RBCC Red Blood Cell Collection

FGA [Confidence: low (only semi-automatic identification from reviews)]
Fibrinogen alpha chain; Fibrinopeptide A; Fibrinogen alpha chain; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02671
ID FIBA_HUMAN Reviewed; 866 AA.
AC P02671; A8K3E4; D3DP14; D3DP15; Q4QQH7; Q9BX62; Q9UCH2;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 2.
DT 22-JAN-2014, entry version 182.
DE RecName: Full=Fibrinogen alpha chain;
DE Contains:
DE RecName: Full=Fibrinopeptide A;
DE Contains:
DE RecName: Full=Fibrinogen alpha chain;
DE Flags: Precursor;
GN Name=FGA;
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 [GENOMIC DNA], AND ALTERNATIVE SPLICING (ISOFORMS
RP 1 AND 2).
RX PubMed=1457396; DOI=10.1021/bi00163a002;
RA Fu Y., Weissbach L., Plant P.W., Oddoux C., Cao Y., Liang T.J.,
RA Roy S.N., Redman C.M., Grieninger G.;
RT "Carboxy-terminal-extended variant of the human fibrinogen alpha
RT subunit: a novel exon conferring marked homology to beta and gamma
RT subunits.";
RL Biochemistry 31:11968-11972(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1).
RA Chung D.W., Grieninger G.;
RT "Fibrinogen DNA and protein sequences.";
RL (In) Ebert R.F. (eds.);
RL Index of variant human fibrinogens, pp.13-24, CRC Press, Boca Raton
RL (1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-6; ALA-331 AND
RP ALA-456.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP ALA-331.
RC TISSUE=Heart;
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 [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [7]
RP NUCLEOTIDE SEQUENCE OF 1-655 (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=2102623;
RA Chung D.W., Harris J.E., Davie E.W.;
RT "Nucleotide sequences of the three genes coding for human
RT fibrinogen.";
RL Adv. Exp. Med. Biol. 281:39-48(1990).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=6575389; DOI=10.1073/pnas.80.13.3953;
RA Kant J.A., Lord S.T., Crabtree G.R.;
RT "Partial mRNA sequences for human A alpha, B beta, and gamma
RT fibrinogen chains: evolutionary and functional implications.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:3953-3957(1983).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-629.
RX PubMed=6688355; DOI=10.1021/bi00282a031;
RA Rixon M.W., Chan W.-Y., Davie E.W., Chung D.W.;
RT "Characterization of a complementary deoxyribonucleic acid coding for
RT the alpha chain of human fibrinogen.";
RL Biochemistry 22:3237-3244(1983).
RN [10]
RP PROTEIN SEQUENCE OF 20-629.
RA Henschen A., Lottspeich F., Southan C., Topfer-Petersen E.;
RT "Human fibrinogen: sequence, sulfur bridges, glycosylation and some
RT structural variants.";
RL (In) Peeters H. (eds.);
RL Protides of the biological fluids, Proc. 28th colloquium, pp.51-56,
RL Pergamon Press, Oxford (1980).
RN [11]
RP PROTEIN SEQUENCE OF 20-629, AND DISULFIDE BONDS.
RX PubMed=518846; DOI=10.1021/bi00591a024;
RA Watt K.W.K., Cottrell B.A., Strong D.D., Doolittle R.F.;
RT "Amino acid sequence studies on the alpha chain of human fibrinogen.
RT Overlapping sequences providing the complete sequence.";
RL Biochemistry 18:5410-5416(1979).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 110-156.
RX PubMed=6689067; DOI=10.1093/nar/11.21.7427;
RA Imam A.M.A., Eaton M.A.W., Williamson R., Humphries S.;
RT "Isolation and characterisation of cDNA clones for the A alpha- and
RT gamma-chains of human fibrinogen.";
RL Nucleic Acids Res. 11:7427-7434(1983).
RN [13]
RP NUCLEOTIDE SEQUENCE OF 605-644 (ISOFORM 2).
