata R.E., Ordonez S.M., Kasper C.K., Sommer S.S.;
RT "Germline mutations in Peruvian patients with hemophilia B: pattern of
RT mutation in Amerindians is similar to the putative endogenous germline
RT pattern.";
RL Hum. Mutat. 11:372-376(1998).
RN [68]
RP VARIANTS HEMB.
RX PubMed=10698280;
RA Wulff K., Bykowska K., Lopaciuk S., Herrmann F.H.;
RT "Molecular analysis of hemophilia B in Poland: 12 novel mutations of
RT the factor IX gene.";
RL Acta Biochim. Pol. 46:721-726(1999).
RN [69]
RP VARIANTS HEMB.
RX PubMed=10094553;
RX DOI=10.1002/(SICI)1098-1004(1999)13:2<160::AID-HUMU9>3.3.CO;2-3;
RA Montejo J.M., Magallon M., Tizzano E., Solera J.;
RT "Identification of twenty-one new mutations in the factor IX gene by
RT SSCP analysis.";
RL Hum. Mutat. 13:160-165(1999).
RN [70]
RP VARIANT ALA-194.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [71]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [72]
RP VARIANTS HEMB CYS-169 AND THR-333.
RX PubMed=11122099; DOI=10.1046/j.1365-2141.2000.02389.x;
RA Vidal F., Farssac E., Altisent C., Puig L., Gallardo D.;
RT "Factor IX gene sequencing by a simple and sensitive 15-hour procedure
RT for haemophilia B diagnosis: identification of two novel mutations.";
RL Br. J. Haematol. 111:549-551(2000).
RN [73]
RP VARIANTS HEMB TYR-28; LEU-43; GLN-43; SER-52; ASP-106; LYS-124;
RP TYR-134; GLN-226; GLY-226; TRP-226; LYS-241; TYR-252; GLN-294;
RP PHE-316; ARG-318; GLY-379; ILE-383; PHE-383; ILE-395; PHE-396; ARG-407
RP AND GLU-412.
RX PubMed=12588353; DOI=10.1046/j.1365-2141.2003.04141.x;
RA Onay U.V., Kavakli K., Kilinc Y., Gurgey A., Aktuglu G., Kemahli S.,
RA Ozbek U., Caglayan S.H.;
RT "Molecular pathology of haemophilia B in Turkish patients:
RT identification of a large deletion and 33 independent point
RT mutations.";
RL Br. J. Haematol. 120:656-659(2003).
RN [74]
RP VARIANTS HEMB TRP-43; ARG-84; ARG-125; VAL-125; PHE-170; ARG-302;
RP MET-342; LEU-344; LEU-395; THR-414; TYR-435; GLU-442 AND TRP-449.
RX PubMed=12604421;
RA Espinos C., Casana P., Haya S., Cid A.R., Aznar J.A.;
RT "Molecular analyses in hemophilia B families: identification of six
RT new mutations in the factor IX gene.";
RL Haematologica 88:235-236(2003).
RN [75]
RP VARIANT THPH8 LEU-384, AND CHARACTERIZATION OF VARIANT THPH8 LEU-384.
RX PubMed=19846852; DOI=10.1056/NEJMoa0904377;
RA Simioni P., Tormene D., Tognin G., Gavasso S., Bulato C.,
RA Iacobelli N.P., Finn J.D., Spiezia L., Radu C., Arruda V.R.;
RT "X-linked thrombophilia with a mutant factor IX (factor IX Padua).";
RL N. Engl. J. Med. 361:1671-1675(2009).
CC -!- FUNCTION: Factor IX is a vitamin K-dependent plasma protein that
CC participates in the intrinsic pathway of blood coagulation by
CC converting factor X to its active form in the presence of Ca(2+)
CC ions, phospholipids, and factor VIIIa.
CC -!- CATALYTIC ACTIVITY: Selective cleavage of Arg-|-Ile bond in factor
CC X to form factor Xa.
CC -!- SUBUNIT: Heterodimer of a light chain and a heavy chain;
CC disulfide-linked.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P00740-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P00740-2; Sequence=VSP_047689;
CC -!- TISSUE SPECIFICITY: Synthesized primarily in the liver and
CC secreted in plasma.
CC -!- DOMAIN: Calcium binds to the gamma-carboxyglutamic acid (Gla)
CC residues and, with stronger affinity, to another site, beyond the
CC Gla domain.
CC -!- PTM: Activated by factor XIa, which excises the activation
CC peptide.
CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of
CC aspartate and asparagine is (R) stereospecific within EGF domains.
CC -!- DISEASE: Hemophilia B (HEMB) [MIM:306900]: An X-linked blood
CC coagulation disorder characterized by a permanent tendency to
CC hemorrhage, due to factor IX deficiency. It is phenotypically
CC similar to hemophilia A, but patients present with fewer symptoms.
CC Many patients are asymptomatic until the hemostatic system is
CC stressed by surgery or trauma. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=Mutations in position 43 (Oxford-3, San Dimas) and
CC 46 (Cambridge) prevents cleavage of the propeptide, mutation in
CC position 93 (Alabama) probably fails to bind to cell membranes,
CC mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya
CC OR Hilo) prevent cleavage of the activation peptide.
CC -!- DISEASE: Thrombophilia, X-linked, due to factor IX defect (THPH8)
CC [MIM:300807]: A hemostatic disorder characterized by a tendency to
CC thrombosis. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- PHARMACEUTICAL: Available under the name BeneFix (Baxter and
CC American Home Products). Used to treat hemophilia B.
CC -!- MISCELLANEOUS: In 1952, one of the earliest researchers of the
CC disease, Dr. R.G. Macfarlane used the patient's surname,
CC Christmas, to refer to the disease and also to refer to the
CC clotting factor which he called the 'Christmas Factor' At the time
CC Stephen Christmas was a 5-year-old boy. He died in 1993 at the age
CC of 46 from acquired immunodeficiency syndrome contracted through
CC treatment with blood products.
CC -!- SIMILARITY: Belongs to the peptidase S1 family.
CC -!- SIMILARITY: Contains 2 EGF-like domains.
CC -!- SIMILARITY: Contains 1 Gla (gamma-carboxy-glutamate) domain.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Factor IX entry;
CC URL="http://en.wikipedia.org/wiki/Factor_IX";
CC -!- WEB RESOURCE: Name=Factor IX Mutation Database;
CC URL="http://www.factorix.org/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/F9";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/f9/";
CC -!- WEB RESOURCE: Name=BeneFix; Note=Clinical information on BeneFix;
CC URL="http://www.pfizer.com/products/rx/rx_product_benefix.jsp";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The Christmas Factor -
CC Issue 41 of December 2003;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt041.shtml";
CC -----------------------------------------------------------------------
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DR EMBL; J00136; AAA98726.1; -; mRNA.
DR EMBL; J00137; AAA52763.1; -; mRNA.
DR EMBL; K02053; AAA56822.1; -; Genomic_DNA.
DR EMBL; K02048; AAA56822.1; JOINED; Genomic_DNA.
DR EMBL; K02049; AAA56822.1; JOINED; Genomic_DNA.
DR EMBL; K02051; AAA56822.1; JOINED; Genomic_DNA.
DR EMBL; K02052; AAA56822.1; JOINED; Genomic_DNA.
DR EMBL; K02402; AAB59620.1; -; Genomic_DNA.
DR EMBL; M11309; AAA52023.1; -; mRNA.
DR EMBL; AL033403; CAI42103.1; -; Genomic_DNA.
DR EMBL; AB186358; BAD89383.1; -; mRNA.
DR EMBL; AF536327; AAM96188.1; -; Genomic_DNA.
DR EMBL; FR846239; CCA61111.1; -; mRNA.
DR EMBL; AK292749; BAF85438.1; -; mRNA.
DR EMBL; CH471150; EAW88433.1; -; Genomic_DNA.
DR EMBL; BC109214; AAI09215.1; -; mRNA.
DR EMBL; BC109215; AAI09216.1; -; mRNA.
DR EMBL; S68634; AAB29758.1; -; Genomic_DNA.
DR EMBL; M35672; AAA51981.1; -; mRNA.
DR EMBL; M19063; AAA52456.1; -; Genomic_DNA.
DR EMBL; S66752; AAB28588.1; -; Genomic_DNA.
DR PIR; A00922; KFHU.
DR RefSeq; NP_000124.1; NM_000133.3.
DR RefSeq; XP_005262453.1; XM_005262396.1.
DR UniGene; Hs.522798; -.
DR PDB; 1CFH; NMR; -; A=47-93.
DR PDB; 1CFI; NMR; -; A=47-93.
DR PDB; 1EDM; X-ray; 1.50 A; B/C=92-130.
DR PDB; 1IXA; NMR; -; A=92-130.
DR PDB; 1MGX; NMR; -; A=47-93.
DR PDB; 1NL0; X-ray; 2.20 A; G=47-91.
DR PDB; 1RFN; X-ray; 2.80 A; A=227-461, B=133-188.
DR PDB; 2WPH; X-ray; 1.50 A; E=133-191, S=227-461.
DR PDB; 2WPI; X-ray; 1.99 A; E=133-191, S=227-461.
DR PDB; 2WPJ; X-ray; 1.60 A; E=133-191, S=227-461.
DR PDB; 2WPK; X-ray; 2.21 A; E=133-191, S=227-461.
DR PDB; 2WPL; X-ray; 1.82 A; E=133-191, S=227-461.
DR PDB; 2WPM; X-ray; 2.00 A; E=133-191, S=227-461.
DR PDB; 3KCG; X-ray; 1.70 A; H=227-461, L=131-188.
DR PDB; 3LC3; X-ray; 1.90 A; A/C=227-461, B/D=133-188.
DR PDB; 3LC5; X-ray; 2.62 A; A=227-461, B=133-188.
DR PDBsum; 1CFH; -.
DR PDBsum; 1CFI; -.
DR PDBsum; 1EDM; -.
DR PDBsum; 1IXA; -.
DR PDBsum; 1MGX; -.
DR PDBsum; 1NL0; -.
DR PDBsum; 1RFN; -.
DR PDBsum; 2WPH; -.
DR PDBsum; 2WPI; -.
DR PDBsum; 2WPJ; -.
DR PDBsum; 2WPK; -.
DR PDBsum; 2WPL; -.
DR PDBsum; 2WPM; -.
DR PDBsum; 3KCG; -.
DR PDBsum; 3LC3; -.
DR PDBsum; 3LC5; -.
DR ProteinModelPortal; P00740; -.
DR SMR; P00740; 47-191, 227-461.
DR DIP; DIP-58520N; -.
DR STRING; 9606.ENSP00000218099; -.
DR BindingDB; P00740; -.
DR ChEMBL; CHEMBL2016; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR DrugBank; DB00100; Coagulation Factor IX.
DR DrugBank; DB01109; Heparin.
DR DrugBank; DB00170; Menadione.
DR GuidetoPHARMACOLOGY; 2364; -.
DR Allergome; 9616; Hom s Factor IX.
DR MEROPS; S01.214; -.
DR PhosphoSite; P00740; -.
DR UniCarbKB; P00740; -.
DR DMDM; 67476446; -.
DR PaxDb; P00740; -.
DR PeptideAtlas; P00740; -.
DR PRIDE; P00740; -.
DR DNASU; 2158; -.
DR Ensembl; ENST00000218099; ENSP00000218099; ENSG00000101981.
DR Ensembl; ENST00000394090; ENSP00000377650; ENSG00000101981.
DR GeneID; 2158; -.
DR KEGG; hsa:2158; -.
DR UCSC; uc004fas.1; human.
DR CTD; 2158; -.
DR GeneCards; GC0XP138612; -.
DR HGNC; HGNC:3551; F9.
DR HPA; HPA000254; -.
DR MIM; 300746; gene.
DR MIM; 300807; phenotype.
DR MIM; 306900; phenotype.
DR neXtProt; NX_P00740; -.
DR Orphanet; 169799; Mild hemophilia B.
DR Orphanet; 169796; Moderately severe hemophilia B.
DR Orphanet; 169793; Severe hemophilia B.
DR Orphanet; 177929; Symptomatic form of hemophilia B in female carriers.
DR PharmGKB; PA27954; -.
DR eggNOG; COG5640; -.
DR HOGENOM; HOG000251821; -.
DR HOVERGEN; HBG013304; -.
DR InParanoid; P00740; -.
DR KO; K01321; -.
DR OMA; SAECTVF; -.
DR OrthoDB; EOG75B84T; -.
DR PhylomeDB; P00740; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR SABIO-RK; P00740; -.
DR EvolutionaryTrace; P00740; -.
DR GeneWiki; Factor_IX; -.
DR GenomeRNAi; 2158; -.
DR NextBio; 8719; -.
DR PMAP-CutDB; P00740; -.
DR PRO; PR:P00740; -.
DR ArrayExpress; P00740; -.
DR Bgee; P00740; -.
DR CleanEx; HS_F9; -.
DR Genevestigator; P00740; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004252; F:serine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0007598; P:blood coagulation, extrinsic pathway; TAS:Reactome.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; TAS:Reactome.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; TAS:Reactome.
DR Gene3D; 4.10.740.10; -; 1.
DR InterPro; IPR017857; Coagulation_fac_subgr_Gla_dom.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR018097; EGF_Ca-bd_CS.
DR InterPro; IPR000294; GLA_domain.
DR InterPro; IPR012224; Pept_S1A_FX.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00008; EGF; 1.
DR Pfam; PF00594; Gla; 1.
DR Pfam; PF00089; Trypsin; 1.
DR PIRSF; PIRSF001143; Factor_X; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR PRINTS; PR00001; GLABLOOD.
DR SMART; SM00181; EGF; 1.
DR SMART; SM00179; EGF_CA; 1.
DR SMART; SM00069; GLA; 1.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57630; SSF57630; 1.
DR PROSITE; PS00010; ASX_HYDROXYL; 1.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS01186; EGF_2; 2.
DR PROSITE; PS50026; EGF_3; 1.
DR PROSITE; PS01187; EGF_CA; 1.
DR PROSITE; PS00011; GLA_1; 1.
DR PROSITE; PS50998; GLA_2; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Blood coagulation; Calcium;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW EGF-like domain; Gamma-carboxyglutamic acid; Glycoprotein; Hemophilia;
KW Hemostasis; Hydrolase; Hydroxylation; Pharmaceutical; Phosphoprotein;
KW Polymorphism; Protease; Reference proteome; Repeat; Secreted;
KW Serine protease; Signal; Sulfation; Thrombophilia; Zymogen.
FT SIGNAL 1 28 Potential.
FT PROPEP 29 46
FT /FTId=PRO_0000027755.
FT CHAIN 47 461 Coagulation factor IX.
FT /FTId=PRO_0000027756.
FT CHAIN 47 191 Coagulation factor IXa light chain.
FT /FTId=PRO_0000027757.
FT PROPEP 192 226 Activation peptide.
FT /FTId=PRO_0000027758.
FT CHAIN 227 461 Coagulation factor IXa heavy chain.
FT /FTId=PRO_0000027759.
FT DOMAIN 47 92 Gla.
FT DOMAIN 93 129 EGF-like 1; calcium-binding (Potential).
FT DOMAIN 130 171 EGF-like 2.
FT DOMAIN 227 459 Peptidase S1.
FT ACT_SITE 267 267 Charge relay system.
FT ACT_SITE 315 315 Charge relay system.
FT ACT_SITE 411 411 Charge relay system.
FT SITE 191 192 Cleavage; by factor XIa.
FT SITE 226 227 Cleavage; by factor XIa.
FT MOD_RES 53 53 4-carboxyglutamate.
FT MOD_RES 54 54 4-carboxyglutamate.
FT MOD_RES 61 61 4-carboxyglutamate.
FT MOD_RES 63 63 4-carboxyglutamate.
FT MOD_RES 66 66 4-carboxyglutamate.
FT MOD_RES 67 67 4-carboxyglutamate.
FT MOD_RES 72 72 4-carboxyglutamate.
FT MOD_RES 73 73 4-carboxyglutamate.
FT MOD_RES 76 76 4-carboxyglutamate.
FT MOD_RES 79 79 4-carboxyglutamate.
FT MOD_RES 82 82 4-carboxyglutamate.
FT MOD_RES 86 86 4-carboxyglutamate.
FT MOD_RES 110 110 (3R)-3-hydroxyaspartate.
FT MOD_RES 114 114 Phosphoserine.
FT MOD_RES 201 201 Sulfotyrosine.
FT MOD_RES 204 204 Phosphoserine.
FT CARBOHYD 99 99 O-linked (Glc...).
FT /FTId=CAR_000009.
FT CARBOHYD 107 107 O-linked (Fuc...).
FT /FTId=CAR_000010.
FT CARBOHYD 203 203 N-linked (GlcNAc...).
FT CARBOHYD 205 205 O-linked (GalNAc...).
FT CARBOHYD 213 213 N-linked (GlcNAc...).
FT CARBOHYD 215 215 O-linked (GalNAc...).
FT DISULFID 64 69
FT DISULFID 97 108
FT DISULFID 102 117
FT DISULFID 119 128
FT DISULFID 134 145
FT DISULFID 141 155
FT DISULFID 157 170
FT DISULFID 178 335
FT DISULFID 252 268
FT DISULFID 382 396
FT DISULFID 407 435
FT VAR_SEQ 93 130 Missing (in isoform 2).
FT /FTId=VSP_047689.
FT VARIANT 7 7 I -> F (in dbSNP:rs150190385).
FT /FTId=VAR_006520.
FT VARIANT 17 17 I -> N (in HEMB; severe; UK 22).
FT /FTId=VAR_006521.
FT VARIANT 28 28 C -> R (in HEMB; moderate; HB130).
FT /FTId=VAR_006522.
FT VARIANT 28 28 C -> Y (in HEMB).
FT /FTId=VAR_017343.
FT VARIANT 30 30 V -> I (in HEMB).
FT /FTId=VAR_006523.
FT VARIANT 37 37 A -> T (in warfarin sensitivity; reduced
FT affinity of the glutamate carboxylase for
FT the factor IX precursor).
FT /FTId=VAR_017307.
FT VARIANT 43 43 R -> L (in HEMB; severe; Bendorf, Beuten,
FT Gleiwitz, etc.).
FT /FTId=VAR_006525.
FT VARIANT 43 43 R -> Q (in HEMB; severe; San Dimas,
FT Oxford-3, Strasbourg-2, etc.).
FT /FTId=VAR_006524.
FT VARIANT 43 43 R -> W (in HEMB; severe; Boxtel, Heiden,
FT Lienen, etc.).
FT /FTId=VAR_006526.
FT VARIANT 45 45 K -> N (in HEMB; severe; Seattle E).
FT /FTId=VAR_006527.
FT VARIANT 46 46 R -> S (in HEMB; severe; Cambridge).
FT /FTId=VAR_006528.
FT VARIANT 46 46 R -> T (in HEMB; severe).
FT /FTId=VAR_006529.
FT VARIANT 48 48 N -> I (in HEMB; severe; Calgary-16).
FT /FTId=VAR_006530.
FT VARIANT 49 49 S -> P (in HEMB).
FT /FTId=VAR_006531.
FT VARIANT 52 52 L -> S (in HEMB; severe; Gla mutant).
FT /FTId=VAR_017344.
FT VARIANT 53 53 E -> A (in HEMB; severe; Oxford-B2; Gla
FT mutant).
FT /FTId=VAR_006532.
FT VARIANT 54 54 E -> G (in HEMB; severe; HB151; Gla
FT mutant).
FT /FTId=VAR_006533.
FT VARIANT 55 55 F -> C (in HEMB).
FT /FTId=VAR_006534.
FT VARIANT 58 58 G -> A (in HEMB; severe; Hong Kong-1).
FT /FTId=VAR_006535.
FT VARIANT 58 58 G -> R (in HEMB; severe; Los Angeles-4).
FT /FTId=VAR_006536.
FT VARIANT 62 63 Missing (in HEMB; severe).
FT /FTId=VAR_006537.
FT VARIANT 66 66 E -> V (in HEMB; moderate).
FT /FTId=VAR_006538.
FT VARIANT 67 67 E -> K (in HEMB; severe; Nagoya-4; Gla
FT mutant).
FT /FTId=VAR_006539.
FT VARIANT 71 71 F -> S (in HEMB; severe).
FT /FTId=VAR_006540.
FT VARIANT 73 73 E -> K (in HEMB; severe; Seattle-3; Gla
FT mutant).
FT /FTId=VAR_006541.
FT VARIANT 73 73 E -> V (in HEMB; severe; Chongqing; Gla
FT mutant).
FT /FTId=VAR_006542.
FT VARIANT 75 75 R -> Q (in HEMB; mild).
FT /FTId=VAR_017308.
FT VARIANT 79 79 E -> D (in HEMB).
FT /FTId=VAR_017309.
FT VARIANT 84 84 T -> R (in HEMB).
FT /FTId=VAR_017345.
FT VARIANT 91 91 Y -> C (in HEMB; moderate).
FT /FTId=VAR_006543.
FT VARIANT 93 93 D -> G (in HEMB; moderate; Alabama).
FT /FTId=VAR_006544.
FT VARIANT 96 96 Q -> P (in HEMB; severe; New London).
FT /FTId=VAR_006545.
FT VARIANT 97 97 C -> S (in HEMB).
FT /FTId=VAR_006546.
FT VARIANT 101 101 P -> R (in HEMB).
FT /FTId=VAR_006547.
FT VARIANT 102 102 C -> R (in HEMB; severe; Basel).
FT /FTId=VAR_006548.
FT VARIANT 106 106 G -> D (in HEMB).
FT /FTId=VAR_017346.
FT VARIANT 106 106 G -> S (in HEMB; mild; Durham).
FT /FTId=VAR_006549.
FT VARIANT 108 108 C -> S (in HEMB).
FT /FTId=VAR_006550.
FT VARIANT 110 110 D -> N (in HEMB; severe; Oxford-D1).
FT /FTId=VAR_006551.
FT VARIANT 112 112 I -> S (in HEMB).
FT /FTId=VAR_006552.
FT VARIANT 113 113 N -> K (in HEMB; mild).
FT /FTId=VAR_006553.
FT VARIANT 115 115 Y -> C (in HEMB; severe).
FT /FTId=VAR_006554.
FT VARIANT 119 119 C -> F (in HEMB; severe).
FT /FTId=VAR_006555.
FT VARIANT 119 119 C -> R (in HEMB; Iran).
FT /FTId=VAR_006556.
FT VARIANT 124 124 E -> K (in HEMB).
FT /FTId=VAR_017347.
FT VARIANT 125 125 G -> E (in HEMB).
FT /FTId=VAR_006557.
FT VARIANT 125 125 G -> R (in HEMB).
FT /FTId=VAR_017348.
FT VARIANT 125 125 G -> V (in HEMB).
FT /FTId=VAR_006558.
FT VARIANT 129 130 Missing (in HEMB).
FT /FTId=VAR_006559.
FT VARIANT 134 134 C -> Y (in HEMB).
FT /FTId=VAR_017349.
FT VARIANT 136 136 I -> T (in HEMB; mild).
FT /FTId=VAR_006560.
FT VARIANT 139 139 G -> D (in HEMB; severe).
FT /FTId=VAR_006561.
FT VARIANT 139 139 G -> S (in HEMB).
FT /FTId=VAR_006562.
FT VARIANT 155 155 C -> F (in HEMB; severe).
FT /FTId=VAR_006563.
FT VARIANT 160 160 G -> E (in HEMB; mild).
FT /FTId=VAR_006564.
FT VARIANT 167 167 Q -> H (in HEMB; mild).
FT /FTId=VAR_006565.
FT VARIANT 169 169 S -> C (in HEMB).
FT /FTId=VAR_017350.
FT VARIANT 170 170 C -> F (in HEMB).
FT /FTId=VAR_017351.
FT VARIANT 178 178 C -> R (in HEMB).
FT /FTId=VAR_006566.
FT VARIANT 178 178 C -> W (in HEMB; severe).
FT /FTId=VAR_006567.
FT VARIANT 191 191 R -> C (in HEMB; moderate; Albuquerque,
FT Cardiff-1, etc.).
FT /FTId=VAR_006569.
FT VARIANT 191 191 R -> H (in HEMB; moderate; Chapel-Hill,
FT Chicago-2, etc.).
FT /FTId=VAR_006568.
FT VARIANT 194 194 T -> A (in dbSNP:rs6048).
FT /FTId=VAR_011773.
FT VARIANT 226 226 R -> G (in HEMB; severe; Madrid).
FT /FTId=VAR_006571.
FT VARIANT 226 226 R -> Q (in HEMB; severe; Hilo and
FT Novara).
FT /FTId=VAR_006572.
FT VARIANT 226 226 R -> W (in HEMB; severe; Nagoya-1,
FT Dernbach, Deventer, Idaho, etc.).
FT /FTId=VAR_006570.
FT VARIANT 227 227 V -> D (in HEMB; mild).
FT /FTId=VAR_006573.
FT VARIANT 227 227 V -> F (in HEMB; Milano).
FT /FTId=VAR_017310.
FT VARIANT 228 228 V -> F (in HEMB; severe; Kashihara).
FT /FTId=VAR_017311.
FT VARIANT 228 228 V -> L (in HEMB; mild; Cardiff-2).
FT /FTId=VAR_006574.
FT VARIANT 241 241 Q -> H (in HEMB).
FT /FTId=VAR_006575.
FT VARIANT 241 241 Q -> K (in HEMB).
FT /FTId=VAR_017352.
FT VARIANT 252 252 C -> S (in HEMB; severe; this is the
FT mutation in the index case of the
FT disease, Stephen Christmas).
FT /FTId=VAR_017312.
FT VARIANT 252 252 C -> Y (in HEMB).
FT /FTId=VAR_017353.
FT VARIANT 253 253 G -> E (in HEMB; severe).
FT /FTId=VAR_006576.
FT VARIANT 253 253 G -> R (in HEMB; severe; Luanda).
FT /FTId=VAR_006577.
FT VARIANT 265 265 A -> T (in HEMB; mild).
FT /FTId=VAR_006578.
FT VARIANT 268 268 C -> W (in HEMB; moderate).
FT /FTId=VAR_017313.
FT VARIANT 279 279 A -> T (in HEMB; mild).
FT /FTId=VAR_006579.
FT VARIANT 283 283 N -> D (in HEMB; severe).
FT /FTId=VAR_006580.
FT VARIANT 286 286 Missing (in HEMB; severe).
FT /FTId=VAR_006581.
FT VARIANT 291 291 E -> V (in HEMB; Monschau).
FT /FTId=VAR_017314.
FT VARIANT 294 294 R -> G (in HEMB; severe).
FT /FTId=VAR_006582.
FT VARIANT 294 294 R -> Q (in HEMB; mild to moderate;
FT Dreihacken, Penafiel and Seattle-4).
FT /FTId=VAR_006583.
FT VARIANT 302 302 H -> R (in HEMB).
FT /FTId=VAR_006584.
FT VARIANT 306 306 N -> S (in HEMB; mild).
FT /FTId=VAR_017315.
FT VARIANT 316 316 I -> F (in HEMB).
FT /FTId=VAR_006585.
FT VARIANT 318 318 L -> R (in HEMB).
FT /FTId=VAR_017354.
FT VARIANT 321 321 L -> Q (in HEMB; severe).
FT /FTId=VAR_006586.
FT VARIANT 333 333 P -> H (in HEMB; severe).
FT /FTId=VAR_006587.
FT VARIANT 333 333 P -> T (in HEMB).
FT /FTId=VAR_017355.
FT VARIANT 342 342 T -> K (in HEMB; mild).
FT /FTId=VAR_006588.
FT VARIANT 342 342 T -> M (in HEMB; moderate).
FT /FTId=VAR_006589.
FT VARIANT 344 344 I -> L (in HEMB).
FT /FTId=VAR_017356.
FT VARIANT 351 351 G -> D (in HEMB).
FT /FTId=VAR_006590.
FT VARIANT 356 356 W -> C (in HEMB; severe).
FT /FTId=VAR_006591.
FT VARIANT 357 357 G -> E (in HEMB; severe; Amagasaki).
FT /FTId=VAR_006592.
FT VARIANT 357 357 G -> R (in HEMB).
FT /FTId=VAR_017316.
FT VARIANT 362 362 K -> E (in HEMB; moderate).
FT /FTId=VAR_006593.
FT VARIANT 363 363 G -> W (in HEMB).
FT /FTId=VAR_006594.
FT VARIANT 366 366 A -> D (in HEMB).
FT /FTId=VAR_006595.
FT VARIANT 379 379 R -> G (in HEMB; moderate).
FT /FTId=VAR_006596.
FT VARIANT 379 379 R -> Q (in HEMB; severe; Iceland-1,
FT London and Sesimbra).
FT /FTId=VAR_006597.
FT VARIANT 382 382 C -> Y (in HEMB).
FT /FTId=VAR_006598.
FT VARIANT 383 383 L -> F (in HEMB).
FT /FTId=VAR_017358.
FT VARIANT 383 383 L -> I (in HEMB).
FT /FTId=VAR_017357.
FT VARIANT 384 384 R -> L (in THPH8; factor IX Padua; higher
FT specific activity than wild-type).
FT /FTId=VAR_062999.
FT VARIANT 387 387 K -> E (in HEMB; mild).
FT /FTId=VAR_006599.
FT VARIANT 390 390 I -> F (in HEMB; severe).
FT /FTId=VAR_006600.
FT VARIANT 394 394 M -> K (in HEMB).
FT /FTId=VAR_006601.
FT VARIANT 395 395 F -> I (in HEMB).
FT /FTId=VAR_017359.
FT VARIANT 395 395 F -> L (in HEMB).
FT /FTId=VAR_017360.
FT VARIANT 396 396 C -> F (in HEMB).
FT /FTId=VAR_017361.
FT VARIANT 396 396 C -> S (in HEMB; severe).
FT /FTId=VAR_006602.
FT VARIANT 397 397 A -> P (in HEMB; mild; Hong Kong-11).
FT /FTId=VAR_017317.
FT VARIANT 404 404 R -> T (in HEMB).
FT /FTId=VAR_006603.
FT VARIANT 407 407 C -> R (in HEMB).
FT /FTId=VAR_017362.
FT VARIANT 407 407 C -> S (in HEMB; severe).
FT /FTId=VAR_006604.
FT VARIANT 410 410 D -> H (in HEMB; Mechtal).
FT /FTId=VAR_017318.
FT VARIANT 411 411 S -> G (in HEMB; Varel).
FT /FTId=VAR_017320.
FT VARIANT 411 411 S -> I (in HEMB; Schmallenberg).
FT /FTId=VAR_017319.
FT VARIANT 412 412 G -> E (in HEMB).
FT /FTId=VAR_017363.
FT VARIANT 413 413 G -> R (in HEMB; moderate to severe).
FT /FTId=VAR_006605.
FT VARIANT 414 414 P -> T (in HEMB; Bergamo).
FT /FTId=VAR_017321.
FT VARIANT 419 419 V -> E (in HEMB; moderately severe).
FT /FTId=VAR_006606.
FT VARIANT 424 424 F -> V (in HEMB).
FT /FTId=VAR_006607.
FT VARIANT 426 426 T -> P (in HEMB; severe; Barcelos).
FT /FTId=VAR_006608.
FT VARIANT 430 430 S -> T (in HEMB).
FT /FTId=VAR_006609.
FT VARIANT 431 431 W -> G (in HEMB).
FT /FTId=VAR_006610.
FT VARIANT 431 431 W -> R (in HEMB; moderate).
FT /FTId=VAR_006611.
FT VARIANT 432 432 G -> S (in HEMB; severe).
FT /FTId=VAR_006612.
FT VARIANT 432 432 G -> V (in HEMB; severe).
FT /FTId=VAR_006613.
FT VARIANT 433 433 E -> A (in HEMB).
FT /FTId=VAR_006614.
FT VARIANT 433 433 E -> K (in HEMB).
FT /FTId=VAR_006615.
FT VARIANT 435 435 C -> Y (in HEMB).
FT /FTId=VAR_017364.
FT VARIANT 436 436 A -> V (in HEMB; moderately severe;
FT Niigata).
FT /FTId=VAR_006616.
FT VARIANT 442 442 G -> E (in HEMB).
FT /FTId=VAR_017365.
FT VARIANT 442 442 G -> R (in HEMB; severe; Angers).
FT /FTId=VAR_017322.
FT VARIANT 443 443 I -> T (in HEMB; moderately severe; Long
FT Beach, Los Angeles and Vancouver).
FT /FTId=VAR_017323.
FT VARIANT 445 445 T -> TIYT (in HEMB; severe; Lousada).
FT /FTId=VAR_006617.
FT VARIANT 449 449 R -> Q (in HEMB; mild).
FT /FTId=VAR_006618.
FT VARIANT 449 449 R -> W (in HEMB; mild).
FT /FTId=VAR_006619.
FT VARIANT 450 450 Y -> C (in HEMB; severe).
FT /FTId=VAR_006620.
FT VARIANT 453 453 W -> R (in HEMB).
FT /FTId=VAR_017324.
FT VARIANT 454 454 I -> T (in HEMB; Italy).
FT /FTId=VAR_006621.
FT VARIANT 461 461 T -> P (in dbSNP:rs4149751).
FT /FTId=VAR_014308.
FT STRAND 50 52
FT HELIX 60 64
FT STRAND 65 67
FT HELIX 71 75
FT STRAND 78 80
FT HELIX 81 90
FT TURN 96 99
FT STRAND 107 111
FT STRAND 114 118
FT TURN 125 128
FT TURN 134 136
FT HELIX 137 140
FT STRAND 142 147
FT STRAND 149 151
FT STRAND 153 156
FT STRAND 161 163
FT STRAND 165 168
FT STRAND 170 176
FT STRAND 187 189
FT STRAND 241 248
FT STRAND 252 258
FT STRAND 261 264
FT HELIX 266 268
FT STRAND 271 273
FT STRAND 276 280
FT STRAND 282 286
FT STRAND 292 301
FT TURN 303 306
FT STRAND 307 310
FT TURN 311 314
FT STRAND 317 323
FT HELIX 339 347
FT STRAND 350 360
FT STRAND 370 377
FT HELIX 379 384
FT STRAND 394 398
FT STRAND 414 419
FT STRAND 422 431
FT STRAND 433 436
FT STRAND 442 446
FT HELIX 447 450
FT HELIX 451 457
SQ SEQUENCE 461 AA; 51778 MW; C4720C1234477EF5 CRC64;
MQRVNMIMAE SPGLITICLL GYLLSAECTV FLDHENANKI LNRPKRYNSG KLEEFVQGNL
ERECMEEKCS FEEAREVFEN TERTTEFWKQ YVDGDQCESN PCLNGGSCKD DINSYECWCP
FGFEGKNCEL DVTCNIKNGR CEQFCKNSAD NKVVCSCTEG YRLAENQKSC EPAVPFPCGR
VSVSQTSKLT RAETVFPDVD YVNSTEAETI LDNITQSTQS FNDFTRVVGG EDAKPGQFPW
QVVLNGKVDA FCGGSIVNEK WIVTAAHCVE TGVKITVVAG EHNIEETEHT EQKRNVIRII
PHHNYNAAIN KYNHDIALLE LDEPLVLNSY VTPICIADKE YTNIFLKFGS GYVSGWGRVF
HKGRSALVLQ YLRVPLVDRA TCLRSTKFTI YNNMFCAGFH EGGRDSCQGD SGGPHVTEVE
GTSFLTGIIS WGEECAMKGK YGIYTKVSRY VNWIKEKTKL T
//

MIM 300746
*RECORD*
*FIELD* NO
300746
*FIELD* TI
*300746 COAGULATION FACTOR IX; F9
;;FACTOR IX;;
PLASMA THROMBOPLASTIN COMPONENT; PTC
read more*FIELD* TX

DESCRIPTION

The F9 gene encodes coagulation factor IX, which circulates as an
inactive zymogen until proteolytic release of its activation peptide
allows it to assume the conformation of an active serine protease (Davie
and Fujikawa, 1975). Its role in the blood coagulation cascade is to
activate factor X (F10; 227600) through interactions with calcium,
membrane phospholipids, and factor VIII (F8; 300841). Factor IX and
factor X both consist of 2 polypeptide chains referred to as the L
(light) and H (heavy) chains. The H chain bears a structural resemblance
to the polypeptide chain of the pancreatic serine protease trypsin
(PRSS1; 276000). The L chain is covalently linked to the H chain by a
single disulfide bond (Fujikawa et al., 1974).

CLONING

Kurachi and Davie (1982) isolated and characterized a cDNA coding for
the human factor IX gene. The deduced 416-residue protein contains a
46-residue leader sequence that includes both a signal sequence and a
pro-sequence for the mature protein that circulates in plasma. The
amino-terminal region contains 12 glutamic acid residues that are
converted to gamma-carboxyglutamic acid in the mature protein. The
arginyl peptide bonds that are cleaved in the conversion of human factor
IX to factor IXa by factor XIa (F11; 264900) were identified as
Arg145-Ala146 and Arg180-Val181. The cleavage of these 2 internal
peptide bonds results in the formation of a 35-residue activation
peptide and factor IXa, a serine protease composed of a 145-residue
light chain and a 236-residue heavy chain that are held together by a
disulfide bond. The homology in the amino acid sequence between human
and bovine factor IX was found to be 83%.

Choo et al. (1982) isolated clones corresponding to the human factor IX
gene from a human cDNA library. The deduced human protein showed 78%
homology with the bovine protein.

Jagadeeswaran et al. (1984) used the peptide sequence of bovine F9 to
develop a probe to screen a human liver cDNA library. They identified a
recombinant clone corresponding to 70% of the coding region of human
factor IX. This F9 cDNA was used to probe restriction endonuclease
digested polymorphism, as well as to verify that the haploid genome
contains a single copy of the gene.

Anson et al. (1984) isolated clones corresponding to the full sequence
of the human factor IX gene from a human liver cDNA library. The gene
encodes a mature 415-residue protein.

GENE STRUCTURE

Anson et al. (1984) determined that the F9 gene contains 8 exons and
spans about 34 kb. Introns accounted for 92% of the gene length. Exons
conformed roughly to previously designated protein regions but the
catalytic region of the protein appeared to be coded by 2 separate
exons, which differed from the arrangement in other characterized serine
protease genes.

GENE FUNCTION

Factor IXa activates factor X as part of an intrinsic activating complex
that also consists of factor VIIIa. Using several chimeric and mutant F9
proteins in coagulation assays, Wilkinson et al. (2002) determined that
residues 88 to 109, excluding arg94, within the second epidermal growth
factor-like domain of factor IX are important for phospholipid surface
assembly of the factor X activating complex.

Rusconi et al. (2002) demonstrated that protein-binding oligonucleotides
(aptamers) against coagulation factor IXa are potent anticoagulants.
They also showed that oligonucleotides complementary to these aptamers
could act as antidotes capable of efficiently reversing the activity of
these new anticoagulants in plasma from healthy volunteers and from
patients who cannot tolerate heparin. Rusconi et al. (2002) concluded
that their strategy was generalizable for rationally designing a
drug-antidote pair, thus opening the way for developing safer
regulatable therapeutics.

MAPPING

Camerino et al. (1983) used a factor IX gene probe to demonstrate close
linkage to the locus for fragile X mental retardation syndrome (300624)
(17 nonrecombinants, 0 recombinants; lod = 5.12 at theta = 0.0).

Chance et al. (1983) assigned the human F9 gene to chromosome Xq27-qter
using somatic cell hybridization. F9 was in a fragment of the X
chromosome associated with no HPRT (308000) activity in the hybrid cell,
suggesting that F9 is distal to HPRT.

Using a cDNA probe in the study of human-mouse hybrid cells, Camerino et
al. (1984) mapped the F9 locus to Xq26-q27. Furthermore, they identified
a TaqI polymorphism with allelic frequencies of about 0.71 and 0.29. By
in situ hybridization and by study of rodent-human somatic cell hybrids
with various aberrations of the human X, Boyd et al. (1984) assigned the
factor IX locus to Xq26-qter. Jagadeeswaran et al. (1984) also mapped
the F9 gene to Xq26-qter.