RX PubMed=6575700; DOI=10.1111/j.1749-6632.1983.tb23265.x;
RA Chung D.W., Rixon M.W., Que B.G., Davie E.W.;
RT "Cloning of fibrinogen genes and their cDNA.";
RL Ann. N. Y. Acad. Sci. 408:449-456(1983).
RN [14]
RP PROTEIN SEQUENCE OF 20-35.
RA Blombaeck B., Blombaeck M., Grondahl N.J., Guthrie C., Hinton M.;
RT "Studies on fibrinopeptides from primates.";
RL Acta Chem. Scand. 19:1788-1789(1965).
RN [15]
RP CROSS-LINKING ACCEPTOR SITES.
RX PubMed=518845; DOI=10.1021/bi00591a023;
RA Cottrell B.A., Strong D.D., Watt K.W.K., Doolittle R.F.;
RT "Amino acid sequence studies on the alpha chain of human fibrinogen.
RT Exact location of cross-linking acceptor sites.";
RL Biochemistry 18:5405-5410(1979).
RN [16]
RP CROSS-LINKING ACCEPTOR SITES.
RX PubMed=632262;
RA Fretto L.J., Ferguson E.W., Steinman H.M., McKee P.A.;
RT "Localization of the alpha-chain cross-link acceptor sites of human
RT fibrin.";
RL J. Biol. Chem. 253:2184-2195(1978).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-686, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [18]
RP DISULFIDE BONDS.
RX PubMed=936108; DOI=10.1016/0049-3848(76)90245-0;
RA Blombaeck B., Hessel B., Hogg D.;
RT "Disulfide bridges in NH2-terminal part of human fibrinogen.";
RL Thromb. Res. 8:639-658(1976).
RN [19]
RP REVIEW, ELECTRON MICROSCOPY, POLYMERIZATION, AND LIGANDS.
RX PubMed=6383194;
RA Doolittle R.F.;
RT "Fibrinogen and fibrin.";
RL Annu. Rev. Biochem. 53:195-229(1984).
RN [20]
RP CROSS-LINKING SITE FOR ALPHA-2-PLASMIN INHIBITOR.
RX PubMed=2877981;
RA Kimura S., Aoki N.;
RT "Cross-linking site in fibrinogen for alpha 2-plasmin inhibitor.";
RL J. Biol. Chem. 261:15591-15595(1986).
RN [21]
RP PHOSPHORYLATION.
RX PubMed=6318767; DOI=10.1016/0006-291X(83)91247-0;
RA Itarte E., Plana M., Guasch M.D., Martos C.;
RT "Phosphorylation of fibrinogen by casein kinase 1.";
RL Biochem. Biophys. Res. Commun. 117:631-636(1983).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Pituitary;
RX PubMed=16807684; DOI=10.1007/s11102-006-8916-x;
RA Beranova-Giorgianni S., Zhao Y., Desiderio D.M., Giorgianni F.;
RT "Phosphoproteomic analysis of the human pituitary.";
RL Pituitary 9:109-120(2006).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-412 AND SER-609, AND
RP MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [24]
RP HYDROXYLATION AT PRO-565.
RX PubMed=19696023; DOI=10.1074/jbc.M109.041749;
RA Ono M., Matsubara J., Honda K., Sakuma T., Hashiguchi T., Nose H.,
RA Nakamori S., Okusaka T., Kosuge T., Sata N., Nagai H., Ioka T.,
RA Tanaka S., Tsuchida A., Aoki T., Shimahara M., Yasunami Y., Itoi T.,
RA Moriyasu F., Negishi A., Kuwabara H., Shoji A., Hirohashi S.,
RA Yamada T.;
RT "Prolyl 4-hydroxylation of alpha-fibrinogen: a novel protein
RT modification revealed by plasma proteomics.";
RL J. Biol. Chem. 284:29041-29049(2009).
RN [25]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-686, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [26]
RP CLEAVAGE BY HEMENTIN AND PLASMIN.
RX PubMed=2143188;
RA Kirschbaum N.E., Budzynski A.Z.;
RT "A unique proteolytic fragment of human fibrinogen containing the A
RT alpha COOH-terminal domain of the native molecule.";
RL J. Biol. Chem. 265:13669-13676(1990).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [28]
RP GLYCOSYLATION AT THR-320 AND SER-351.
RX PubMed=23050552; DOI=10.1021/pr3005937;
RA Zauner G., Hoffmann M., Rapp E., Koeleman C.A., Dragan I.,
RA Deelder A.M., Wuhrer M., Hensbergen P.J.;
RT "Glycoproteomic analysis of human fibrinogen reveals novel regions of
RT O-glycosylation.";
RL J. Proteome Res. 11:5804-5814(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 26-39.
RX PubMed=1560020;
RA Martin P.D., Robertson W., Turk D., Huber R., Bode W., Edwards B.F.P.;
RT "The structure of residues 7-16 of the A alpha-chain of human
RT fibrinogen bound to bovine thrombin at 2.3-A resolution.";
RL J. Biol. Chem. 267:7911-7920(1992).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 130-216.
RX PubMed=9333233; DOI=10.1038/38947;
RA Spraggon G., Everse S.J., Doolittle R.F.;
RT "Crystal structures of fragment D from human fibrinogen and its
RT crosslinked counterpart from fibrin.";
RL Nature 389:455-462(1997).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 130-216.
RX PubMed=9628725; DOI=10.1021/bi9804129;
RA Everse S.J., Spraggon G., Veerapandian L., Riley M., Doolittle R.F.;
RT "Crystal structure of fragment double-D from human fibrin with two
RT different bound ligands.";
RL Biochemistry 37:8637-8642(1998).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 670-866.
RX PubMed=9689040; DOI=10.1073/pnas.95.16.9099;
RA Spraggon G., Applegate D., Everse S.J., Zhang J.Z., Veerapandian L.,
RA Redman C., Doolittle R.F., Grieninger G.;
RT "Crystal structure of a recombinant alphaEC domain from human
RT fibrinogen-420.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:9099-9104(1998).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 130-216.
RX PubMed=10074346; DOI=10.1021/bi982626w;
RA Everse S.J., Spraggon G., Veerapandian L., Doolittle R.F.;
RT "Conformational changes in fragments D and double-D from human
RT fibrin(ogen) upon binding the peptide ligand Gly-His-Arg-Pro-amide.";
RL Biochemistry 38:2941-2946(1999).
RN [34]
RP VARIANT KYOTO-2 LEU-37.
RX PubMed=2070049;
RA Yoshida N., Okuma M., Hirata H., Matsuda M., Yamazumi K., Asakura S.;
RT "Fibrinogen Kyoto II, a new congenitally abnormal molecule,
RT characterized by the replacement of A alpha proline-18 by leucine.";
RL Blood 78:149-153(1991).
RN [35]
RP VARIANT LIMA SER-160.
RX PubMed=1634621; DOI=10.1172/JCI115857;
RA Maekawa H., Yamazumi K., Muramatsu S., Kaneko M., Hirata H.,
RA Takahashi N., Arocha-Pinango C.L., Rodriguez S., Nagy H.,
RA Perez-Requejo J.L., Matsuda M.;
RT "Fibrinogen Lima: a homozygous dysfibrinogen with an A alpha-arginine-
RT 141 to serine substitution associated with extra N-glycosylation at A
RT alpha-asparagine-139. Impaired fibrin gel formation but normal fibrin-
RT facilitated plasminogen activation catalyzed by tissue-type
RT plasminogen activator.";
RL J. Clin. Invest. 90:67-76(1992).
RN [36]
RP VARIANT CARACAS-2 ASN-453.