MOLECULAR GENETICS

- Hemophilia B

Using genomic DNA probes, Chen et al. (1985) identified a partial
intragenic deletion in the F9 gene in 7 affected members of a family
with severe hemophilia B (306900).

In affected members of a family with severe factor IX deficiency and no
detectable factor IX protein, Taylor et al. (1988) identified a complete
deletion of the F9 gene that extended at least 80 kb 3-prime of the
gene. The proband did not have antibodies to factor IX, despite total
deletion of the gene.

Matthews et al. (1988) discussed the family originally reported by Peake
et al. (1984) as having an X-chromosome deletion of minimum size 114 kb
that included the entire F9 gene. By isolation of further 3-prime
flanking probes, they located the 3-prime breakpoint of the deletion to
a position 145 kb 3-prime to the start of the F9 gene. Abnormal junction
fragments detected at the breakpoint were used in the detection of
carriers.

In a patient with severe hemophilia B, Siguret et al. (1988) found loss
of the TaqI restriction site at the 5-prime end of exon 8 of the F9
gene. Using oligonucleotide probes and PCR-amplified DNA for sequencing
of the affected region, the authors identified a C-to-T change in the
catalytic domain of the protein, resulting in premature termination. The
change resulted from a CpG mutation.

By use of PCR followed by sequencing, Bottema et al. (1989) identified
mutations in the F9 gene (see, e.g., 300746.0051) in all 14 hemophilia B
patients studied. Analysis for heterozygosity in at-risk female
relatives was then done, either by sequencing the appropriate region or
by detection of an altered restriction site.

Green et al. (1991) provided a list of point mutations that cause
hemophilia B. Sommer et al. (1992) estimated that missense mutations
cause only 59% of moderate and severe hemophilia B and that these
mutations are almost always (95%) of independent origin (i.e., de novo
mutations). In contrast, missense mutations were found in virtually all
(97%) families with mild disease and only a minority of these (41%) were
of independent origin.

Giannelli et al. (1993) reported on the findings in a database of 806
patients with hemophilia B in whom the defect in factor IX had been
identified at the molecular level. A total of 379 independent mutations
were described. The list included 234 different amino acid
substitutions. There were 13 promoter mutations, 18 mutations in donor
splice sites, 15 mutations in acceptor splice sites, and 4 mutations
creating cryptic splice sites. In analyses of DNA from 290 families with
hemophilia B (203 independent mutations), Ketterling et al. (1994) found
12 deletions more than 20 bp long. Eleven of these were more than 2 kb
long and one was 1.1 kb.

Giannelli et al. (1996) described the sixth edition of their hemophilia
B database of point mutations and short (less than 30 bp) additions and
deletions. The 1,380 patient entries were ordered by the nucleotide
number of their mutation. References to published mutations were given
and the laboratories generating the data were indicated. Giannelli et
al. (1997) described the seventh edition of their database; 1,535
patient entries were ordered by the nucleotide number of their mutation.
When known, details were given on factor IX activity, factor IX antigen
in the circulation, presence of inhibitor, and origin of mutation.

Ljung et al. (2001) surveyed a series comprising all 77 known families
with hemophilia B in Sweden. The disorder was severe in 38, moderate in
10, and mild in 29. A total of 51 different mutations were found. Ten of
the mutations, all C-to-T or G-to-A transitions, recurred in 1 to 6
additional families. Using haplotype analysis of 7 polymorphisms in the
F9 gene, Ljung et al. (2001) found that the 77 families carried 65
unique, independent mutations. Of the 48 families with severe or
moderate hemophilia, 23 (48%) had a sporadic case compared with 31
families of 78 (40%) in the whole series. Five of those 23 sporadic
cases carried de novo mutations; 11 of 23 of the mothers were proven
carriers; and in the remaining 7 families, it was not possible to
determine carriership.

- X-Linked Thrombophilia due to Factor IX Defect

In an Italian man with deep venous thrombosis of the femoral-popliteal
veins (THPH8; 300807), Simioni et al. (2009) identified a hemizygous
mutation in the F9 gene (R338L; 300746.0112). Coagulation studies showed
that he had normal levels of F9 antigen, but very high levels of F9
activity (776% of control values).

- Mechanism of Mutation Generation

Methylation of CpG dinucleotides constitutes an endogenous mechanism of
mutation, which results from insufficient repair of the deamination
product to 5-methyl cytosine (Ketterling et al., 1993). Among 22
patients with hemophilia B, Koeberl et al. (1989) found a high rate of
mutation at CpG dinucleotides. Transitions of CpG accounted for 31% (5
out of 16) of distinct mutations and for 38% (5 out of 13) of single
base changes. The authors used a method of genome amplification with
transcript sequencing to perform direct sequencing on 8 regions of the
F9 gene.

Cooper and Krawczak (1990) made an extensive survey of single basepair
substitutions that cause various human genetic diseases and found that
32% were CG-to-TG or CG-to-CA transitions. This was a 12-fold increase
over the frequency predicted from random expectation. They presented a
computer model (MUTPRED) designed to predict the location of mutations
within gene coding regions causing human genetic disease. The model
predicted successfully the rank order of disease prevalence and/or
mutation rates associated with various human autosomal dominant and
X-linked recessive conditions. The mutational spectrum predicted for the
F9 gene resembled closely that observed for point mutations causing
hemophilia B. Cooper and Krawczak (1990) quoted from Edmund Spenser's
'The Faerie Queene' (circa 1609): '...mutability in them doth play her
cruell cruell sports, to many men's decay.'

To study the nature of spontaneous mutation, Koeberl et al. (1990)
sequenced 8 regions (a total of 2.46 kb) of likely functional
significance in the F9 gene in 60 consecutive, unrelated patients with
hemophilia B. From the pattern of mutations causing disease and from a
knowledge of evolutionarily conserved amino acids, they reconstructed
the underlying pattern of mutation and calculated the mutation rates per
basepair per generation for transitions (G-A or C-T changes) as 27 x
10(-10), transversions (A-T, A-C, G-T, or G-C changes) as 4.1 x 10(-10),
and deletions as 0.9 x 10(-10), for a total mutation rate of 32 x
10(-10). No insertions were observed in this sample. The proportion of
transitions at non-CpG dinucleotides was raised 7-fold over that
expected if 1 base substitution were as likely as another; at the
dinucleotide CpG, transitions were found to be increased 24-fold
relative to transitions at other sites. Mutations putatively affecting
splicing accounted for at least 13% of mutations, indicating that the
division of the gene into 8 exons represents a significant genetic cost
to the organism. All the missense mutations occurred at evolutionarily
conserved amino acids.

Bottema et al. (1990) found that in Asians (mostly Koreans), as in
Caucasians, transitions dominate among F9 mutations, followed by
transversions and microdeletions/insertions. On the basis of their data
combined with previous data, the authors concluded that more than
two-thirds of the missense mutations that can occur at nonconserved
amino acids do not cause hemophilia B.

In their series of patients with hemophilia B, Chen et al. (1991) found
that 23 (45%) of 51 substitutions in the F9 gene occurred as C-to-T or
G-to-A transitions at 11 sites within CpG dinucleotides. More than 1
family had identical defects for 6 of the CpG mutations. At 4 of these
sites, most patients had different haplotypes compatible with distinct
mutations. Non-CpG mutations occurred throughout the coding regions with
only 1 mutation in more than one family.

Bottema et al. (1991) identified 95 independent missense mutations in
the F9 gene resulting in hemophilia B; 94 of these occurred at amino
acids that are evolutionarily conserved in mammalian factor IX
sequences. They pointed out that the likelihood of a missense mutation
causing hemophilia B depends on whether the residue is also conserved in
the factor IX-related proteases: factor VII, factor X (F10; see 227600),
and protein C (PROC; 612283). They found that most of the possible
missense mutations in residues conserved in factor IX in all the related
proteases resulted in disease, whereas missense mutations not conserved
in the related proteases were 6-fold less likely to cause disease.
Missense mutations at nonconserved residues were 33-fold less likely to
cause disease. Bottema et al. (1991) concluded that many of the residues
in factor IX are spacers; that is, the main chains are presumably
necessary to keep other amino acid interactions in register, but the
nature of the side chain is unimportant.

Bottema et al. (1991) found that transversions at CpG dinucleotides are
elevated an estimated 7.7-fold relative to other transversions. On the
other hand, the mutation rates at non-CpG dinucleotides are relatively
uniform. They suggested that the high rate of CpG transversions accounts
for the fact that the F9 gene has a G+C content of approximately 40%.

Bottema et al. (1993) gave an updated estimate on mutations at CpG
dinucleotides in the F9 gene. Of the independent transitions they had
delineated in a consecutive sample of 290 families with hemophilia B,
42% occurred at CpG sites. Overall, CpG mutations represented 36% of the
point mutations and 30% of all mutations in their sample. An observed
20-fold enhancement for mutation at CpG sites with frequent mutations
reflected, they suggested, the situation at fully or mostly methylated
sites.

Based particularly on his extensive experience with mutation analysis in
hemophilia B, Sommer (1994) proposed an ingenious hypothesis concerning
the role of cancer in mediating evolutionary selection for a constant
rate of germline mutation. The hypothesis was based on data suggesting
that most germline mutations are due to endogenous processes such as
methylation of DNA at CpG dinucleotides. Furthermore, despite
differences in environment, diet, lifestyle, and occupational exposure,
the pattern of factor IX mutations is remarkably similar in populations
all over the world. Also despite the many differences in the environment
of modern day humans, the biases in the dinucleotide mutation rates
during the past 150 years are compatible with the ancient pattern that
fashioned the G+C content of 40%. Assuming that somatic mutation leading
to early-onset cancer occurs at rates similar to the germline mutation
rate, then these cancers that interfere with reproduction might cap the
germline mutation rate. Some have pointed out that cancer is a sensitive
mediator of negative selection because the multiple mutations required
for carcinogenesis can amplify the effects of small increases in the
mutation rate. A certain rate of mutation is required to generate
sufficient variation for adaptation during evolutionary time. Sexual
reproduction and recombination serves to enhance variation, but
ultimately new germline mutation is required to replenish variant
alleles lost secondary to negative selection, genetic drift, and
population bottlenecks. Unfortunately, the requisite mutation rate
carries a terrible price, since for each advantageous mutation, there
are many disadvantageous ones. Consequently, the optimal mutation rate
should be at a level just sufficient to maintain the variation needed
for adaptation. Mechanisms for negative selection are needed to keep the
mutation rate in check. Cancer may serve that role.

Of 727 independent mutations (0.28%) of the F9 gene in patients with
hemophilia B, Li et al. (2001) observed only 2 germline
retrotransposition mutations: a 279-bp insertion in exon 8 originating
from an Alu family of short interspersed elements not previously known
to be active, and a 463-bp insertion in exon e of a LINE-1 element
originating in a maternal grandmother. The authors stated that if the
rates of recent germline mutation in F9 are typical of the genome, a
retrotransposition event is estimated to occur somewhere in the genome
of about 1 in every 17 children born. Analysis of other estimates for
retrotransposition frequency and overall mutation rates suggested that
the actual rate of retrotransposition is likely to be in the range of 1
in every 2.4 to 1 in every 28 live births. Kazazian (1999) analyzed the
frequency of retrotransposition events involving 860 genes. These
included retrotranspositions identified in X-linked and severe autosomal
dominant disorders, likely to have occurred within the last 150 years,
and autosomal recessive disorders in which the mutations may have
occurred 10,000 or more years ago.

GENOTYPE/PHENOTYPE CORRELATIONS

Hirosawa et al. (1990) noted that all 5 families with hemophilia B
Leyden, in which a severe bleeding disorder in childhood becomes mild
after puberty, had mutations in an approximately 40-kb region in the
5-prime untranslated region of F9, which the authors referred to as the
Leyden-specific region (LSR). Base changes at nucleotide -20
(300746.0001) as well as at nucleotide -6 (300746.0002) and deletions of
the 3-prime half of the LS region reduced expression of the factor IX
gene to about 15-31% that of normal controls, as assessed in a cultured
cell (HepG2) expression system. Androgen significantly increased the
transcriptional activities of both mutant and normal factor IX genes in
a concentration-dependent manner. The findings suggested that a
mutations in this region could lead to a switch from constitutive to
steroid hormone-dependent gene expression.

Kurachi et al. (2009) stated that the LSR has been narrowed to an
approximately 50-bp region between nucleotides -34 and +19. Crossley and
Brownlee (1990) identified a binding site for the CCAAT/enhancer binding
protein (C/EBP, CEBPA; 116897) extending from +1 to +18 in the F9 gene,
which is capable of transactivating a factor IX promoter. Hepatocyte
nuclear factor-4 (HNF4; 600281), a member of the steroid hormone
receptor superfamily of transcription factors, also binds to nucleotides
-26 to -20 of the promoter region in the F9 gene (Reijnen et al., 1992).

ANIMAL MODEL

Kundu et al. (1998) generated a transgenic mouse model of hemophilia B
by targeted disruption of the murine F9 gene. The tail bleeding time of
hemizygous male mice was markedly prolonged compared with those of
normal and carrier female littermates. Seven of 19 affected male mice
died of exsanguination after tail snipping, and 2 affected mice died of
umbilical cord bleeding. Ten affected mice survived to 4 months of age.
Aside from the factor IX defect, carrier female and hemizygous male mice
had no liver pathology by histologic examination, were fertile, and
transmitted the mutation in the expected mendelian frequency.

Gu et al. (1999) found factor IX deficiency in 2 distinct dog breeds. In
1 breed, the disorder was associated with a large deletion mutation,
spanning the entire 5-prime region of the F9 gene extending to exon 6.
In the second breed, an insertion of approximately 5 kb disrupted exon
8. The insertion was associated with alternative splicing between a
donor site 5-prime and acceptor site 3-prime to the normal exon 8 splice
junction, with introduction of a new stop codon.

Brooks et al. (2003) found that mild hemophilia B in a large pedigree of
German wirehaired pointers was caused by a line-1 insertion in the
factor IX gene. The insertion could be traced through at least 5
generations and segregated with the hemophilia B phenotype.

Blood coagulation capacity increases with age in healthy individuals.
Through extensive longitudinal analyses of human factor IX gene
expression in transgenic mice, Kurachi et al. (1999) identified 2
essential age regulatory elements that they termed AE5-prime and
AE3-prime. These elements are required and together are sufficient for
normal age regulation of factor IX expression. AE5-prime, located
between nucleotides -770 through -802, is a PEA3-related element present
in the 5-prime upstream region of the gene encoding factor IX and is
responsible for age-stable expression of the gene. AE3-prime, located in
the middle of the 3-prime untranslated region, is responsible for
age-associated elevation in mRNA levels. In a concerted manner,
AE5-prime and AE3-prime recapitulate natural patterns of the advancing
age-associated increase in factor IX gene expression.

In transgenic mice with hemophilia B Leyden (-20T-A; 300746.0001), which
usually show amelioration of the disorder after puberty, Kurachi et al.
(2009) found that expression of different F9 minigenes with or without
the age-related stability element (ASE) in the 5-prime untranslated
region resulted in different disease course. Mice with no ASE failed to
show the Leyden phenotype, showing only transient F9 expression at
puberty, whereas mice with ASE showed normal pubertal F9 recovery. These
changes were not sex-dependent, indicating that testosterone and
androgen are not responsible. Further studies showed that the
transcription factor Ets1 (164720) was the specific ASE-binding protein
responsible for its activation and F9 gene expression. In addition, F9
expression was abolished by hypophysectomy, but restored with growth
hormone (GH; 139250) administration in both males and females. These
results provided a molecular mechanism for the puberty-related Leyden
phenotype. Kurachi et al. (2009) also generated transgenic mice
expressing the Brandenberg F9 mutation (-26G-C; 300746.0097), which
showed a severe phenotype without amelioration after puberty.

*FIELD* AV
.0001
HEMOPHILIA B LEYDEN
F9, -20T-A

Veltkamp et al. (1970) described a variant of hemophilia B, termed
hemophilia B Leyden (see 306900), in a Dutch family. The disorder was
characterized by the disappearance of the bleeding diathesis as the
patient aged. In affected individuals, plasma factor IX levels were less
than 1% of normal before puberty, but after puberty factor IX activity
and antigen levels rose steadily in a 1:1 ratio to a maximum of 50 to
60%. Briet et al. (1982) described a similar variant of hemophilia B
that took a severe form early in life but remitted after puberty, with
an increase in factor IX levels from below 1% of normal to about 50% of
normal by age 80 years. Three pedigrees with 27 affected males with this
disorder could be traced to a small village in the east of the
Netherlands. In affected members of 2 Dutch pedigrees with hemophilia B
Leyden, Reitsma et al. (1988) found that patients with hemophilia B
Leyden had a T-to-A transversion in the promoter region of the F9 gene
at position -20. The findings suggested that a point mutation in this
region could lead to a switch from constitutive to steroid
hormone-dependent gene expression.

Reijnen et al. (1992) demonstrated that the -20 promoter mutation
disrupts the binding of hepatocyte nuclear factor-4 (HNF4; 600281), a
member of the steroid hormone receptor superfamily of transcription
factors. Studies also demonstrated that the G-to-C mutation at -26
(300746.0097) also disrupts the binding of HNF4. Whereas HNF4
transactivated the wildtype promoter sequence in liver and nonliver
(e.g., HeLa) cell types, it transactivated the -20 mutated promoter to
only a limited extent and the -26 mutated promoter not at all. The data
suggested that HNF4 is a major factor controlling factor IX expression
in the normal individual. Furthermore, the severity of the hemophilia
phenotype appeared to be related directly to the degree of disruption of
HNF4 binding and transactivation; the -26 G-to-C mutation was
accompanied by a bleeding tendency did not ameliorate after puberty.

.0002
HEMOPHILIA B LEYDEN
F9, -6G-A

Fahner et al. (1988) found a G-to-A change at nucleotide -6 as the cause
of hemophilia B Leyden (see 306900), in which a severe bleeding disorder
in childhood becomes mild after puberty.

Crossley et al. (1990) also identified a G-to-A change at position -6 as
the cause of hemophilia B Leyden.

.0003
HEMOPHILIA B LEYDEN
F9, -6G-C

Attree et al. (1989) found a G-to-C change at nucleotide -6. Vidaud et
al. (1993) cited evidence indicating that the G-C transversion at
position -6 produces much milder hemophilia B Leyden (see 306900) than
does the G-A transition at the same position (300746.0002).

.0004
HEMOPHILIA B LEYDEN
F9, 1-BP DEL, +13A

Reitsma et al. (1989) studied the F9 gene in a Greek patient and an
American patient of Armenian descent with hemophilia B Leyden (see
306900). In one they found deletion of A at position +13 of the factor
IX gene and in the other an A-to-G mutation at the same position
(300746.0090), 32 bp downstream of the point mutation in the Dutch
kindred (Reitsma et al., 1988). See also Crossley et al. (1989).
Crossley and Brownlee (1990) identified a binding site for the
CCAAT/enhancer binding protein (C/EBP) extending from +1 to +18. They
showed that the A-to-G mutation at +13 prevents the binding of C/EBP to
this site. Furthermore, they showed that C/EBP is capable of
transactivating a cotransfected normal factor IX promoter but not the
mutant promoter.

.0005
FACTOR IX POLYMORPHISM
F9, ILE-40PHE

Koeberl et al. (1989) described a normal variant, isoleucine or
phenylalanine, at position -40 in exon 1 of the F9 gene.

.0006
FACTOR IX POLYMORPHISM
F9, IVS1, 192A-G

Tanimoto et al. (1988) found a normal polymorphism, A to G, at
nucleotide 192 in IVS1 of the F9 gene.

.0007
HEMOPHILIA B
F9, ARG-4TRP

In a review of known factor IX mutations from all hemophilia B (306900)
patients registered at the Malmo hemophilia center in Sweden and from
the entire UK hemophilia population, Green et al. (1992) noted that 4 of
7 arg-4trp (R-4W) mutations, resulting from a 6364C-T transition,
occurred on different haplotypes, indicating that they were independent
mutations.

.0008
HEMOPHILIA B
F9, ARG-4GLN

This variant has been called factor IX San Dimas and factor IX
Kawachinagano.