RX PubMed=1675636;
RA Maekawa H., Yamazumi K., Muramatsu S., Kaneko M., Hirata H.,
RA Takahashi N., de Bosch N.B., Carvajal Z., Ojeda A.,
RA Arocha-Pinango C.L., Matsuda M.;
RT "An A alpha Ser-434 to N-glycosylated Asn substitution in a
RT dysfibrinogen, fibrinogen Caracas II, characterized by impaired fibrin
RT gel formation.";
RL J. Biol. Chem. 266:11575-11581(1991).
RN [37]
RP VARIANT DUSART/PARIS-5 CYS-573.
RX PubMed=8473507; DOI=10.1172/JCI116371;
RA Koopman J., Haverkate F., Grimbergen J., Lord S.T., Mosesson M.W.,
RA Diorio J.P., Siebenlist K.S., Legrand C., Soria J., Soria C.,
RA Caen J.P.;
RT "Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its
RT association with abnormal fibrin polymerization and thrombophilia.";
RL J. Clin. Invest. 91:1637-1643(1993).
RN [38]
RP VARIANT AMYL8 LEU-573.
RX PubMed=8097946; DOI=10.1038/ng0393-252;
RA Benson M.D., Liepnieks J., Uemichi T., Wheeler G., Correa R.;
RT "Hereditary renal amyloidosis associated with a mutant fibrinogen
RT alpha-chain.";
RL Nat. Genet. 3:252-255(1993).
RN [39]
RP VARIANT OSAKA IV HIS-35.
RX PubMed=8461606; DOI=10.1007/BF00308999;
RA Yamazumi K., Terukina S., Matsuda M., Kanbayashi J., Sakon M.,
RA Tsujinaka T.;
RT "Fibrinogen Osaka IV: a congenital dysfibrinogenemia found in a
RT patient originally reported in relation to surgery, now defined to
RT have an A alpha arginine-16 to histidine substitution.";
RL Surg. Today 23:45-50(1993).
RN [40]
RP VARIANT CANTERBURY ASP-39.
RX PubMed=8675656; DOI=10.1172/JCI118356;
RA Brennan S.O., Hammonds B., George P.M.;
RT "Aberrant hepatic processing causes removal of activation peptide and
RT primary polymerisation site from fibrinogen Canterbury (A-alpha 20
RT Val-to-Asp).";
RL J. Clin. Invest. 96:2854-2858(1995).
RN [41]
RP VARIANTS ALA-331 AND GLU-446.
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 [42]
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).
CC -!- FUNCTION: Fibrinogen has a double function: yielding monomers that
CC polymerize into fibrin and acting as a cofactor in platelet
CC aggregation.
CC -!- SUBUNIT: Heterohexamer; disulfide linked. Contains 2 sets of 3
CC non-identical chains (alpha, beta and gamma). The 2 heterotrimers
CC are in head to head conformation with the N-termini in a small
CC central domain.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Alpha-E;
CC IsoId=P02671-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha;
CC IsoId=P02671-2; Sequence=VSP_001531, VSP_001532;
CC Note=Ref.3 (AAK31372) sequence is in conflict in positions:
CC 640:PSLSP->LPCPPRLS;
CC -!- TISSUE SPECIFICITY: Plasma.
CC -!- DOMAIN: A long coiled coil structure formed by 3 polypeptide
CC chains connects the central nodule to the C-terminal domains
CC (distal nodules). The long C-terminal ends of the alpha chains
CC fold back, contributing a fourth strand to the coiled coil
CC structure.
CC -!- PTM: The alpha chain is not glycosylated.
CC -!- PTM: Forms F13A-mediated cross-links between a glutamine and the
CC epsilon-amino group of a lysine residue, forming fibronectin-
CC fibrinogen heteropolymers.
CC -!- PTM: About one-third of the alpha chains in the molecules in blood
CC were found to be phosphorylated.
CC -!- PTM: Conversion of fibrinogen to fibrin is triggered by thrombin,
CC which cleaves fibrinopeptides A and B from alpha and beta chains,
CC and thus exposes the N-terminal polymerization sites responsible
CC for the formation of the soft clot. The soft clot is converted
CC into the hard clot by factor XIIIA which catalyzes the epsilon-
CC (gamma-glutamyl)lysine cross-linking between gamma chains
CC (stronger) and between alpha chains (weaker) of different
CC monomers.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- DISEASE: Congenital afibrinogenemia (CAFBN) [MIM:202400]: Rare
CC autosomal recessive disorder is characterized by bleeding that
CC varies from mild to severe and by complete absence or extremely
CC low levels of plasma and platelet fibrinogen. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC The majority of cases of afibrinogenemia are due to truncating
CC mutations. Variations in position Arg-35 (the site of cleavage of
CC fibrinopeptide a by thrombin) leads to alpha-dysfibrinogenemias.
CC -!- DISEASE: Amyloidosis 8 (AMYL8) [MIM:105200]: A hereditary
CC generalized amyloidosis due to deposition of apolipoprotein A1,
CC fibrinogen and lysozyme amyloids. Viscera are particularly
CC affected. There is no involvement of the nervous system. Clinical
CC features include renal amyloidosis resulting in nephrotic
CC syndrome, arterial hypertension, hepatosplenomegaly, cholestasis,
CC petechial skin rash. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 fibrinogen C-terminal domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FGA";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=FGA";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Fibrinogen entry;
CC URL="http://en.wikipedia.org/wiki/Fibrinogen";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/fga/";
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DR EMBL; M64982; AAA17056.1; -; Genomic_DNA.
DR EMBL; M64982; AAA17055.1; -; Genomic_DNA.
DR EMBL; M58569; AAC97142.1; -; Transcribed_RNA.
DR EMBL; M58569; AAC97143.1; -; Transcribed_RNA.
DR EMBL; AF361104; AAK31372.1; -; Genomic_DNA.
DR EMBL; AF361104; AAK31373.1; -; Genomic_DNA.
DR EMBL; AK290559; BAF83248.1; -; mRNA.
DR EMBL; CH471056; EAX04925.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04926.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04927.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04928.1; -; Genomic_DNA.
DR EMBL; BC098280; AAH98280.1; -; mRNA.
DR EMBL; BC099706; AAH99706.1; -; mRNA.
DR EMBL; BC099720; AAH99720.1; -; mRNA.
DR EMBL; BC101935; AAI01936.1; -; mRNA.
DR EMBL; J00128; AAA52427.1; -; mRNA.
DR EMBL; J00127; AAA52426.1; -; mRNA.
DR EMBL; K02272; AAA52428.1; -; mRNA.
DR EMBL; M26878; AAA52444.1; -; mRNA.
DR PIR; A93956; FGHUA.
DR PIR; D44234; D44234.
DR RefSeq; NP_000499.1; NM_000508.3.
DR RefSeq; NP_068657.1; NM_021871.2.
DR UniGene; Hs.351593; -.
DR PDB; 1BBR; X-ray; 2.30 A; F/G/I=26-35.
DR PDB; 1DM4; X-ray; 2.50 A; C=26-35.
DR PDB; 1FZA; X-ray; 2.90 A; A/D=130-216.
DR PDB; 1FZB; X-ray; 2.90 A; A/D=130-216.
DR PDB; 1FZC; X-ray; 2.30 A; A/D=130-216.
DR PDB; 1FZD; X-ray; 2.10 A; A/B/C/D/E/F/G/H=666-866.
DR PDB; 1FZE; X-ray; 3.00 A; A/D=130-216.
DR PDB; 1FZF; X-ray; 2.70 A; A/D=130-216.
DR PDB; 1FZG; X-ray; 2.50 A; A/D=130-216.
DR PDB; 1LT9; X-ray; 2.80 A; A/D=145-210.
DR PDB; 1LTJ; X-ray; 2.80 A; A/D=145-210.
DR PDB; 1N86; X-ray; 3.20 A; A/D=130-216.
DR PDB; 1N8E; X-ray; 4.50 A; A/D=130-218.
DR PDB; 1RE3; X-ray; 2.45 A; A/D=145-210.