In a case (designated Ox3) of severe hemophilia B (306900) of the
CRM-positive type, Bentley et al. (1986) of Oxford University found
mutation of arginine to glutamine at position -4, leading to defective
cleavage of the N-terminal propeptide. The type of mutation in this
mutant factor IX is similar to that in the procollagen molecule (either
the alpha-1 or alpha-2 chain of type I collagen) in cases of type VII
Ehlers-Danlos syndrome. Two proteolytic cleavages normally occur to
remove the prepeptide and the propeptide regions. The mutant F9 had 18
additional amino acids on the N-terminal portion. Normally the signal
peptidase cleaves the peptide bond between residues -18 and -19. Further
cleavage to mature F9 depends on the arginine residue at -4. Arginine at
-4 shows evolutionary conservation in factor X, prothrombin, C3, C4, C5,
and tissue type plasminogen activator--all proteins that, like F9, are
processed by site-specific trypsin-like enzymes. In addition to the
CRM-positive and CRM-negative forms, there is a CRM-reduced class.
Sugimoto et al. (1989) demonstrated by amino acid sequence that the
mutant factor IX retained the propeptide region of 18 amino acids due to
a substitution of arginine at position -4 by glutamine. They assumed
that this attached propeptide region of the molecule directly interferes
with the adjacent NH(2)-terminus and prevents the metal-induced
conformational changes that are essential for biologic activity of
normal factor IX.

Ware et al. (1989) studied the intragenic defect in factor IX San Dimas,
which was derived from a patient with moderately severe hemophilia B
(306900) who had 98% factor IX antigen but very low factor IX clotting
activity. They found that a G-to-A transition in exon 2 of the F9 gene
resulted in the substitution of a glutamine for an arginine codon -4 in
the propeptide of factor IX. The variant protein circulated in the
plasma as profactor IX with a mutant 18-amino acid propeptide still
attached. Factor IX San Dimas shows similarities to factor IX Cambridge,
which has a substitution of serine for arginine at -1 (300746.0009).

Factor IX Kawachinagano is a mutant factor IX protein initially
recognized in a patient with severe hemophilia B who had 46% of normal
factor IX antigen but no detectable clotting activity. This mutant
factor IX is not activated by factor XIa in the presence of calcium
ions. Sugimoto et al. (1989) determined that factor IX Kawachinagano
results from an arg-to-gln substitution at the -4 position of the F9
gene. The substitution resulted in impaired function of the Gla-domain
caused by an attached propeptide region.

.0009
HEMOPHILIA B
F9, ARG-1SER

Diuguid et al. (1986) found that mutant factor IX Cambridge, isolated
from a patient with severe hemophilia B (306900), has an 18-residue
propeptide attached to its NH2-end. A point mutation at residue -1, from
arginine to serine, precluded cleavage of the propeptide by the
processing protease and interfered also with gamma-carboxylation of the
mutant factor IX. The last effect indicates the importance of the leader
sequence in substrate recognition by the vitamin K-dependent
carboxylase.

.0010
HEMOPHILIA B
F9, GLU7ASP

See Winship (1989).

.0011
HEMOPHILIA B
F9, GLN11TER

See Winship (1989); the patient studied had a severe form of hemophilia
B (306900).

.0012
HEMOPHILIA B
F9, CYS18ARG

Information was provided by Bertina (1989); the patient studied had a
severe form of hemophilia B (306900).

.0013
HEMOPHILIA B
F9, GLU27LYS

This variant has been designated factor IX Seattle-3.

Chen et al. (1989) studied 5 patients with severe hemophilia B (306900)
and detectable factor IX antigen that showed altered reactivity to a
specific polyclonal antibody fraction or monoclonal anti-factor IX
antibody. By the PCR technique, they identified a single base transition
in each of the 5 families. Three different mutations were identified:
factor IX Seattle-3 showed a G-to-A transition in exon 2, changing the
codon for glu27 to lys; factor IX Durham showed a G-to-A transition in
exon 4, changing the codon for gly60 to ser; and factor IX Seattle-4
showed a G-to-A transition in exon 8, changing arg248 to gln in exon 8.

.0014
HEMOPHILIA B
F9, GLU27VAL

This variant has been designated factor IX Chongqing.

Wang et al. (1990) studied a Chinese patient with sporadic hemophilia B
(306900) of severe form. A defect in the factor IX Gla domain was
suspected because of low antigen on an assay using a calcium-dependent
antibody fraction. Since the Gla domain is coded mainly by exon 2, Wang
et al. (1990) amplified and sequenced the exon and found an A-to-T
substitution at nucleotide 6455. The transversion changed glutamic
acid-27 to valine. In leukocyte DNA from the patient's mother, the
nucleotide sequence of exon 2 was entirely normal.

.0015
HEMOPHILIA B
F9, ARG29TER

See Green et al. (1989). This mutation, which is due to a transition at
a CpG dinucleotide, was found by Koeberl et al. (1990) in 2 cases of
severe hemophilia B (306900). Koeberl et al. (1990) estimated that
approximately 1 in 4 individuals with hemophilia B can be expected to
have a mutation at arginine and concluded that nonsense mutations at 1
of the 6 arginine residues are common causes of severe hemophilia.

.0016
HEMOPHILIA B
F9, ARG29GLN

See Koeberl et al. (1989) and Zhang et al. (1989). The hemophilia
(306900) was clinically mild.

.0017
HEMOPHILIA B
F9, GLU33ASP

See Koeberl et al. (1989).

.0018
HEMOPHILIA B
F9, IVS3DS, T-G

Brownlee (1988) described a GT-to-GG donor splice site mutation in IVS3
in association with severe hemophilia B (306900).

.0019
HEMOPHILIA B
F9, ASP47GLY

Davis et al. (1984, 1987) found that factor IX Alabama, a CRM+ mutation
responsible for a clinically moderate form of hemophilia B (306900), has
an adenine to guanine transition in the first nucleotide of exon d,
causing substitution of glycine for aspartic acid (GAT to GGT) at
residue 47. The structural defect in factor IX Alabama results in a
molecule with 10% of normal coagulant activity. McCord et al. (1990)
concluded that the asp47-to-gly mutation, which occurs in a
calcium-binding site, results in a loss of a stable calcium-mediated
conformational change, leading to improper interaction with factor VIIIa
and factor X.

.0020
HEMOPHILIA B
F9, GLN50PRO

See Lozier et al. (1989). The hemophilia (306900) was clinically severe.

.0021
HEMOPHILIA B
F9, PRO55ALA

This variant has been designated factor IX Hollywood.

See Green et al. (1989) and Spitzer et al. (1989). The hemophilia
(306900) was clinically mild.

.0022
HEMOPHILIA B
F9, GLY60SER

This variant has been designated factor IX Durham.

In 2 men with mild hemophilia B (306900), Denton et al. (1988) found
that the highly conserved gly60 residue had been changed to ser. The
mutation was accompanied by defective epitope expression in the 2
patients, suggesting that a change in the tertiary structure of the
EGF-like domain is the cause of the mild hemophilia B. See Chen et al.
(1989).

Poort et al. (1989) found the same mutation in a Dutch family. A G-to-A
change at position 10430 in exon 4 was responsible. The presence of the
same mutation in 3 patients from distinct geographic areas confirmed the
notion that CpG dinucleotides are 'hotspots' for mutation.

.0023
HEMOPHILIA B
F9, ASP64GLY

See Green et al. (1989). The hemophilia (306900) was clinically mild.

.0024
HEMOPHILIA B
F9, GLY114ALA

See Winship et al. (1989). The hemophilia (306900) was clinically
severe.

.0025
HEMOPHILIA B
F9, ASN120TYR

See Green et al. (1989). The hemophilia (306900) was clinically severe.

.0026
HEMOPHILIA B
F9, ARG145CYS

Liddell et al. (1989) described a molecular defect in factor IX Cardiff,
a variant that showed faulty activation with the production of a stable
reaction product with a molecular weight compatible with that of a
putative light chain-activation intermediate. A single C-to-T transition
was discovered that changed the arg residue at position 145 (the first
residue of the first bond in the activation peptide) to a cys. The
hemophilia (306900) was clinically moderate to severe.

.0027
HEMOPHILIA B
F9, ARG145HIS

Factor IX Chapel Hill, a CRM+ variant of mild hemophilia B (306900),
results from an arg-to-his change at residue 145, which prevents
cleavage at one of the activation sites (Noyes et al., 1983). See
Koeberl et al. (1989). Suehiro et al. (1990) concluded that the
arg145-to-his substitution impairs the cleavage between the light chain
and the activation peptide by factor XIa/calcium ions.

This variant has also been called factor IX Nagoya-3.

.0028
DEEP VENOUS THROMBOSIS, PROTECTION AGAINST
F9, THR148ALA

McGraw et al. (1985) identified a common polymorphism at the third amino
acid residue in the activation peptide of the F9 gene: an A-to-G
transition resulting in a thr148-to-ala (T148A) substitution.

Winship and Brownlee (1986) also identified the 20422A-G transition in
the F9 gene and found that it gave rise to an MnlI RFLP. However,
technical problems made it difficult to detect the polymorphic fragments
by conventional Southern blotting. The polymorphism as identified by
oligonucleotide probes was used for linkage studies in a 3-generation
family.

Graham et al. (1988) showed that the F9 protein with thr148 reacted to
the mouse monoclonal antibody, whereas that with ala148 did not. The
polymorphism is referred to as the F9 Malmo polymorphism; positive
reactors are designated Malmo A, and negative reactors are designated
Malmo B. Strong linkage disequilibrium was found with 2 other intragenic
RFLPs.

Bezemer et al. (2008) reported that the G allele (ala148) of F9 Malmo
(dbSNP rs6048) was associated with a 15 to 43% decrease in deep vein
thrombosis risk compared to the A allele in 3 case-control studies of
deep vein thrombosis. This common variant has a minor allele frequency
of 0.32. The substitution occurs in the portion of the factor IX zymogen
that is cleaved from the zymogen to activate factor IX. The authors
noted that this variant had not been reported to be associated with
hemophilia B (306900). In a follow-up study from 3 case-control studies
involving a total of 1,445 male patients with deep venous thrombosis and
2,351 male controls, Bezemer et al. (2009) found that the G allele of F9
Malmo conferred protection against deep venous thrombosis (odds ratio of
0.80); see 300807. The pooled corresponding odds ratio in a comparable
number of women with deep venous thrombosis was 0.89. However, factor IX
antigen level, factor IX activation peptide levels, and endogenous
thrombin potential did not differ between the F9 Malmo genotypes.
Although F9 Malmo was the most strongly associated with protection from
deep vein thrombosis, the biologic mechanism remained unknown.

.0029
HEMOPHILIA B
F9, GLN173TER

See Koeberl et al. (1989). The hemophilia (306900) was clinically
severe.

.0030
HEMOPHILIA B
F9, ARG180TRP

This variant has been called factor IX B(M) Nagoya and factor IX
Deventer.

Suehiro et al. (1989) demonstrated substitution of tryptophan for
arginine at position 180 in the factor IX protein of a patient with
severe hemophilia B (306900). Bertina et al. (1990) found the same
mutation.

.0031
HEMOPHILIA B(M)
F9, ARG180GLN

This variant has been called factor IX Hilo and factor IX Novara.

A subset of hemophilia B patients have a prolonged prothrombin time (PT)
when exposed to bovine (or ox) brain tissue; these CRM+ patients are
classified as having hemophilia B(M) (see 306900). Huang et al. (1989)
demonstrated a point mutation in a hemophilia B(M) variant, factor IX
Hilo. Glutamine (CAG) was substituted for arginine (CGG) at amino acid
180 in exon 6 (G-to-A at nucleotide 20519). Bertina et al. (1990) found
the same mutation. The hemophilia was clinically severe.

Lefkowitz et al. (1993) noted that the bovine brain tissue in studies of
hemophilia B(M) is the source of thromboplastin, or tissue factor (F3;
134390); PT times determined with thromboplastin from rabbit brain or
human brain are not reported to be prolonged. However, in various
studies of factor IX Hilo, Lefkowitz et al. (1993) found that either
normal F9 or Hilo F9 prolonged the PT regardless of the tissue factor
source, but the prolongation required high concentrations of factor IX
when rabbit or human brain was used. With bovine thromboplastin, factor
IX Hilo was significantly better than normal factor IX at prolonging the
PT. In addition, the prolongation times depended on the amounts of
factors IX and X used in the assays.

.0032
HEMOPHILIA B
F9, VAL181PHE

This variant has been designated factor IX Milano. See Bertina et al.
(1989, 1990).

.0033
HEMOPHILIA B
F9, VAL182PHE

Sakai et al. (1989) found that the defect in hemophilia B (306900)
(factor IX Kashihara), a severe hemorrhagic disorder in which a factor
IX antigen is present in normal amounts but factor IX biological
activity is markedly reduced, has a defect in valine-182 (equivalent to
valine-17 in the chymotrypsin numbering system), which is replaced by
phenylalanine. The change appears to hinder sterically the cleavage of
arg180-val181 required for the activation of this zymogen.

.0034
HEMOPHILIA B(M)
F9, VAL182LEU

This variant has been designated factor IX Cardiff II. See Taylor et al.
(1989). One of the variant forms of hemophilia B in which normal levels
of a dysfunctional factor IX protein is found is referred to as
hemophilia B(M) (see 306900) (Hougie and Twomey, 1967; Kasper et al.,
1977). The abnormal factor IX results in prolongation of the prothrombin
time performed with ox brain thromboplastin. In 1 such patient, Taylor
et al. (1990) found a G-to-C transversion at nucleotide 20524, changing
the amino acid encoded at residue 182 from valine to leucine. The
abnormal factor IX protein showed a normal molecular weight and normal
calcium-binding properties. Activation of the mutant factor IX with
factor XIa showed normal proteolytic cleavage. Hemophilia was clinically
mild in these patients.

.0035
HEMOPHILIA B
F9, GLN191TER

See Matsushita et al. (1989). The hemophilia (306900) was clinically
severe.

.0036
HEMOPHILIA B
F9, GLN191LEU

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically severe.

.0037
HEMOPHILIA B
F9, TRP194TER

See Green et al. (1989). The hemophilia (306900) was clinically severe.

.0038
HEMOPHILIA B
F9, IVS6DS, G-T

In a severely affected, antigen-negative (CRM-negative) patient with
hemophilia B (306900), Rees et al. (1985) found a point mutation in the
F9 gene that changed an obligatory GT to a TT within the donor splice
junction of exon 6. This was comparable to point mutations in splice
junctions that lead to beta-zero-thalassemia (see 613985).

.0039
HEMOPHILIA B
F9, TRP215TER

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically severe.

.0040
HEMOPHILIA B
F9, CYS222TRP

See Koeberl et al. (1989). The hemophilia (306900) was clinically
moderate in severity.

.0041
FACTOR IX, DNA POLYMORPHISM
F9, VAL227VAL

A T-to-C substitution in codon 227 produced no change in amino acid
(Koeberl et al., 1989).

.0042
HEMOPHILIA B
F9, ALA233THR

See Koeberl et al. (1989). The hemophilia (306900) was clinically mild.

.0043
HEMOPHILIA B
F9, IVS7AS, G-A

Matsushita et al. (1989) found a G-to-A substitution in the last
nucleotide in the 3-prime acceptor splice site of IVS7. The hemophilia
(306900) was severe and was associated with a serum inhibitor.

.0044
HEMOPHILIA B
F9, ARG248TER

See Green et al. (1989).

.0045
HEMOPHILIA B
F9, ARG248GLN

This variant has been called factor IX Seattle-4 and factor IX
Dreihacken.

See Chen et al. (1989). In a patient with hemophilia B (306900), Ludwig
et al. (1992) identified a G-to-A transition at nucleotide 30864 of the
F9 gene, resulting in replacement of arg248 by gln in the mature factor
IX protein.

.0046
HEMOPHILIA B
F9, ARG252TER

In male sibs with severe hemophilia B (306900), Chen et al. (1989)
demonstrated a C-to-T change at nucleotide 30875 resulting in a nonsense
mutation (TGA) and termination of protein synthesis at amino acid
residue 252. The change involved a CpG dinucleotide. The protein was
designated factor IX Portland.

.0047
HEMOPHILIA B
F9, ASN260SER

See Koeberl et al. (1989). The hemophilia (306900) was clinically mild.

.0048
HEMOPHILIA B
F9, PRO287LEU

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically severe.

.0049
HEMOPHILIA B
F9, ALA291PRO

See Winship et al. (1989).

.0050
HEMOPHILIA B
F9, THR296MET

See Koeberl et al. (1989). Hemophilia B (306900) is an X-linked disorder
relatively frequent among the Amish, particularly those living in Ohio
(Wall et al., 1967). Ketterling et al. (1991) demonstrated that the
Amish mutation is thr296-to-met. Among 64 families of European descent
with hemophilia B, Ketterling et al. (1991) found that 6 (9%) had a
C-to-T transition at base 31008 leading to the thr296-to-met mutation in
the catalytic domain of factor IX. Five of the patients had the same
haplotype and were known or presumed to be from the Amish group. All 6
patients had clinically mild disease.

.0051
HEMOPHILIA B
F9, VAL307ALA

See Bottema et al. (1989). The hemophilia (306900) was clinically mild.

.0052
HEMOPHILIA B
F9, GLY309VAL

See Thompson et al. (1989). The hemophilia (306900) was clinically
severe.

.0053
HEMOPHILIA B
F9, TRP310TER

See Wang et al. (1990). The hemophilia (306900) was clinically severe.

.0054
HEMOPHILIA B
F9, GLY311ARG

See Koeberl et al. (1989).

.0055
HEMOPHILIA B
F9, ARG333TER

See Zhang et al. (1989). This mutation, due to a transition at a CpG
dinucleotide, was found by Koeberl et al. (1990) in 2 patients with
severe hemophilia B (306900).

.0056
HEMOPHILIA B
F9, ARG333GLN

Tsang et al. (1988) characterized the mutation in factor IX London-2,
which caused a severe CRM+ hemophilia B (306900). Tsang et al. (1988)
found a G-to-A transition at position 31119. The mutation resulted in
substitution of glutamine for arginine at position 333. This arginine
residue is conserved in the catalytic domain of normal human and bovine
factor IX, factor X, and prothrombin. This mutation pinpoints a
functionally critical feature of factor IX which may be involved in
substrate or cofactor binding.

.0057
HEMOPHILIA B
F9, CYS336ARG

See Green et al. (1989). The hemophilia (306900) was clinically of
moderate severity.

.0058
HEMOPHILIA B
F9, ARG338TER

Ludwig et al. (1989) demonstrated a C-to-T transition at amino acid 338,
converting the CGA codon for arginine to a TGA stop codon. The variant
was called factor IX Bonn-1. The hemophilia (306900) was clinically
severe.

.0059
REMOVED FROM DATABASE
.0060
HEMOPHILIA B
F9, MET348VAL

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically of moderate severity.

.0061
HEMOPHILIA B
F9, SER360LEU

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically of moderate severity.

.0062
HEMOPHILIA B
F9, GLY363VAL

See Spitzer et al. (1988). The hemophilia (306900) was clinically of
moderate severity.

.0063
HEMOPHILIA B
F9, GLY367ARG

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically severe.

.0064
HEMOPHILIA B
F9, PRO368THR

See Bertina et al. (1989, 1990).

.0065
HEMOPHILIA B
F9, PHE378LEU

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was clinically severe.

.0066
HEMOPHILIA B
F9, ALA390GLU

Information was provided by Thompson (1989). The hemophilia (306900) was
clinically of moderate severity.

.0067
HEMOPHILIA B
F9, ALA390VAL

Spitzer et al. (1988) found substitution of valine for alanine at
position 390, resulting from a single base substitution (C-to-T) in exon
8. Sugimoto et al. (1988) demonstrated substitution of valine for
alanine at position 390 in the catalytic domain as the molecular defect
in factor IX Niigata. The patient had a moderately severe form of
hemophilia B (306900) with a normal level of factor IX antigen but very
low clotting activity.

Bertina et al. (1990) referred to this mutation as factor IX Lake
Elsinore.