DR PDB; 1RE4; X-ray; 2.70 A; A/D=145-210.
DR PDB; 1RF0; X-ray; 2.81 A; A/D=145-210.
DR PDB; 1RF1; X-ray; 2.53 A; A/D=145-210.
DR PDB; 1YCP; X-ray; 2.50 A; F/N=20-42.
DR PDB; 2A45; X-ray; 3.65 A; G/J=36-92.
DR PDB; 2FFD; X-ray; 2.89 A; A/D=145-210.
DR PDB; 2H43; X-ray; 2.70 A; A/D=130-216.
DR PDB; 2HLO; X-ray; 2.60 A; A/D=130-216.
DR PDB; 2HOD; X-ray; 2.90 A; A/D/G/J=130-216.
DR PDB; 2HPC; X-ray; 2.90 A; A/D/G/J=130-216.
DR PDB; 2OYH; X-ray; 2.40 A; A/D=145-210.
DR PDB; 2OYI; X-ray; 2.70 A; A/D=145-210.
DR PDB; 2Q9I; X-ray; 2.80 A; A/D=130-216.
DR PDB; 2XNX; X-ray; 3.30 A; A/D/G/J=130-216.
DR PDB; 2XNY; X-ray; 7.50 A; A/D=130-216.
DR PDB; 2Z4E; X-ray; 2.70 A; A/D=130-216.
DR PDB; 3AT0; X-ray; 2.50 A; B=332-347.
DR PDB; 3BVH; X-ray; 2.60 A; A/D=148-209.
DR PDB; 3E1I; X-ray; 2.30 A; A/D=130-216.
DR PDB; 3GHG; X-ray; 2.90 A; A/D/G/J=20-581.
DR PDB; 3H32; X-ray; 3.60 A; A/D=20-216.
DR PDB; 3HUS; X-ray; 3.04 A; A/D=145-210.
DR PDB; 4F27; X-ray; 1.92 A; Q=336-347.
DR PDBsum; 1BBR; -.
DR PDBsum; 1DM4; -.
DR PDBsum; 1FZA; -.
DR PDBsum; 1FZB; -.
DR PDBsum; 1FZC; -.
DR PDBsum; 1FZD; -.
DR PDBsum; 1FZE; -.
DR PDBsum; 1FZF; -.
DR PDBsum; 1FZG; -.
DR PDBsum; 1LT9; -.
DR PDBsum; 1LTJ; -.
DR PDBsum; 1N86; -.
DR PDBsum; 1N8E; -.
DR PDBsum; 1RE3; -.
DR PDBsum; 1RE4; -.
DR PDBsum; 1RF0; -.
DR PDBsum; 1RF1; -.
DR PDBsum; 1YCP; -.
DR PDBsum; 2A45; -.
DR PDBsum; 2FFD; -.
DR PDBsum; 2H43; -.
DR PDBsum; 2HLO; -.
DR PDBsum; 2HOD; -.
DR PDBsum; 2HPC; -.
DR PDBsum; 2OYH; -.
DR PDBsum; 2OYI; -.
DR PDBsum; 2Q9I; -.
DR PDBsum; 2XNX; -.
DR PDBsum; 2XNY; -.
DR PDBsum; 2Z4E; -.
DR PDBsum; 3AT0; -.
DR PDBsum; 3BVH; -.
DR PDBsum; 3E1I; -.
DR PDBsum; 3GHG; -.
DR PDBsum; 3H32; -.
DR PDBsum; 3HUS; -.
DR PDBsum; 4F27; -.
DR ProteinModelPortal; P02671; -.
DR SMR; P02671; 46-231, 411-524, 596-866.
DR DIP; DIP-29643N; -.
DR IntAct; P02671; 12.
DR MINT; MINT-1033042; -.
DR STRING; 9606.ENSP00000306361; -.
DR BindingDB; P02671; -.
DR ChEMBL; CHEMBL2364709; -.
DR DrugBank; DB00009; Alteplase.
DR DrugBank; DB00029; Anistreplase.
DR DrugBank; DB00015; Reteplase.
DR DrugBank; DB00364; Sucralfate.
DR DrugBank; DB00031; Tenecteplase.
DR PhosphoSite; P02671; -.
DR DMDM; 1706799; -.
DR OGP; P02671; -.
DR SWISS-2DPAGE; P02671; -.
DR PaxDb; P02671; -.
DR PeptideAtlas; P02671; -.
DR PRIDE; P02671; -.
DR DNASU; 2243; -.
DR Ensembl; ENST00000302053; ENSP00000306361; ENSG00000171560.
DR Ensembl; ENST00000403106; ENSP00000385981; ENSG00000171560.
DR GeneID; 2243; -.
DR KEGG; hsa:2243; -.
DR UCSC; uc003iod.1; human.
DR CTD; 2243; -.
DR GeneCards; GC04M155504; -.
DR HGNC; HGNC:3661; FGA.
DR HPA; CAB016776; -.
DR MIM; 105200; phenotype.
DR MIM; 134820; gene+phenotype.
DR MIM; 202400; phenotype.
DR neXtProt; NX_P02671; -.
DR Orphanet; 98880; Familial afibrinogenemia.
DR Orphanet; 98881; Familial dysfibrinogenemia.
DR Orphanet; 248408; Familial hypodysfibrinogenemia.
DR Orphanet; 101041; Familial hypofibrinogenemia.
DR Orphanet; 93562; Familial renal amyloidosis due to fibrinogen A alpha-chain variant.
DR PharmGKB; PA429; -.
DR eggNOG; NOG114889; -.
DR HOGENOM; HOG000285947; -.
DR HOVERGEN; HBG005668; -.
DR InParanoid; P02671; -.
DR KO; K03903; -.
DR OMA; YKCPSGC; -.
DR OrthoDB; EOG7X9G60; -.
DR PhylomeDB; P02671; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; FGA; human.
DR EvolutionaryTrace; P02671; -.
DR GeneWiki; Fibrinogen_alpha_chain; -.
DR GenomeRNAi; 2243; -.
DR NextBio; 9073; -.
DR PMAP-CutDB; P02671; -.
DR PRO; PR:P02671; -.
DR ArrayExpress; P02671; -.
DR Bgee; P02671; -.
DR CleanEx; HS_FGA; -.
DR Genevestigator; P02671; -.
DR GO; GO:0005938; C:cell cortex; IEA:Ensembl.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005577; C:fibrinogen complex; TAS:ProtInc.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0051258; P:protein polymerization; IEA:InterPro.
DR GO; GO:0051592; P:response to calcium ion; IDA:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
DR Gene3D; 3.90.215.10; -; 1.
DR Gene3D; 4.10.530.10; -; 1.
DR InterPro; IPR014716; Fibrinogen_a/b/g_C_1.
DR InterPro; IPR014715; Fibrinogen_a/b/g_C_2.
DR InterPro; IPR002181; Fibrinogen_a/b/g_C_dom.
DR InterPro; IPR012290; Fibrinogen_a/b/g_coil_dom.
DR InterPro; IPR021996; Fibrinogen_aC.
DR InterPro; IPR020837; Fibrinogen_CS.
DR Pfam; PF08702; Fib_alpha; 1.
DR Pfam; PF12160; Fibrinogen_aC; 1.
DR Pfam; PF00147; Fibrinogen_C; 1.
DR SMART; SM00186; FBG; 1.
DR SUPFAM; SSF56496; SSF56496; 1.
DR PROSITE; PS00514; FIBRINOGEN_C_1; 1.
DR PROSITE; PS51406; FIBRINOGEN_C_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amyloid; Amyloidosis;
KW Blood coagulation; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hemostasis; Hydroxylation; Isopeptide bond;
KW Phosphoprotein; Polymorphism; Reference proteome; Secreted; Signal.
FT SIGNAL 1 19
FT PEPTIDE 20 35 Fibrinopeptide A.