.0068
HEMOPHILIA B
F9, GLY396ARG

Attree et al. (1989) designed a strategy allowing rapid analysis of the
critical serine protease catalytic domain of activated factor IX,
encoded by exons 7 and 8 of the gene. The method involved enzymatic
amplification of genomic DNA, analysis of the amplification products by
denaturing gradient gel electrophoresis, and direct sequencing of the
fragments displaying an altered melting behavior. They used this
procedure to characterize 2 'new' mutations in hemophilia B (306900):
factor IX Angers, a G-to-A substitution generating an arg in place of a
gly at amino acid 396 of the mature factor IX protein; and factor IX
Bordeaux, an A-to-T substitution introducing a nonsense codon in place
of the normal codon for lys at position 411 (300746.0071). The
hemophilia was clinically severe.

.0069
HEMOPHILIA B
F9, ILE397THR

Ware et al. (1988) demonstrated that the defect in factor IX(Long Beach)
is a result of a thymine-to-cytosine transition leading to the
substitution of a threonine codon (ACA) for an isoleucine codon (ATA) in
exon 8 of the F9 gene. In a case of hemophilia B (306900) of moderate
severity, Geddes et al. (1989) found a mutation in the protease domain
of factor IX that changed the codon for isoleucine-397 (ATA) to a
threonine codon (ACA). The resulting abnormal protein had been named
factor IX(Vancouver) (Geddes et al., 1987). Thus, factor IX Long Beach,
factor IX Vancouver, and factor IX Los Angeles have the same defect. In
11 of 65 consecutive males with hemophilia B (17%), Bottema et al.
(1990) found this mutation, a T-to-C transition at base 31311, which
substitutes threonine for isoleucine-397. The 11 patients were of
western European descent and had the same haplotype. Judging from the
frequency of this haplotype, the probability of the same mutation
occurring independently 11 times in this haplotype was considered to be
minuscule. Despite the lack of overlapping pedigrees, a common ancestor
for these patients was suspected. The clinical symptoms were
considerably moderate/mild. Sarkar et al. (1991) found this mutation in
2 females with hemophilia B. Both were heterozygous, coming from
unrelated families. Nonrandom X inactivation was proposed, although
other possibilities included a second undetected intronic or promoter
mutation. Chen et al. (1991) found this mutation in 7 families which all
shared a rare haplotype, suggesting a common ancestor.

.0070
HEMOPHILIA B
F9, TRP407ARG

See Koeberl et al. (1989).

.0071
HEMOPHILIA B
F9, LYS411TER

This variant has been designated factor IX Bordeaux. See Attree et al.
(1989). The hemophilia (306900) was clinically severe.

.0072
HEMOPHILIA B
F9, EX1-8DEL

Deletions of various sizes deleting exons 1-8 were reported by Giannelli
et al. (1983), Anson et al. (1988), Taylor et al. (1988), Matthews et
al. (1987), Ludwig et al. (1989), Wadelius et al. (1988), Bernardi et
al. (1985), Mikami et al. (1987), Tanimoto et al. (1988), Koeberl et al.
(1989), and Hassan et al. (1985). Some of the deletions were associated
with development of inhibitors and others of comparable size were not.
The hemophilia (306900) was clinically severe.

.0073
HEMOPHILIA B
F9, EX1DEL

Ludwig et al. (1989) described deletion of exon 1 in a case of severe
hemophilia B (306900).

.0074
HEMOPHILIA B
F9, EX1-3DEL

See Ludwig et al. (1989). The hemophilia (306900) was severe and was
associated with serum inhibitors.

.0075
HEMOPHILIA B
F9, EX2-8DEL

Information was provided by Chen and Thompson (1989). The hemophilia
(306900) was severe and was associated with serum inhibitors.

.0076
HEMOPHILIA B
F9, EX4-5DEL

See Ludwig et al. (1989). The hemophilia (306900) was clinically severe.

.0077
HEMOPHILIA B
F9, EX4DEL

See Vidaud et al. (1986). The hemophilia (306900) was clinically severe.

.0078
HEMOPHILIA B
F9, EX4INS

In a patient with moderate to severe hemophilia B (306900), Chen et al.
(1988) found a large insertion in the F9 gene, which appeared to have
originated from outside the gene rather than to represent an internal
duplication. The variant was called factor IX El Salvador for the
birthplace of the patient.

.0079
HEMOPHILIA B
F9, EX5-8DEL

See Matthews et al. (1987) and Peake et al. (1989). The hemophilia
(306900) was severe and was associated with serum inhibitors.

.0080
HEMOPHILIA B
F9, EX51INS

See Vidaud et al. (1989). The hemophilia (306900) was clinically severe.

.0081
HEMOPHILIA B
F9, EX7DEL

See Ludwig et al. (1989). The hemophilia (306900) was clinically severe.

.0082
HEMOPHILIA B
F9, 1-BP DEL, ASP85FS

This variant has been designated factor IX Seattle-2.

In a case of severe hemophilia B (306900), Schach et al. (1987) found
deletion of a single adenine nucleotide in exon 5. This resulted in a
frameshift that converted an aspartic acid at position 85 in the protein
to a valine and the formation of a stop signal at position 86.

.0083
HEMOPHILIA B
F9, VAL328PHE

Winship (1990) found a substitution of valine by phenylalanine at
residue 328 in exon h of factor IX in a patient with hemophilia B
(306900) referred to as hemophilia B Oxford h5 (Oxh5). The substitution
was caused by a G-to-T transversion at nucleotide 31103. Arg327-val328
is the major thrombin cleavage site in factor IX. Winship (1990)
suggested that the mutant protein may have increased susceptibility to
thrombin cleavage with resulting in vivo instability of the mutant
protein.

.0084
HEMOPHILIA B
F9, ARG116TER

In a 4-year-old boy with severe hemophilia B (306900), an isolated case
in his family, Montandon et al. (1990) identified a C-to-T transition at
residue 17762 resulting in a translation stop at codon arginine-116. A
second mutation in this patient at residue 30890 resulted in a
his257-to-tyr substitution (300746.0085); this mutation was subsequently
shown to be neutral by the fact that its origin preceded the maternal
grandfather and it produced no reduction in factor IX coagulant and
antigen level in the grandfather. On the other hand, analysis of other
family members showed that the mutation for arg116-to-ter had occurred
at gametogenesis in the paternal grandfather. The patient was referred
to as Malmo 7.

.0085
FACTOR IX POLYMORPHISM
F9, HIS257TYR

See 300746.0084.

.0086
HEMOPHILIA B
F9, CYS350SER

Taylor et al. (1991) described a male patient with hemophilia B (306900)
in whom they documented somatic mosaicism for a cysteine-to-serine
alteration at codon 350 in the catalytic domain of factor IX. The
mutation resulted from a G-to-C transversion at nucleotide 31170. Using
a combination of allele-specific oligonucleotide hybridization and
differential termination of primer extension, Taylor et al. (1991)
showed that hepatic, renal, smooth muscle, and hematopoietic cells
possessed both normal and mutant factor IX sequences. An additional
unusual phenomenon in this pedigree was the presence of 2 females in
successive generations with moderately severe factor IX deficiency.
These females were the daughter and granddaughter of the proband. No
evidence of X chromosome or autosome cytogenetic abnormalities was
found, no additional sequence alterations were identified in the factor
IX gene in either woman and no gross changes were observed on Southern
analysis of the regulatory regions in the 5-prime and 3-prime ends of
the gene. The normal X chromosomes of the 2 women were shown to have
different haplotypes at the factor IX locus. Taylor et al. (1991)
speculated that the X chromosome bearing the normal factor IX gene has
been exclusively inactivated in both affected women, possibly secondary
to a second genetic change affecting the primary inactivation center on
the mutant X chromosome and resulting in a failure of inactivation of
the mutant factor IX sequences.

.0087
HEMOPHILIA B
F9, ASP64ASN

Winship and Dragon (1991) described a G-to-A transition at nucleotide
10442 of the F9 gene, resulting in substitution of asparagine for
aspartic acid-64 (D64N). The change resulted in a functionally defective
factor IX molecule that altered calcium-binding properties.

.0088
HEMOPHILIA B LEYDEN
F9, +8T-C

In an Anglo-Irish family living in New Zealand, Royle et al. (1991)
identified a T-to-C transition at position +8 in the promoter region of
the F9 gene as the cause of hemophilia B Leyden (see 306900). This
mutation is situated within the repeat consensus sequence in the
transcribed but untranslated portion of the gene. The mutation had
arisen de novo in the proband.

.0089
HEMOPHILIA B LEYDEN
F9, -5A-T

In a 3-year-old boy with hemophilia B Leyden (306900), Picketts et al.
(1992) described an A-to-T transversion at position -5 of the factor IX
promoter. Picketts et al. (1993) identified 5 transcription factor
binding sites within the F9 promoter and showed that the Leyden mutation
at nucleotide -5 interfered with the binding of proteins to 1 of 3 newly
identified sites. The correlation between the postpubertal recovery of
these mutants and the induction of the transcription factor DBP (D-site
binding protein; 124097) led Picketts et al. (1993) to the discovery of
a synergistic interaction between DBP and C/EBP (CCAAT/enhancer binding
protein; 116897).

.0090
HEMOPHILIA B LEYDEN
F9, +13A-G

As indicated in 300746.0004, Reitsma et al. (1989) found an A-to-G
mutation at position +13 of the factor IX gene in an American patient of
Armenian descent with hemophilia B Leyden (see 306900).

.0091
HEMOPHILIA B
F9, GLY311GLU

In a patient with hemophilia B (306900), Miyata et al. (1991) identified
a G-to-A substitution in exon 8 resulting in replacement of glycine-311,
a highly conserved amino acid residue among serine proteases, by
glutamic acid. The mutation resulted in complete loss of both coagulant
activity and esterase activity. The variant was designated factor IX
Amagasaki.

.0092
HEMOPHILIA B
F9, IVS4, 4442-BP DEL

In a 17-year-old male with severe hemophilia B (306900), Solera et al.
(1992) found a 4,442-bp deletion, which removed both the donor splice
site located at the 5-prime end of intron d and the last 2 coding
nucleotides located at the 3-prime end of exon 4. This fragment had been
replaced by a 47-bp sequence from the normal factor IX gene, inserted in
inverted orientation. They identified 2 homologous sequences at the ends
of the deleted DNA fragment. The variant was designated factor IX
Madrid-2.

.0093
HEMOPHILIA B
F9, SER365ILE

Ludwig et al. (1992) described the molecular basis of hemophilia B
(306900) in 5 patients who had neither deletions nor rearrangements of
the F9 gene. By enzymatic amplification and sequencing of all exons and
promoter regions, a causative mutation in the protease domain was
identified in each patient. The first was a G-to-T transversion at
nucleotide 31215, leading to substitution of isoleucine for serine-365.
The variant was designated factor IX Schmallenberg.

.0094
HEMOPHILIA B
F9, SER365GLY

In a patient with hemophilia B (306900), Ludwig et al. (1992)
demonstrated an A-to-G transition at nucleotide 31214 resulting in
replacement of serine-365 by glycine. The variant was designated factor
IX Varel. The mutation occurs at the same codon as that involved in
factor IX Schmallenberg (300746.0093). This patient also had a silent
mutation (GAT to GAC) at asp364. Thus, this patient had a double
basepair substitution of TA to CG at nucleotides 31213 and 31214 but
only a single amino acid change of ser365-to-gly. This patient also
developed an antibody to factor IX during replacement therapy, which
suggested that deletion of the factor IX gene is not necessary for
development of antibody.

.0095
HEMOPHILIA B
F9, ASP364HIS

In a patient with hemophilia B (306900), Ludwig et al. (1992) identified
a G-to-C transversion at nucleotide 31211, resulting in substitution of
his for asp364. The variant was designated factor IX Mechtal.

.0096
HEMOPHILIA B
F9, GLU245VAL

In a patient with hemophilia B (306900), Ludwig et al. (1992) identified
an A-to-T transversion at nucleotide 30855, resulting in substitution of
valine for glutamic acid-245. The variant was designated factor IX
Monschau.

.0097
HEMOPHILIA B BRANDENBURG
F9, -26G-C

Unlike other F9 promoter mutations which result in hemophilia B Leyden
(see 306900) (e.g., 300746.0001), this promoter mutation, a G-to-C
change at -26, is accompanied by a bleeding tendency that is not
ameliorated after puberty (Reijnen et al., 1992). Reijnen et al. (1992)
demonstrated that this mutation disrupted the binding of hepatocyte
nuclear factor-4 (HNF4; 600281), a member of the steroid hormone
receptor superfamily of transcription factors, which normally binds at
nucleotides -34 to -10. Whereas HNF4 transactivated the wildtype
promoter sequence in liver and nonliver (e.g., HeLa) cell types, it did
not at all transactivate the -26 mutated promoter.

Crossley et al. (1992) provided an explanation for why the -20 promoter
mutation shows recovery at puberty and the -26 Brandenburg mutation does
not. Both mutations impair transcription by disrupting the binding site
for the liver-enriched transcription factor LF-A1/HNF4. The -26 but not
the -20 mutation also disrupts an androgen-responsive element, which
overlaps the LF-A1/HNF4 site. This explains the failure of improvement
in -26 patients.

.0098
HEMOPHILIA B
F9, ALU INSERTION, EX5

In a patient with severe hemophilia B (306900), Vidaud et al. (1993)
discovered a de novo insertion of a human-specific Alu repeat element
within exon 5 of the F9 gene. The element interrupted the reading frame
of the mature factor IX at glutamic acid 96 resulting in a stop codon
within the inserted sequence. The Alu repeat was 322 bp long and was
thought to have been inserted through retroposition. Insertional
mutagenesis involving an Alu element has been reported in type I
neurofibromatosis (162200.0001) and in gyrate atrophy (258870.0023). The
involvement of Alu elements in gene deletion through homologous
recombination and unequal crossing-over has been demonstrated in
familial hypercholesterolemia (e.g., 143890.0029) and ADA deficiency
(102700.0008).

.0099
HEMOPHILIA B
HEMB, ILE-30ASN

Among the many mutations of the F9 gene described in hemophilia B
(306900) (Giannelli et al., 1992), the density of amino acid
substitutions in the domains coded by the different exons is similar,
except for exon 'a' where it is much lower. Exon 'a' codes for the
predomain of the signal peptide that is necessary for the transport of
factor IX to the endoplasmic reticulum and for its secretion. Comparison
of the signal peptide of secreted proteins shows lack of conservation of
the primary amino acid sequence, and the only constant features are the
presence of a charged residue at the amino end and a core of 8-12
hydrophobic residues. In a patient with severe, antigen-negative
hemophilia B, Green et al. (1993) found an A-to-T transversion causing
substitution of isoleucine by asparagine at position -30. This change
disrupted the hydrophobic core of the prepeptide, a feature required for
secretion. Thus, hemophilia in this patient was caused by failure to
secrete factor IX from the hepatocytes. Only one other amino acid
substitution had been reported in the prepeptide of factor IX; a
cys-to-arg mutation at position -19 affecting the cleavage site between
the pre- and propeptide (cys-19/thr-18) caused mild hemophilia (Bottema
et al., 1991) (300746.0100).

.0100
HEMOPHILIA B
HEMB, CYS-19ARG

See 300746.0099.

.0101
HEMOPHILIA B
F9, VAL373GLU

Aguilar-Martinez et al. (1994) identified a val373-to-glu mutation in a
40-year-old man in whom the diagnosis of hemophilia (306900) was made at
the age of 4 and who had been suffering hemarthrosis since the age of
13. A first cousin was affected. The mutation was located in the serine
protease catalytic domain of the F9 gene.

.0102
WARFARIN SENSITIVITY
F9, ALA-10THR

The propeptide sequences of the vitamin K-dependent clotting factors
serve as a recognition site for the enzyme gamma-glutamyl carboxylase
(137167), which catalyzes the carboxylation of glutamic acid residues in
the amino terminus of the mature protein. Chu et al. (1996) described a
mutation in the propeptide of factor IX that resulted in warfarin
sensitivity (122700) because of reduced affinity of the carboxylase for
the factor IX precursor. The patient studied in this report was a
49-year-old Caucasian male who was referred for evaluation of bleeding
complications that developed during anticoagulation with warfarin. The
patient had a congenital bicuspid aortic valve with accompanying aortic
stenosis and regurgitation. An artificial valve was inserted when he was
49 years old. Bleeding complications occurred when he was given warfarin
for anticoagulation after surgery. The patient's family history was
negative for bleeding diatheses. The patient had mild
Charcot-Marie-Tooth disease and several members of his family in several
generations were also affected. The proband had a factor IX activity
level of more than 100% when not receiving warfarin and less than 1%
when receiving warfarin, at a point where other vitamin K-dependent
factors were at 30 to 40% activity levels. Direct sequence analysis of
amplified genomic DNA from all 8 exons and exon-intron junctions showed
a G-to-A transition at nucleotide 6346 resulting in an
alanine-to-threonine change at residue -10 in the propeptide. To define
the mechanism by which the mutation resulted in warfarin sensitivity,
they analyzed wildtype and mutant recombinant peptides in an in vitro
carboxylation reaction. The peptides that were analyzed included the
wildtype sequence of F9, the ala-10thr sequence, and the ala-10gly
substitution which reflects the sequence in bone gamma-carboxyglutamic
acid protein (112260). Measurement of carbon dioxide incorporation at a
range of peptide concentrations demonstrated about twice normal V(max)
values for both A-10T and A-10G, whereas K(m) values showed a 33-fold
difference between wildtype and the variants. These studies delineated a
novel mechanism for warfarin sensitivity and explained the observation
that bone gamma-carboxyglutamic acid protein is more sensitive to
warfarin than the coagulation proteins.

.0103
WARFARIN SENSITIVITY
F9, ALA-10VAL

Oldenburg et al. (1997) reported 3 patients in whom mutations in the
factor IX propeptide was found to cause severe bleeding during coumarin
therapy (122700). Strikingly, the bleeding occurred within the
therapeutic ranges of the prothrombin time (PT) and international
normalized ratio (INR). In all 3 patients, coumarin therapy caused an
unusually selective decrease of factor IX activity to levels below 1 to
3%. Upon withdrawal of coumarin, factor IX levels increased to subnormal
or normal values of 55, 85 and 125%, respectively. In 1 patient the
ala-10-to-thr mutation (300746.0102) was found; in 2 patients the
missense mutation affecting the ala-10 residue was ala (GCC) to val
(GTC). The mutation in the propeptide at a position that is essential
for the carboxylase recognition site causes a reduced affinity of the
carboxylase enzyme to the propeptide. This effect leads to an impaired
carboxylase epoxidase reaction that is decisively triggered by the
vitamin K concentration.

.0104
HEMOPHILIA B
F9, ALA351PRO

Chan et al. (1998) found that a 20-year-old female student with mild
hemophilia B (306900) was heterozygous for a mutation in codon 351 of
the F9 gene: GCT (ala) was converted to CCT (pro). She had inherited the
mutation from her carrier mother. Analysis of the methyl-sensitive HpaII
sites at the 5-prime end of the hypoxanthine phosphoribosyltransferase
gene (HPRT; 308000) showed that skewed inactivation of the X chromosome
carrying her normal F9 gene accounted for the hemophilia phenotype.

.0105
HEMOPHILIA B
F9, 17747G-A

Drost et al. (2000) demonstrated that nucleotide 17747 of the F9 gene is
a mutation hotspot for hemophilia B (306900) in all Latin American
population samples but not in other populations. Two substitutions were
observed, G-A and G-C (300746.0106). The authors suggested that this was
the first evidence of population-specific effects on germline mutation
that causes human genetic disease.

.0106
HEMOPHILIA B
F9, 17747G-C

See (300746.0105) and Drost et al. (2000).

.0107
HEMOPHILIA B
F9, IVS3DS, T-C, +2

In a woman with moderately severe hemophilia B (306900), Costa et al.
(2000) found a T-to-C transition at position +2 in the 5-prime splice
site of intron 3 (6704T-C) and an ile344-to-thr missense mutation
(360900.0108). The splice site mutation came from the mother who was a
somatic mosaic; the missense mutation appeared to be a de novo mutation
from the father.

.0108
HEMOPHILIA B
F9, ILE344THR

See 300746.0107 and Costa et al. (2000).

.0109
HEMOPHILIA B
F9, CYS206SER

Taylor et al. (1992) found that the causative mutation in the first
reported patient with Christmas disease (306900) (Biggs et al., 1952)
was a cys206-to-ser change in the F9 gene. The patient died at the age
of 46 years from acquired immunodeficiency syndrome, contracted through
treatment with blood products (Giangrande, 2003).

.0110
HEMOPHILIA B
F9, 2-BP DEL

Cutler et al. (2004) described a family in which the maternal
grandfather of a severely affected infant with hemophilia B (306900) was
a somatic and germline mosaic and had very mild factor IX deficiency.
The maternal grandfather was apparently a somatic and germline mosaic
for the family mutation, a 2-bp deletion (AG within codons 134-135) in
the F9 gene causing a frameshift mutation and the creation of a
premature termination sequence in exon 6 at codon 141. One daughter, the
mother of the proband, was a carrier of the mutation; the other
daughter, was not a carrier.

.0111
HEMOPHILIA B
F9, ARG338PRO

In a patient with a mild form of hemophilia B (306900), Ketterling et
al. (1994) identified a G-to-C transversion in the F9 gene, resulting in
an arg338-to-pro (R338P) substitution. There was 16% residual F9
activity.

.0112
THROMBOPHILIA, X-LINKED, DUE TO FACTOR IX DEFECT
F9, ARG338LEU

This mutation is known as factor IX Padua.

In a 21-year-old Italian man with thrombophilia and a deep venous
thrombosis in the right leg (300807), Simioni et al. (2009) identified a
hemizygous 31134G-T transversion in exon 8 of the F9 gene, resulting in
an arg338-to-leu (R338L) substitution. Coagulation studies showed that
he had normal levels of F9 antigen, but very high levels of F9 activity
(776% of control values). His 11-year-old brother and mother, who were
hemizygous and heterozygous for the mutation, respectively, also had
normal F9 antigen levels and increased F9 activity levels (551% and
337%, respectively). The mutation was not found in 200 control
individuals or in 200 patients with documented thromboembolism. In vitro
functional expression studies showed that the mutant F9 had 8-fold
increased activity compared to wildtype, consistent with a gain of
function. The affected residue is important for binding to F10 (see
227600), and the R338L substitution apparently increases the efficiency
of this binding. Simioni et al. (2009) noted that another mutation at
this residue, R338P (300746.0111), results in hemophilia B (306900).

.0113
HEMOPHILIA B
F9, IVS3, A-G, -3

Although the X-linked blood disorder known as the 'royal disease'
transmitted from Queen Victoria (1819-1901) to European royal families
had been known to be a form of hemophilia, its molecular basis had not
been established. In the remains of the Russian Empress Alexandra,
granddaughter of Queen Victoria, and her son, Crown Prince Alexei,
Rogaev et al. (2009) identified an A-to-G transition at the -3 position
of intron 3 of the F9 gene. The mutation activated a cryptic splice
acceptor site, shifting the open reading frame of the F9 mRNA and
leading to a premature stop codon. The mutation was also identified in
one of Alexei's sisters, presumed to be Anastasia. The identification of
this mutation in the F9 gene allowed the recognition of the 'royal
disease' as a severe form of hemophilia B, also known as 'Christmas
disease' (306900).

*FIELD* SA
Anson et al. (1985); Bertina et al. (1979); Bertina and van der Linden
(1982); Bertina and Veltkamp (1978); Bottema et al. (1990); Bottema
et al. (1989); Braunstein et al. (1981); Bray and Thompson (1986);
Brinkhous et al. (1973); Camerino et al. (1985); Chan et al. (1989);
Chen et al. (1989); Choo et al. (1987); Drayna et al. (1984); Giannelli
et al. (1999); Graham et al. (1962); Gray and Winship (1989); Green
et al. (1999); Kling et al. (1992); Koeberl et al. (1990); Koeberl
et al. (1990); Liebman et al. (1985); Little et al. (1992); Mandalaki
et al. (1986); Mattei et al. (1985); Smith (1985); Spitzer et al.
(1988); Thompson (1987); Usharani et al. (1985); Vidaud et al. (1993);
Vogel and Motulsky (1986); Wang et al. (1997); Yoshioka et al. (1986)
*FIELD* RF
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168. Wall, R. L.; McConnell, J.; Moore, D.; Macpherson, C. R.; Marson,
A.: Christmas disease, color-blindness and blood group Xg(a). Am.
J. Med. 43: 214-226, 1967.

169. Wang, L.; Zoppe, M.; Hackeng, T. M.; Griffin, J. H.; Lee, K.-F.;
Verma, I. M.: A factor IX-deficient mouse model for hemophilia B
gene therapy. Proc. Nat. Acad. Sci. 94: 11563-11566, 1997.

170. Wang, N. S.; Zhang, M.; Thompson, A. R.; Chen, S.-H.: Factor
IX(Chongqing): a new mutation in the calcium-binding domain of factor
IX resulting in severe hemophilia B. Thromb. Haemost. 63: 24-26,
1990.

171. Ware, J.; Davis, L.; Frazier, D.; Bajaj, S. P.; Stafford, D.
W.: Genetic defect responsible for the dysfunctional protein: factor
IX (Long Beach). Blood 72: 820-822, 1988.

172. Ware, J.; Diuguid, D. L.; Liebman, H. A.; Rabiet, M.-J.; Kasper,
C. K.; Furie, B. C.; Furie, B.; Stafford, D. W.: Factor IX San Dimas:
substitution of glutamine for arg(-4) in the propeptide leads to incomplete
gamma-carboxylation and altered phospholipid binding properties. J.
Biol. Chem. 264: 11401-11406, 1989.

173. Wilkinson, F. H.; London, F. S.; Walsh, P. N.: Residues 88-109
of factor IXa are important for assembly of the factor X activating
complex. J. Biol. Chem. 277: 5725-5733, 2002.

174. Winship, P. R.: Haemophilia B caused by mutation of a potential
thrombin cleavage site in factor IX. Nucleic Acids Res. 18: 1310,
1990.

175. Winship, P. R.: Characterisation of the molecular defect in
haemophilia B patients using the polymerase chain reaction procedure.
(Abstract) Thromb. Haemost. 62: 465, 1989.

176. Winship, P. R.; Brownlee, G. G.: Diagnosis of haemophilia B
carriers using intragenic oligonucleotide probes. (Letter) Lancet 328:
218-219, 1986. Note: Originally Volume 2.

177. Winship, P. R.; Dragon, A. C.: Identification of haemophilia
B patients with mutations in the two calcium binding domains of factor
IX: importance of a beta-OH asp64-to-asn change. Brit. J. Haemat. 77:
102-109, 1991. Note: Erratum: Brit. J. Haemat. 77: 446 only, 1991.

178. Winship, P. R.; Rees, D. J. G.; Alkan, M.: Detection of polymorphisms
at cytosine phosphoguanidine dinucleotides and diagnosis of haemophilia
B carriers. Lancet 333: 631-634, 1989. Note: Originally Volume 1.

179. Yoshioka, A.; Ohkubo, Y.; Nishimura, T.; Tanaka, I.; Fukui, H.;
Ogata, K.; Kamiya, T.; Takahashi, H.: Heterogeneity of factor IX
BM: difference in cleavage sites by factor XIa and Ca(2+) in factor
IX Kashihara, factor IX Nagoya and factor IX Niigata. Thromb. Res. 42:
595-604, 1986.

180. Zhang, M.; Chen, S.-H.; Thompson, A. R.; Lovrien, E.; Scott,
C. R.: CG dinucleotides are 'hot spots' in the factor IX gene for
point mutations: evidence from the study of 25 families with defined
mutations causing hemophilia B. (Abstract) Am. J. Hum. Genet. 45:
A231, 1989.

*FIELD* CN
Ada Hamosh - updated: 12/29/2009
Cassandra L. Kniffin - updated: 11/25/2009
Cassandra L. Kniffin - updated: 11/10/2009
Cassandra L. Kniffin - updated: 10/24/2008

*FIELD* CD
Cassandra L. Kniffin: 10/9/2008

*FIELD* ED
carol: 09/11/2013
carol: 11/12/2012
carol: 3/1/2012
carol: 2/29/2012
carol: 2/28/2012
carol: 7/6/2011
terry: 5/20/2011
carol: 4/7/2011
carol: 1/26/2011
carol: 10/12/2010
alopez: 1/5/2010
terry: 12/29/2009
wwang: 12/2/2009
terry: 12/1/2009
ckniffin: 11/25/2009
carol: 11/11/2009
ckniffin: 11/10/2009
terry: 6/5/2009
terry: 6/3/2009
terry: 4/13/2009
terry: 4/9/2009
carol: 11/20/2008
terry: 11/19/2008
carol: 10/30/2008
ckniffin: 10/24/2008
carol: 10/21/2008
ckniffin: 10/15/2008

MIM 300807
*RECORD*
*FIELD* NO
300807
*FIELD* TI
#300807 THROMBOPHILIA, X-LINKED, DUE TO FACTOR IX DEFECT; THPH8
DEEP VENOUS THROMBOSIS, PROTECTION AGAINST, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because X-linked thrombophilia
can be caused by a gain-of-function mutation in the gene encoding factor
IX (F9; 300746) on Xq27.1.

CLINICAL FEATURES

Simioni et al. (2009) reported a 21-year-old Italian man who developed a
deep venous thrombosis in the right leg after mild muscular stretching.
Treatment with heparin and warfarin resulted in resolution and no
further thrombosis.

In a study of 473 healthy controls, van Hylckama Vlieg et al. (2000)
found that factor IX levels, as measured by enzyme-linked immunosorbent
assay (ELISA), increased with age after the age of 55 years. Factor IX
levels were substantially higher among 153 premenopausal women who used
oral contraceptives. Ten percent of healthy control individuals had
factor IX levels about 129 U/dl (90th percentile). More than 20% of 426
patients with deep venous thrombosis (DVT) had factor IX levels
exceeding this cutoff point. The results indicated that individuals with
factor IX levels above 129 U/dl have a 2.3-fold increased risk of
developing a DVT compared to those with factor IX levels below this
cutoff point. The risk of thrombosis increased with plasma levels of
factor IX, indicating a dose-response effect. The risk was not affected
by adjustment for possible confounders (age, sex, oral contraceptive
use, and high levels of other coagulation factors). The risk for DVT was
higher in women (odds ratio of 2.6) than in men (odds ratio of 1.9), and
was highest in the group of premenopausal women not using oral
contraceptives (odds ratio of 12.4).

INHERITANCE

The findings in the family reported by Simioni et al. (2009) were
consistent with X-linked recessive inheritance.

MOLECULAR GENETICS

In an Italian man with deep venous thrombosis of the femoral-popliteal
veins, Simioni et al. (2009) identified a hemizygous mutation in the F9
gene (R338L; 300746.0112). Coagulation studies showed that he had normal
levels of F9 antigen, but very high levels of F9 activity (776% of
control values). His 11-year-old brother and mother, who were hemizygous
and heterozygous for the mutation, respectively, also had normal F9
antigen levels and increased F9 activity levels (551 and 337%,
respectively). In vitro functional expression studies showed that the
mutant F9 had 8-fold increased activity compared to wildtype, consistent
with a gain of function. The affected residue is important for binding
to factor X (F10; 613872), and the R338L substitution apparently
increases the efficiency of this binding. Simioni et al. (2009) noted
that Chang et al. (1998) had generated mutant F9 molecules designed to
locate the residues of F9a that bind FVIIIa (F8; 300841) in vitro and
had identified a variant at the same residue (R338A) that appeared to be
part of a macromolecular binding site (exosite) for factor X.

Bezemer et al. (2008) reported that the G allele (ala148) of F9 Malmo
(300746.0028) was associated with a 15 to 43% decrease in deep vein
thrombosis risk compared to the A allele in 3 case-control studies of
deep vein thrombosis. This common variant has a minor allele frequency
of 0.32. In a follow-up study from 3 case-control studies involving a
total of 1,445 male patients with deep venous thrombosis and 2,351 male
controls, Bezemer et al. (2009) found that the G allele of F9 Malmo
conferred protection against deep venous thrombosis (odds ratio of
0.80). The pooled corresponding odds ratio in a comparable number of
women with deep venous thrombosis was 0.89. However, factor IX antigen
level, factor IX activation peptide levels, and endogenous thrombin
potential did not differ between the F9 Malmo genotypes. Although F9
Malmo was the most strongly associated with protection from deep vein
thrombosis, the biologic mechanism remained unknown.

Van Minkelen et al. (2008) sequenced the F9 gene in the cohort of
patients studied by van Hylckama Vlieg et al. (2000) to determine if
there were genetic variants that could explain increased F9 levels.
Although several SNPs were identified, none had a significant effect on
F9 levels or deep venous thrombosis. Haplotype analysis showed a
decreased risk in men for certain haplotypes, especially those including
the known protective variant F9 Malmo (T148A; 300746.0028), but the
effect in women did not reach significance. The authors concluded that
variation in F9 may affect the risk of DVT, but that genetic variation
does not explain F9 antigen levels.

*FIELD* RF
1. Bezemer, I. D.; Arellano, A. R.; Tong, C. H.; Rowland, C. M.; Ireland,
H. A.; Bauer, K. A.; Catanese, J.; Reitsma, P. H.; Doggen, C. J. M.;
Devlin, J. J.; Rosendaal, F. R.; Bare, L. A.: F9 Malmo, factor IX
and deep vein thrombosis. Haematologica 94: 693-699, 2009.

2. Bezemer, I. D.; Bare, L. A.; Doggen, C. J. M.; Arellano, A. R.;
Tong, C.; Rowland, C. M.; Catanese, J.; Young, B. A.; Reitsma, P.
H.; Devlin, J. J.; Rosendaal, F. R.: Gene variants associated with
deep vein thrombosis. JAMA 299: 1306-1314, 2008.

3. Chang, J.; Jin, J.; Lollar, P.; Bode, W.; Brandstetter, H.; Hamaguchi,
N.; Straight, D. L.; Stafford, D. W.: Changing residue 338 in human
factor IX from arginine to alanine causes an increase in catalytic
activity. J. Biol. Chem. 273: 12089-12094, 1998.

4. Simioni, P.; Tormene, D.; Tognin, G.; Gavasso, S.; Bulato, C.;
Iacobelli, N. P.; Finn, J. D.; Spiezia, L.; Radu, C.; Arruda, V. R.
: X-linked thrombophilia with a mutant factor IX (factor IX Padua). New
Eng. J. Med. 361: 1671-1675, 2009.

5. van Hylckama Vlieg, A.; van der Linden, I. K.; Bertina, R. M.;
Rosendaal, F. R.: High levels of factor IX increase the risk of venous
thrombosis. Blood 95: 3678-3682, 2000.

6. van Minkelen, R.; de Visser, M. C. H.; van Hylckama Vlieg, A.;
Vos, H. L.; Bertina, R. M.: Sequence variants and haplotypes of the
factor IX gene and the risk of venous thrombosis. (Letter) J. Thromb.
Haemost. 6: 1610-1613, 2008.

*FIELD* CD
Cassandra L. Knffin: 11/6/2009

*FIELD* ED
carol: 03/01/2012
carol: 2/29/2012
carol: 2/28/2012
ckniffin: 2/23/2012
carol: 4/8/2011
carol: 4/7/2011
carol: 11/11/2009
ckniffin: 11/10/2009

MIM 306900
*RECORD*
*FIELD* NO
306900
*FIELD* TI
#306900 HEMOPHILIA B; HEMB
;;CHRISTMAS DISEASE;;
FACTOR IX DEFICIENCY;;
F9 DEFICIENCY;;
read morePLASMA THROMBOPLASTIN COMPONENT DEFICIENCY
HEMOPHILIA B(M), INCLUDED;;
HEMOPHILIA B LEYDEN, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because hemophilia B, also
known as Christmas disease, is caused by mutation in the gene encoding
coagulation factor IX (F9; 300746).

DESCRIPTION

Hemophilia B due to factor IX deficiency is phenotypically
indistinguishable from hemophilia A (306700), which results from
deficiency of coagulation factor VIII (F8; 300841). The classic
laboratory findings in hemophilia B include a prolonged activated
partial thromboplastin time (aPTT) and a normal prothrombin time (PT)
(Lefkowitz et al., 1993).

Early studies made a distinction between cross-reactive-material
(CRM)-negative and CRM-positive hemophilia B mutants. This
classification referred to detection of the F9 antigen in plasma, even
in the presence of decreased F9 activity. Detection of the antigen
indicated the presence of a dysfunctional F9 protein. Roberts et al.
(1968) found that about 90% of patients with hemophilia B were
CRM-negative, whereas about 10% were CRM-positive. However, Bertina and
Veltkamp (1978) found that a rather large proportion of the hemophilia B
patients could be characterized as hemophilia B CRM+. They identified 14
cases of hemophilia B CRM+ from 11 families among a group of 33
patients. After immunologic and activity comparisons, they found at
least 7 different factor IX variants. Bertina and Veltkamp (1978) noted
the high heterogeneity within this group. In an editorial on variants of
vitamin K-dependent coagulation factors, Bertina et al. (1979) stated
that 9 defective variants of factor II, 5 variants of factor X, and many
variants (about 180 pedigrees) of factor IX had been identified. At
least one variant of factor VII (Padua) was also known.

CLINICAL FEATURES

Aggeler et al. (1952) described a 16-year-old white male with a
hemophilia-like disorder in which there appeared to be a deficiency of a
coagulation factor, which the authors called 'plasma thromboplastin
component' (PTC). They cited reports indicating that blood from some
patients with hemophilia was capable of correcting the coagulation
defect in other cases of hemophilia in vitro. The authors concluded that
these patients had a combined defect of PTC deficiency and 'true'
hemophilia (hemophilia A). It was not clear at that time if the disorder
was hereditary.

Biggs et al. (1952) in the December 27 (Christmas) issue of the British
Medical Journal reported a 5-year-old boy, with a surname of 'Christmas'
who had this disorder, as well as other patients, some of whom came from
families showing a typical X-linked pattern of inheritance, Biggs et al.
(1952) defended the familial eponym in the following way: 'The naming of
clinical disorders after patients was introduced by Sir Jonathan
Hutchinson and is now familiar from serological research; it has the
advantage that no hypothetical implication is attached to such a name.'
Giangrande (2003) provided historical information concerning the patient
Stephen Christmas (1947-1993), whose mutation in the F9 gene
(300746.0109) was reported by Taylor et al. (1992) and his physicians.

- Hemophilia B(M)

A subset of hemophilia B patients have a prolonged prothrombin time when
exposed to bovine (or ox) brain tissue, which serves as a source of
thromboplastin, or tissue factor (F3; 134390); these CRM+ patients are
classified as having hemophilia B(M) (Lefkowitz et al., 1993).

Several workers (e.g., Nour-Eldin and Wilkinson, 1959) observed the
combination of factor IX deficiency with factor VII (F7; 613878)
deficiency. However, inheritance was always X-linked, even though F7 is
on chromosome 13. Verstraete et al. (1962) reported 4 families in which
all affected males had both Christmas disease and factor VII deficiency.
The authors suggested that factor VII deficiency was a consistent
secondary phenomenon; thus no separate mutation for the combined defect
would be necessary.

Hougie and Twomey (1967) defined a variant of hemophilia B that differed
from the usual form by the presence of a prolonged PT. They presented
evidence these patients had a structurally abnormal and inactive form of
factor IX that acted as an inhibitor of the normal reaction between
factor VII and bovine brain. They called the variant hemophilia B(M),
after the initial of the family surname.

Denson et al. (1968) identified 3 blood samples of hemophilia B(M) among
samples derived from 27 patients with Christmas disease. In a series of
coagulation assays, Denson et al. (1968) demonstrated that the
prolongation of the PT involved inhibition of the reaction between ox
brain tissue factor, factor VII, and factor X. Noting that this distinct
abnormality had only been observed in patients with factor IX
deficiency, the authors postulated that the 'inhibitor' may be an
abnormal protein similar to or identical with factor IX. Subsequent
studies showed that this inhibitor was an abnormal form of factor IX
that was functionally inactive but was antigenically indistinguishable
from normal factor IX.

Lefkowitz et al. (1993) noted that the bovine brain tissue in studies of
hemophilia B(M) is the source of thromboplastin, or tissue factor (F3;
134390); PT times determined with thromboplastin from rabbit brain or
human brain are not reported to be prolonged. However, in various
studies of factor IX Hilo (300746.0031), Lefkowitz et al. (1993) found
that either normal F9 or Hilo F9 prolonged the PT regardless of the
tissue factor source, but the prolongation required high concentrations
of factor IX when rabbit or human brain was used. With bovine
thromboplastin, factor IX Hilo was significantly better than normal
factor IX at prolonging the PT. In addition, the prolongation times
depended on the amounts of factors IX and X used in the assays.

- Hemophilia B Leyden

Veltkamp et al. (1970) described a variant of hemophilia B, termed
hemophilia B Leyden, in a Dutch family. The disorder was characterized
by the disappearance of the bleeding diathesis as the patient aged. In
affected individuals, plasma factor IX levels were less than 1% of
normal before puberty, but after puberty factor IX activity and antigen
levels rose steadily in a 1:1 ratio to a maximum of 50 to 60%.

Briet et al. (1982) described a similar variant of hemophilia B that
took a severe form early in life but remitted after puberty, with an
increase in factor IX levels from below 1% of normal to about 50% of
normal by age 80 years. Three pedigrees with 27 affected males with this
disorder could be traced to a small village in the east of the
Netherlands.

In affected members of 2 Dutch pedigrees with hemophilia B Leyden,
Reitsma et al. (1988) found that patients with hemophilia B Leyden had a
mutation in the promoter region of the F9 gene (300746.0001). The
findings suggested that a point mutation could lead to a switch from
constitutive to steroid hormone-dependent gene expression. The families
were probably related.

Mandalaki et al. (1986) reported a 5-generation Greek family with
hemophilia B. The factor IX levels in the 3 patients from the last
generation were extremely low, while those of patients in the older
generations were much higher. In 1 patient, the rise of factor IX levels
appeared between ages 13 and 14 years. In addition, older patients in
the family had much milder symptoms compared to the younger patients.
The phenotype was similar to hemophilia B Leyden as described by
Veltkamp et al. (1970).

- Manifesting Females

Lascari et al. (1969) described a daughter of a male with hemophilia B
who had an XX karyotype, factor IX level of 5%, and hemarthrosis. The
factor IX level in the mother was 100%. The girl was thought to be a
manifesting heterozygote with unfortunate lyonization.

Spinelli et al. (1976) observed deletion of the short arm of 1 of the X
chromosomes in a female with hemophilia B. Family investigations were
negative. Hashimi et al. (1978) reported a girl with Christmas disease.
Her father was affected, and her parents were related as first cousins,
suggesting possible homozygosity for the defect. They referred to a
similar instance of plausible homozygosity.

Wadelius et al. (1993) reported a female with hemophilia B with factor
IX activity of about 1%. Her father had severe hemophilia B. No
chromosomal abnormality could be detected, and DNA analysis gave no
indication of deletions or mutations of TaqI cleavage sites in the F9
gene. Analysis of the methylation pattern of locus DXS255 indicated that
the expression of hemophilia B in this girl was caused by nonrandom X
inactivation.

Vianna-Morgante et al. (1986) observed de novo t(X;1)(q27;q23) in a girl
with hemophilia B who had no affected relatives. In a full description
of the case, Krepischi-Santos et al. (2001) stated that the translocated
X was preferentially active and that methylation analysis of the DXS255
locus confirmed the skewed X inactivation with the paternal allele being
the active one. Molecular analysis showed deletion of at least part of
the F9 gene.

Nisen et al. (1986) described hemophilia B in a girl with the karyotype
46,X,del(X)q27. They showed that the X chromosome with the deletion was
inactivated in all cells. The mother's identical twin sister had a son
with severe hemophilia B. The proband was also lacking the paternal
factor VIII gene, indicating that the deletion had occurred in the
paternal X chromosome and had included the factor VIII locus. However,
both the maternal and the paternal factor IX loci were present. The
interpretation applied by Nisen et al. (1986) was that inactivation of
the deleted, paternally derived X chromosome in all cells had provided
the opportunity for expression of the hemophilia B gene which the
proband had inherited from her mother.

By sequencing the complete factor IX gene in 2 sisters with hemophilia B
with different phenotypes and no family history of hemorrhagic
diathesis, Costa et al. (2000) found a common 5-prime splice site
mutation in intron 3 (300746.0107) and an additional missense mutation
(I344T; 300746.0108) in 1 sister. The presence of dysfunctional antigen
in the latter strongly suggested that these mutations were in trans.
Neither mutation was found in leukocyte DNA from the asymptomatic
parents, but the mother was a somatic mosaic for the shared splice site
mutation. The somatic mosaicism in the mother for the splice site
mutation was demonstrated by studies of buccal and uroepithelial cells.
The missense mutation was presumed to have resulted from a de novo
mutation in the father's gametes. The compound heterozygous proband was
a 14-year-old girl with moderate hemophilia B, manifest by hematomas,
hemarthrosis, and epistaxis. A sister suffered only from rare hematomas.

In a population-based survey in the Netherlands, Plug et al. (2006)
found that female carriers of hemophilia A and B bled more frequently
than noncarrier women, especially after medical procedures, such as
tooth extraction or tonsillectomy. Reduced clotting factor levels
correlated with a mild hemophilia phenotype. Variation in clotting
levels was attributed to lyonization.

OTHER FEATURES

Chronic synovitis occurs in about 10% of Indian patients with severe
hemophilia. Ghosh et al. (2003) reported an association between the
development of chronic synovitis in patients with hemophilia and the
HLA-B27 allele (142830.0001). They studied 473 patients, 424 with
hemophilia A and 49 with hemophilia B. Twenty-one (64%) of 33 patients
with both disorders had HLA-B27, compared to 23 (5%) of 440 with severe
hemophilia without synovitis (odds ratio of 31.6). There were 3 sib
pairs with hemophilia in whom only 1 sib had synovitis; all the affected
sibs had the HLA-B27 allele, whereas the unaffected sibs did not.
Chronic synovitis presented as swelling of the joint with heat and
redness and absence of response to treatment with factor concentrate.
Ghosh et al. (2003) suggested that patients with HLA-B27 may not be able
to easily downregulate inflammatory mediators after bleeding in the
joints, leading to chronic synovitis.

INHERITANCE

Hemophilia B is classically transmitted as an X-linked recessive
disorder. Cutler et al. (2004) described a family in which the usual
pattern of X-linked inheritance of hemophilia B was complicated by
mosaicism in the proband's maternal grandfather. The proband was a male
infant with severe factor IX deficiency who was initially thought to be
a sporadic case. Testing of other family members identified his mother
as a carrier and his asymptomatic maternal grandfather as having very
mild factor IX deficiency. The causative mutation was identified as a
2-bp deletion (AG within codons 134-135) in the F9 gene (300746.0110).

CLINICAL MANAGEMENT

- Acquired Inhibitor

The treatment for factor IX deficiency is replacement of the missing
coagulation factor by transfusion of plasma from a healthy individual.
However, a subset of patients develop IgG antibodies against normal
factor IX, which complicates treatment. George et al. (1971) reported a
family in which 3 of 4 members with Christmas disease developed an
inhibitor to factor IX after transfusion. The inhibitor was an IgG
antibody directed against the activated form of factor IX (IXa). There
was no immunologically detectable factor IX-like material in the
affected family members without an inhibitor. The findings were
consistent with previous postulates that inhibitors to factor IX develop
only in patients with Christmas disease who lack the factor IX antigen.
The fourth member of the family, who had no factor IX antigen, was
transfused several times, but failed to develop antibodies to factor IX.
George et al. (1971) noted that inhibitors to factor IX develop
infrequently compared to factor VIII, suggesting that there may be a
predisposition to the development of an inhibitor.

Giannelli et al. (1983) noted that treatment of patients with factor IX
deficiency with normal plasma resulted in the development of specific
anti-F9 antibodies in about 1% of all cases and about 2.5% of severe
cases. The authors postulated that this may be due to complete absence
of 'self' factor IX in the plasma recipient, such that the immune system
regards the infused normal factor IX as foreign. Indeed, 4 patients with
factor IX deficiency and F9 antibodies were found to have gross
deletions in the F9 gene, resulting in complete absence of the protein.

In a patient with severe F9 deficiency who had developed a high-titer
antibody, Hassan et al. (1985) observed a deletion of about 33 kb at the
F9 locus.

By Southern blot analysis of 9 patients, including 2 brothers, with
hemophilia B and F9 antibodies, Matthews et al. (1987) found that 2 had
a total deletion of the F9 gene. The brothers were shown to have a
presumably identical complex rearrangement of the gene involving 2
separate deletions. Five other patients had a structurally intact F9
gene. Matthews et al. (1987) concluded that whereas large structural
defects in the F9 gene can predispose the patients to the development of
antibody, the phenomenon can also be associated with other defects of
the gene.

Green et al. (1988) identified a partial deletion in the F9 gene in a
boy and his uncle, both of whom had hemophilia B and inhibitors to
factor IX. The mother of the boy was a carrier. The deletion, called
'London-1,' most likely arose by nonhomologous recombination.

Wadelius et al. (1988) found total deletion of the F9 gene in 3 affected
males in 1 family who did not have antibodies against native factor IX.
Two of the patients, who were cousins, had inherited the same maternal
HLA haplotype, suggesting that immune gene(s) located at the MHC locus
may be important for the development of antibodies against factor IX.

Ljung et al. (2001) found that 11 (23%) of 48 patients with severe
hemophilia B developed inhibitors and all of them had deletions or
nonsense mutations. Thus, 11 of 37 (30%) patients with severe hemophilia
B as a result of deletion/nonsense mutations developed inhibitors
compared with none of 11 patients with missense mutations.

DIAGNOSIS

In a patient with severe F9 deficiency who developed an inhibitor, Peake
et al. (1984) detected a deletion in the F9 gene using 4 genomic gene
probes. Similar studies of 8 female relatives using this method
identified 2 as carriers. Used a genomic probe containing a TaqI
polymorphism in the F9 gene, Giannelli et al. (1984) successfully
identified carriers of Christmas disease in 3 affected families.

In eukaryotic DNA, a high proportion of CpG dinucleotides are methylated
at the cytosine residue to give 5-methylcytosine. The restriction enzyme
HhaI will not cleave at methylated CpG sites, but PCR can overcome this
limitation. Winship et al. (1989) used PCR to detect a polymorphic HhaI
site located 8 kb 3-prime to the F9 gene and estimated that almost half
of female subjects can be expected to be heterozygous at this site.
Detection of this marker using PCR was predicted to increase the
proportion of persons in whom the carrier state of hemophilia B could be
diagnosed, compared to using the restriction enzyme alone, which could
be influenced by methylation status.

Koeberl et al. (1990) compared RFLP-based carrier detection of an
X-linked disease with a direct method involving genomic amplification
with transcript sequencing (GAWTS). They pointed out that the RFLP
approach 'suffers from multiple levels of uncertainty.' They found that
22 at-risk females were diagnosed by direct testing, whereas only 11
females could be diagnosed by standard RFLP analysis.

Giannelli et al. (1992) used hemophilia B as a model of a genetic
disease with marked mutational heterogeneity to lay out an overall
strategy for genetic counseling. They started with the construction of a
national database which could be used for diagnosis and genetic
counseling on the basis of DNA abnormality. In the U.K. there were just
over 1,000 patients with hemophilia B and these were probably derived
from 500 to 600 families. They characterized the mutation in a group of
unrelated patients and in only 1 of 170 patients examined from the
Swedish and British series did they fail to find a mutation in the
essential regions of the gene. Thus the screening procedures used were
capable of detecting all types of mutations. By phenotype/genotype
correlations the authors generated information of prognostic value
concerning each of those mutations.

- Prenatal Diagnosis

In 5 kindreds studied in detail, Poon et al. (1987) were able to
determine the carrier status of hemophilia B in all 11 females at risk;
prenatal diagnosis could be offered to the offspring of each of the 6
carriers identified.

Green et al. (1991) suggested a strategy for facilitating carrier and
prenatal diagnosis by identification of all hemophilia B mutations in a
given population so that only the relevant parts of the molecule need be
focused on when performing amplification mismatch detection (AMD) as
developed by Montandon et al. (1989).

MAPPING

Linkage studies in the early 1960s suggested that the hemophilia A and B
loci were not allelic; hemophilia A was found to be tightly linked to
colorblindness (CBD; 303800) on Xq28, whereas hemophilia B apparently
was not linked to colorblindness. In the dog, Brinkhous et al. (1973)
showed that the loci for hemophilias A and B were probably 50 map units
or more apart. The genetic distance between the 2 loci was estimated to
be about 50 map units in man as well.

By in situ hybridization, Purrello et al. (1985) showed that the loci
for hemophilia A and hemophilia B flank the fragile X site (300624). The
authors believed that this finding, combined with the knowledge that
hemophilia B recombines freely with at least 2 loci of the G6PD (305900)
cluster, supported the Siniscalco hypothesis that the chromosomal
segment in which the fragile X site occurs is normally a region of high
meiotic recombination (Szabo et al., 1984).

MOLECULAR GENETICS

Using genomic DNA probes, Chen et al. (1985) identified a partial
intragenic deletion in the F9 gene in 7 affected members of a family
with severe hemophilia B.

In affected members of a family with severe factor IX deficiency and no
detectable factor IX protein, Taylor et al. (1988) identified a complete
deletion of the F9 gene that extended at least 80 kb 3-prime of the
gene. The proband did not have antibodies to factor IX, despite total
deletion of the gene.

Matthews et al. (1988) discussed the family originally reported by Peake
et al. (1984) as having an X-chromosome deletion of minimum size 114 kb
that included the entire F9 gene. By isolation of further 3-prime
flanking probes, they located the 3-prime breakpoint of the deletion to
a position 145 kb 3-prime to the start of the F9 gene. Abnormal junction
fragments detected at the breakpoint were used in the detection of
carriers.

In a patient with severe hemophilia B, Siguret et al. (1988) found loss
of the Taq1 restriction site at the 5-prime end of exon 8 of the F9
gene. Using oligonucleotide probes and PCR-amplified DNA for sequencing
of the affected region, the authors identified a C-to-T change in the
catalytic domain of the protein, resulting in premature truncation. The
change resulted from a CpG mutation.

By use of PCR followed by sequencing, Bottema et al. (1989) identified
mutations in the F9 gene (see, e.g., 300746.0051) in all 14 hemophilia B
patients studied. Analysis for heterozygosity in at-risk female
relatives was then done, either by sequencing the appropriate region or
by detection of an altered restriction site.

Green et al. (1991) provided a list of point mutations that cause
hemophilia B. Sommer et al. (1992) estimated that missense mutations
cause only 59% of moderate and severe hemophilia B and that these
mutations are almost always (95%) of independent origin (i.e., de novo
mutations). In contrast, missense mutations were found in virtually all
(97%) families with mild disease and only a minority of these (41%) were
of independent origin.

Giannelli et al. (1993) reported on the findings in a database of 806
patients with hemophilia B in whom the defect in factor IX had been
identified at the molecular level. A total of 379 independent mutations
were described. The list included 234 different amino acid
substitutions. There were 13 promoter mutations, 18 mutations in donor
splice sites, 15 mutations in acceptor splice sites, and 4 mutations
creating cryptic splice sites. In analyses of DNA from 290 families with
hemophilia B (203 independent mutations), Ketterling et al. (1994) found
12 deletions more than 20 bp long. Eleven of these were more than 2 kb
long and one was 1.1 kb.

Giannelli et al. (1996) described the sixth edition of their hemophilia
B database of point mutations and short (less than 30 bp) additions and
deletions. The 1,380 patient entries were ordered by the nucleotide
number of their mutation. References to published mutations were given
and the laboratories generating the data were indicated. Giannelli et
al. (1997) described the seventh edition of their database; 1,535
patient entries were ordered by the nucleotide number of their mutation.
When known, details were given on factor IX activity, factor IX antigen
in the circulation, presence of inhibitor, and origin of mutation.

Ljung et al. (2001) surveyed a series comprising all 77 known families
with hemophilia B in Sweden. The disorder was severe in 38, moderate in
10, and mild in 29. A total of 51 different mutations were found. Ten of
the mutations, all C-to-T or G-to-A transitions, recurred in 1 to 6
additional families. Using haplotype analysis of 7 polymorphisms in the
F9 gene, Ljung et al. (2001) found that the 77 families carried 65
unique, independent mutations. Of the 48 families with severe or
moderate hemophilia, 23 (48%) had a sporadic case compared with 31
families of 78 (40%) in the whole series. Five of those 23 sporadic
cases carried de novo mutations; 11 of 23 of the mothers were proven
carriers; and in the remaining 7 families, it was not possible to
determine carriership.

Rogaev et al. (2009) identified a splice site mutation in the F9 gene
(300746.0113) as the causative mutation for the 'Royal disease,' the
form of hemophilia transmitted from Queen Victoria to European royal
families and transmitted to her granddaughter, Russian Empress Alexandra
and her son, Crown Prince Alexei.

- Mutation Rate

In an analysis of 1,485 families with hemophilia A or hemophilia B,
Barrai et al. (1985) estimated the proportion of sporadic cases to be
0.166 and 0.078, respectively. The age of maternal grandfathers at birth
of the mother of hemophilia B cases was higher than that of appropriate
controls.

In the population of families with hemophilia B at the Malmo Haemophilia
Centre, Montandon et al. (1992) estimated that the overall mutation rate
was 4.1 x 10(-6) and that the ratio of male to female specific mutation
rates was 11. Three of 13 isolated cases had a new mutation, whereas the
other 10 had mothers who carried a new mutation.

Kling et al. (1992) found that 24 of 45 hemophilia B patients in Malmo,
Sweden, had no affected family members. Three of 13 families with 1
patient available for study had a do novo mutation, whereas the defect
was inherited from a carrier mother in the remaining 10. All 10 of these
carrier mothers had de novo mutation, as their fathers were
phenotypically normal and the grandmothers were noncarriers. In all 6 of
the 10 cases in whom RFLP patterns were informative, the mutation was of
paternal origin, and the average age of the father at the birth of the
new carrier female was 41.5 years. These data supported a paternal age
effect and a higher mutation rate in males than in females regarding
factor IX mutations.

Among 43 families with hemophilia B, Ketterling et al. (1993) found that
25 had a mutation in the female germline and 18 in the male germline.
The excess of germline origins in females did not imply an overall
excess mutation rate per basepair, because when the mother and maternal
grandparents were analyzed, the excess of X chromosomes in females, 4:1,
skewed the data in favor of female origins. Bayesian analysis corrected
for this bias and indicated that the 25:18 ratio actually represented a
predominance of mutations in males. Transitions at the dinucleotide CpG,
estimated to account for 36% of mutations in the F9 gene (Koeberl et
al., 1990), showed the most striking male predominance of mutation,
11:1. This finding was comparable with previous data suggesting that
methylation at CpG dinucleotides is reduced or absent in the female
germline (Driscoll and Migeon, 1990). This effect, rather than an
increased number of replications in the male germ cells, likely
accounted for the male excess.

In studies of the patterns of independent mutation resulting in
hemophilia B in 127 Caucasian and 44 non-Caucasian patients, Gostout et
al. (1993) could find no differences, suggesting either predominance of
endogenous processes or common mutagen exposure rather than mutagen
exposure specifically associated with non-Caucasian status or
non-Western life style.

Green et al. (1999) conducted a population-based study of hemophilia B
mutations in the United Kingdom in order to construct a national
confidential database of mutations and pedigrees to be used for the
provision of carrier and prenatal diagnoses based on mutation detection.
This allowed the direct estimate of overall mutation rate, male mutation
rate, and female mutation rate for hemophilia B. The values obtained per
gamete per generation and the 95% confidence intervals were 7.73
(6.29-9.12) x 10(-6) for overall mutation rate; 18.8 (14.5-22.9) x
10(-6) for male mutation rate; and 2.18 (1.44-3.16) x 10(-6) for female
mutation rate. The ratio of male-to-female mutation rates was 8.64 (95%
CI, 5.46-14.5). Attempts to detect evidence of gonadal mosaicism for
hemophilia B mutation in suitable families did not detect any instances
of ovarian mosaicism in 47 available opportunities. This suggested that
the risk of a noncarrier mother manifesting as a gonadal mosaic by
transmitting the mutation to a second child should be less than 0.062.

Giannelli et al. (1999) also estimated the rates per base per generation
of specific types of mutations, using their direct estimate of the
overall mutation rate for hemophilia B and information on the mutations
present in the U.K. population as well as those reported year by year in
the hemophilia B world database. These rates were as follows:
transitions at CpG sites, 9.7 x 10(-8); other transitions, 7.3 x 10(-9);
transversions at CpG sites, 5.4 x 10(-9); other transversions, 6.9 x
10(-9); and small deletions/insertions causing frameshifts, 3.2 x
10(-10).

Ketterling et al. (1999) estimated the male:female ratio of mutations in
the F9 gene by Bayesian analysis of 59 families. The overall ratio was
estimated at 3.75. It varied with the type of mutation, from 6.65 and
6.10 for transitions at CpG and A:T to G:C transitions at non-CpG
dinucleotides, respectively, to 0.57 and 0.42 for
microdeletions/microinsertions and large deletions (more than 1 kb),
respectively. The value for the 2 subsets of non-CpG transitions
differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism
was detected in 11% of the 45 'origin individuals' for whom the
causative mutation was visualized directly by genomic sequencing of
leukocyte DNA (estimated sensitivity of approximately 1 part in 20).
Four of the 5 defined somatic mosaics had G:C to A:T transitions at
non-CpG dinucleotides, hinting that this mutation subtype may occur
commonly early in embryogenesis. The age at conception was analyzed for
41 U.S. Caucasian families in which the age of the origin parent and the
year of conception for the first carrier/hemophiliac were available. No
evidence for a paternal age effect was seen; however, an advanced
maternal age effect was observed (P = 0.03) and was particularly
prominent in transversions. This suggested that an increased maternal
age results in a higher rate of transmitted mutations, whereas the
increased number of mitotic replications associated with advanced
paternal age has little, if any, effect on the rate of transmitted
mutation.

Liu et al. (2000) found that the pattern of germline mutations in 66
hemophilia B patients from mainland China was similar to that in U.S.
Caucasians, blacks, and Mexican Hispanics. The existence of a ubiquitous
mutagen or the possibility that multiple mutagens could produce the same
pattern of mutation was considered unlikely; the findings were
compatible with the inference that endogenous processes predominate in
germline mutations.

Ljung et al. (2001) found that the ratio of male to female mutation
rates was 5:3 and that the overall mutation rate per gamete per
generation was 5.4 x 10(-6).

GENE THERAPY

Gerrard et al. (1993) introduced a recombinant human F9 cDNA into
cultured primary human keratinocytes by means of a defective retroviral
vector. In tissue culture, transduced keratinocytes were found to
secrete biologically active factor IX. After transplantation of these
cells into nude mice, human factor IX was detected in the bloodstream in
small quantities for 1 week.

Kay et al. (2000) initiated a clinical study of intramuscular injection
of an AAV vector expressing human factor IX in adults with severe
hemophilia B. The study had a dose-escalation design. Assessment in the
first 3 patients of safety and gene transfer and expression showed no
evidence of germline transmission of vector sequences or formation of
inhibitory antibodies against factor IX. By PCR and Southern blot
analyses of muscle biopsies, Kay et al. (2000) found that the vector
sequences were present in muscle, and demonstrated expression of factor
IX by immunohistochemistry. They observed modest changes in clinical
endpoints, including circulating levels of factor IX and frequency of
factor IX protein infusion. The evidence of gene expression at low doses
of vector suggested that dose calculations based on animal data may have
overestimated the amount of vector required to achieve therapeutic
levels in humans, and that the approach offered the possibility of
converting severe hemophilia B to a milder form of the disease.

Manno et al. (2003) investigated the safety of intramuscular injection
of a recombinant AAV (rAAV) vector expressing factor IX in patients with
hemophilia B. Muscle biopsies of injection sites performed 2 to 10
months after vector administration confirmed gene transfer as evidenced
by Southern blot and transgene expression as evidenced by
immunohistochemical staining. However, circulating levels of factor IX
were less than 2% in all cases and less than 1% in most. Manno et al.
(2003) concluded that the results demonstrated the safety of
intramuscular rAAV administration in humans in a manner similar to that
used in mice and hemophilic dogs (Herzog et al., 1997, 1999).

POPULATION GENETICS

Giannelli et al. (1983) stated that 798 cases of Christmas disease were
known in the U.K., corresponding to a frequency of 1 in 30,000 males.

Connor et al. (1985), by total ascertainment, found 28 families with
hemophilia B in the west of Scotland (prevalence = 1/26,870 males). Of
26 living obligate carriers, 42% were heterozygous for a TaqI
polymorphism recognized by the factor IX genomic probe. Linkage
disequilibrium was apparent for this RFLP and hemophilia B in the west
of Scotland. This surprising finding suggested that some of these
families might be related.

Soucie et al. (1998) studied the frequency of hemophilia A and
hemophilia B in 6 U.S. states: Colorado, Georgia, Louisiana,
Massachusetts, New York, and Oklahoma. The age-adjusted prevalence of
hemophilia in all 6 states in 1994 was 13.4 cases per 100,000 males
(10.5 hemophilia A and 2.9 hemophilia B). The prevalence by
race/ethnicity was 13.2 cases per 100,000 white, 11.0% among African
American, and 11.5% among Hispanic males. Application of age-specific
prevalence rates from the 6 surveillance states to the U.S. population
resulted in an estimated national population of 13,320 cases of
hemophilia A and 3,640 cases of hemophilia B. For the 10-year period
1982 to 1991, the average incidence of hemophilia A and B in the 6
surveillance states was estimated to be 1 in 5,032 live male births.

ANIMAL MODEL

Kundu et al. (1998) generated a transgenic mouse model of hemophilia B
by targeted disruption of the murine f9 gene. The tail bleeding time of
hemizygous male mice was markedly prolonged compared with those of
normal and carrier female litter mates. Seven of 19 affected male mice
died of exsanguination after tail snipping, and 2 affected mice died of
umbilical cord bleeding. Ten affected mice survived to 4 months of age.
Aside from the factor IX defect, carrier female and hemizygous male mice
had no liver pathology by histologic examination, were fertile, and
transmitted the mutation in the expected mendelian frequency.

Gu et al. (1999) found factor IX deficiency in 2 distinct dog breeds. In
1 breed, the disorder was associated with a large deletion mutation,
spanning the entire 5-prime region of the F9 gene extending to exon 6.
In the second breed, an insertion of approximately 5 kb disrupted exon
8. The insertion was associated with alternative splicing between a
donor site 5-prime and acceptor site 3-prime to the normal exon 8 splice
junction, with introduction of a new stop codon.

Brooks et al. (2003) found that mild hemophilia B in a large pedigree of
German wirehaired pointers was caused by a line-1 insertion in the
factor IX gene. The insert could be traced through at least 5
generations and segregated with the hemophilia B phenotype.

In transgenic mice with the hemophilia B Leyden phenotype (-20T-A;
300746.0001), which usually show amelioration of the disorder after
puberty, Kurachi et al. (2009) found that expression of different F9
minigenes with or without the age-related stability element (ASE) in the
5-prime untranslated region resulted in different disease course. Mice
lacking the ASE failed to show the Leyden phenotype with only transient
F9 expression at puberty, whereas mice with ASE showed normal and
sustained pubertal F9 recovery. These changes were not sex-dependent,
indicating that testosterone and androgen are not responsible. Further
studies showed that the transcription factor Ets1 (164720) was the
specific ASE-binding protein, and F9 expression was abolished by
hypophysectomy, but restored with growth hormone (GH; 139250)
administration in both males and females. These results provided a
molecular mechanism for the puberty-related Leyden phenotype. Kurachi et
al. (2009) also generated transgenic mice expressing the Brandenberg F9
mutation (-26G-C; 300746.0097), which showed a severe phenotype without
amelioration after puberty.

- Animal Studies of Gene Therapy

Busby et al. (1985) transfected baby hamster kidney (BHK) cells with a
plasmid containing a gene for human factor IX and a plasmid containing a
selectable marker. The cells secreted material that these authors
believed to be authentic factor IX. Armentano et al. (1990) used a
recombinant retroviral factor to transfer the human factor IX gene into
hepatocytes from 3-week old New Zealand white rabbits. The infected
cells produced human factor IX that was indistinguishable from the
enzyme derived from normal human plasma.

Choo et al. (1987) introduced a full-length human factor IX cDNA
containing all the natural mRNA sequences plus some flanking intron
sequences combined with a metallothionein promoter. This DNA clone was
microinjected into the pronuclei of fertilized murine eggs. The
transgenic mice expressed high levels of mRNA, gamma-carboxylated and
glycosylated protein, and biologic clotting activity that were
indistinguishable from normal human plasma factor IX.

Armentano et al. (1990) used a recombinant retroviral factor to transfer
the factor IX gene into hepatocytes from 3-week old New Zealand white
rabbits. The infected cells produced human factor IX that was
indistinguishable from the enzyme derived from normal human plasma.

Axelrod et al. (1990) demonstrated that primary skin fibroblasts from
hemophilic dogs, transduced by recombinant retrovirus containing a
canine factor IX cDNA, secreted high levels of biologically active
canine factor IX into the medium.

Yao et al. (1991) infected rat capillary endothelial cells (CECs) with a
Moloney murine leukemia virus-derived retrovirus vector that contained
human factor IX cDNA. They found that a single RNA transcript of 4.4 kb,
predicted by the construct, and a recombinant factor IX of 68 kD
identical to purified plasma factor IX were formed. The recombinant
factor IX that was produced showed full clotting activity, demonstrating
that CECs have an efficient mechanism for posttranslational
modifications, including gamma-carboxylation, essential for its biologic
activity. These results, in addition to other properties of the
endothelium, suggested that CECs could serve as an efficient drug
delivery vehicle producing factor IX for somatic gene therapy of
hemophilia B.

Kay et al. (1993) developed a method for hepatic gene transfer in vivo
by the direct infusion of recombinant retroviral vectors into the portal
vasculature, and showed that the method resulted in the persistent
expression of exogenous genes. When canine factor IX cDNA was transduced
directly into hepatocytes of affected dogs in vivo, the animals
constitutively expressed low levels of canine factor IX for more than 5
months. Persistent expression of the clotting factor resulted in
reduction of whole blood clotting time and partial thromboplastin time
of the treated animals.

Wang et al. (1997) generated a mouse model in which the gene encoding
factor IX was disrupted by homologous recombination. The nullizygous
mice were devoid of factor IX antigen in plasma. Consistent with the
bleeding disorder, the factor IX coagulant activities for wildtype,
heterozygous, and homozygous mice were 92, 53, and less than 5%,
respectively, in activated partial thromboplastin time assays. Plasma
factor IX activity in the deficient -/- mice was restored by introducing
wildtype murine factor IX gene via adenoviral vectors. Thus, these
factor IX-deficient mice provided a useful animal model for gene therapy
studies of hemophilia B. The factor IX-deficient mice showed extensive
bleeding after clipping a portion of the tail and bled to death unless
the wound was cauterized. Additionally, in contrast to the normal mice,
they showed swollen extremities and extensive hemorrhagic lesions after
trauma. Female homozygous -/- mice gave birth without complications.

Schnieke et al. (1997) produced transgenic sheep carrying the human
factor IX gene by nuclear transfer. Ovine primary fetal fibroblasts were
cotransfected with a neomycin-resistance marker gene (neo) and a human
coagulation factor IX genomic construct designed for expression of the
encoded protein in sheep milk. Nuclear transfer to enucleated oocytes
was performed using either cloned transfectant fibroblasts or a
population of neomycin-resistant cells as donors. Six transgenic lambs
were liveborn: 3 produced from cloned transfectant cells contained
factor IX and neo transgenes, whereas 3 produced from the uncloned
population contained the marker gene only.

Preclinical studies in mice and hemophilic dogs showed that introduction
of an adeno-associated viral (AAV) vector encoding blood coagulation
factor IX into skeletal muscle results in sustained expression of factor
IX at levels sufficient to correct the hemophilic phenotype (Herzog et
al., 1997; Herzog et al., 1999).

Yant et al. (2000) described the successful use of transposon technology
for the nonhomologous insertion of foreign genes into the genomes of
adult mammals using naked DNA. Yant et al. (2000) showed that the
'Sleeping Beauty' transposase, the product of a synthetic transposable
element, can efficiently insert transposon DNA into the mouse genome in
approximately 5 to 6% of transfected mouse liver cells. Chromosomal
transposition resulted in long-term expression (greater than 5 months)
of human blood coagulation factor IX at levels that were therapeutic in
a mouse model of hemophilia B.

Li et al. (2011) showed that zinc finger nucleases are able to induce
double-strand breaks efficiently when delivered directly to mouse liver
and that, when codelivered with an appropriately designed gene targeting
vector, they can stimulate gene replacement through both
homology-directed and homology-independent targeted gene insertion at
the zinc finger nuclease-specified locus. The level of gene targeting
achieved was sufficient to correct the prolonged clotting times in a
mouse model of hemophilia B, and remained persistent after induced liver
regeneration. Thus, Li et al. (2011) concluded that zinc finger
nuclease-driven gene correction can be achieved in vivo, raising the
possibility of genome editing as a viable strategy for the treatment of
genetic disease.

*FIELD* SA
Bernardi et al. (1985); Blackburn et al. (1962); Brown et al. (1970);
Brownlee (1988); Chan et al. (1998); Connor et al. (1986); Crossley
et al. (1990); Crossley et al. (1989); Didisheim and Vandervoort (1962);
Giannelli et al. (1992); Girolami et al. (1980); Goldsmith et al.
(1979); Green et al. (1989); Green et al. (1993); Green et al. (1991);
Grunebaum et al. (1984); Hay et al. (1986); Hirosawa et al. (1990);
Holmberg et al. (1980); Kasper et al. (1977); Ketterling et al. (1991);
Kitchens et al. (1976); Koeberl et al. (1990); Lillicrap et al. (1986);
Montandon et al. (1990); Neal et al. (1973); Neuschatz and Necheles
(1973); Orstavik et al. (1985); Orstavik et al. (1979); Peake et al.
(1989); Poort et al. (1989); Tanimoto et al. (1988); Taylor et al.
(1991); Vidaud et al. (1993); Wall et al. (1967); Whittaker et al.
(1962)
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M. A.: Somatic integration and long-term transgene expression in
normal and haemophilic mice using a DNA transposon system. Nature
Genet. 25: 35-41, 2000.

124. Yao, S.-N.; Wilson, J. M.; Nabel, E. G.; Kurachi, S.; Hachiya,
H. L.; Kurachi, K.: Expression of human factor IX in rat capillary
endothelial cells: toward somatic gene therapy for hemophilia B. Proc.
Nat. Acad. Sci. 88: 8101-8105, 1991.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEMATOLOGY:
Factor IX deficiency

LABORATORY ABNORMALITIES:
Factor IX deficiency;
PTT prolonged;
PT normal;
Platelet count normal;
Platelet function normal

MISCELLANEOUS:
Patient with factor IX Leyden variants (see, e.g., 300746.0001)
have bleeding in childhood that improves or resolves after puberty;
Patients with hemophilia B(M) variants (see, e.g., 300746.0030)
also have prolonged PT;
Phenotypically indistinguishable from hemophilia A (306700)

MOLECULAR BASIS:
Caused by mutation in the coagulation factor IX gene (F9, 300746.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/22/2008

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 12/09/2008
ckniffin: 10/22/2008
alopez: 1/19/2005

*FIELD* CN
Ada Hamosh - updated: 8/24/2011
Ada Hamosh - updated: 12/29/2009
Cassandra L. Kniffin - updated: 11/25/2009
Cassandra L. Kniffin - updated: 12/3/2008
Cassandra L. Kniffin - reorganized: 10/21/2008
Cassandra L. Kniffin - updated: 11/13/2007
Victor A. McKusick - updated: 1/11/2005
Victor A. McKusick - updated: 4/22/2004
Victor A. McKusick - updated: 9/4/2003
Victor A. McKusick - updated: 7/18/2003
Ada Hamosh - updated: 9/12/2002
Victor A. McKusick - updated: 9/20/2001
Victor A. McKusick - updated: 6/26/2001
Victor A. McKusick - updated: 6/22/2001
Victor A. McKusick - updated: 1/10/2001
Victor A. McKusick - updated: 9/22/2000
Victor A. McKusick - updated: 8/17/2000
Ada Hamosh - updated: 4/28/2000
Victor A. McKusick - updated: 3/1/2000
Victor A. McKusick - updated: 1/14/2000
Victor A. McKusick - updated: 1/13/2000
Victor A. McKusick - updated: 12/20/1999
Ada Hamosh - updated: 7/28/1999
Victor A. McKusick - updated: 2/14/1999
Victor A. McKusick - updated: 8/17/1998
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 12/18/1997
Victor A. McKusick - updated: 11/6/1997
Victor A. McKusick - updated: 9/16/1997
Victor A. McKusick - updated: 3/21/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 02/29/2012
terry: 1/18/2012
alopez: 8/25/2011
terry: 8/24/2011
carol: 4/11/2011
carol: 4/7/2011
alopez: 1/5/2010
terry: 12/29/2009
wwang: 12/2/2009
carol: 12/2/2009
ckniffin: 11/25/2009
terry: 6/5/2009
terry: 4/9/2009
wwang: 12/4/2008
ckniffin: 12/3/2008
terry: 11/19/2008
carol: 10/21/2008
ckniffin: 10/15/2008
carol: 10/9/2008
terry: 8/26/2008
wwang: 11/20/2007
ckniffin: 11/13/2007
carol: 11/27/2006
terry: 11/10/2005
wwang: 1/14/2005
wwang: 1/12/2005
terry: 1/11/2005
terry: 4/22/2004
alopez: 4/7/2004
carol: 3/17/2004
cwells: 9/30/2003
terry: 9/4/2003
tkritzer: 7/29/2003
terry: 7/18/2003
carol: 7/7/2003
alopez: 9/12/2002
cwells: 9/12/2002
mcapotos: 1/2/2002
mcapotos: 9/27/2001
terry: 9/20/2001
mcapotos: 7/5/2001
mcapotos: 6/26/2001
terry: 6/26/2001
terry: 6/22/2001
mcapotos: 3/27/2001
cwells: 1/17/2001
terry: 1/10/2001
mcapotos: 10/3/2000
mcapotos: 9/22/2000
carol: 8/18/2000
terry: 8/17/2000
alopez: 5/1/2000
terry: 4/28/2000
alopez: 3/1/2000
terry: 3/1/2000
mgross: 2/21/2000
terry: 1/14/2000
terry: 1/13/2000
carol: 12/27/1999
terry: 12/20/1999
terry: 9/21/1999
alopez: 7/30/1999
carol: 7/28/1999
kayiaros: 7/8/1999
carol: 2/14/1999
carol: 2/5/1999
psherman: 1/8/1999
dkim: 12/15/1998
dkim: 12/10/1998
dkim: 9/22/1998
carol: 8/18/1998
terry: 8/17/1998
dkim: 7/21/1998
carol: 7/16/1998
terry: 7/13/1998
alopez: 5/21/1998
mark: 12/18/1997
terry: 12/16/1997
terry: 11/13/1997
terry: 11/6/1997
mark: 9/22/1997
terry: 9/16/1997
alopez: 7/29/1997
alopez: 7/8/1997
terry: 5/28/1997
terry: 3/21/1997
terry: 3/17/1997
mark: 11/12/1996
terry: 10/24/1996
mark: 7/22/1996
mark: 7/9/1996
mark: 3/30/1996
terry: 3/12/1996
mark: 12/20/1995
jason: 7/19/1994
carol: 5/23/1994
terry: 4/26/1994
warfield: 4/20/1994
mimadm: 4/15/1994
pfoster: 4/5/1994

RBCC Red Blood Cell Collection

Full text data of F9