FT /FTId=PRO_0000009021.
FT CHAIN 36 866 Fibrinogen alpha chain.
FT /FTId=PRO_0000009022.
FT DOMAIN 623 864 Fibrinogen C-terminal.
FT REGION 36 38 Alpha-chain polymerization, binding
FT distal domain of another fibrin gamma
FT chain.
FT COILED 68 631 By similarity.
FT SITE 35 36 Cleavage; by thrombin; to release
FT fibrinopeptide A.
FT SITE 100 101 Cleavage; by plasmin; to break down
FT fibrin clots.
FT SITE 121 122 Cleavage; by hementin; to prevent blood
FT coagulation.
FT SITE 123 124 Cleavage; by plasmin; to break down
FT fibrin clots.
FT MOD_RES 22 22 Phosphoserine.
FT MOD_RES 412 412 Phosphothreonine.
FT MOD_RES 565 565 4-hydroxyproline; by P4HA1.
FT MOD_RES 609 609 Phosphoserine.
FT CARBOHYD 320 320 O-linked (GalNAc...).
FT CARBOHYD 351 351 O-linked (GalNAc...).
FT CARBOHYD 453 453 N-linked (GlcNAc...); in variant Caracas-
FT 2.
FT CARBOHYD 686 686 N-linked (GlcNAc...).
FT DISULFID 47 47 Interchain.
FT DISULFID 55 55 Interchain (with C-95 in beta chain).
FT DISULFID 64 64 Interchain (with C-49 in gamma chain).
FT DISULFID 68 68 Interchain (with C-106 in beta chain).
FT DISULFID 180 180 Interchain (with C-165 in gamma chain).
FT DISULFID 184 184 Interchain (with C-223 in beta chain).
FT DISULFID 461 491
FT CROSSLNK 322 322 Isoglutamyl lysine isopeptide (Lys-Gln)
FT (interchain with Q-41 in alpha-2-
FT antiplasmin).
FT CROSSLNK 347 347 Isoglutamyl lysine isopeptide (Gln-Lys)
FT (interchain with K-?).
FT CROSSLNK 385 385 Isoglutamyl lysine isopeptide (Gln-Lys)
FT (interchain with K-?).
FT CROSSLNK 527 527 Isoglutamyl lysine isopeptide (Lys-Gln)
FT (interchain with Q-?) (Potential).
FT CROSSLNK 558 558 Isoglutamyl lysine isopeptide (Lys-Gln)
FT (interchain with Q-?) (Potential).
FT CROSSLNK 575 575 Isoglutamyl lysine isopeptide (Lys-Gln)
FT (interchain with Q-?) (Potential).
FT CROSSLNK 581 581 Isoglutamyl lysine isopeptide (Lys-Gln)
FT (interchain with Q-?) (Potential).
FT CROSSLNK 599 599 Isoglutamyl lysine isopeptide (Lys-Gln)
FT (interchain with Q-?) (Potential).
FT VAR_SEQ 631 644 DCDDVLQTHPSGTQ -> GIHTSPLGKPSLSP (in
FT isoform 2).
FT /FTId=VSP_001531.
FT VAR_SEQ 645 866 Missing (in isoform 2).
FT /FTId=VSP_001532.
FT VARIANT 6 6 I -> V (in dbSNP:rs2070025).
FT /FTId=VAR_011609.
FT VARIANT 26 26 D -> N (in Lille-1).
FT /FTId=VAR_002390.
FT VARIANT 31 31 G -> V (in Rouen-1).
FT /FTId=VAR_002391.
FT VARIANT 35 35 R -> C.
FT /FTId=VAR_002392.
FT VARIANT 35 35 R -> H.
FT /FTId=VAR_002393.
FT VARIANT 37 37 P -> L (in Kyoto-2).
FT /FTId=VAR_002394.
FT VARIANT 38 38 R -> G (in Aarhus-1).
FT /FTId=VAR_002397.
FT VARIANT 38 38 R -> N (in Munich-1; requires 2
FT nucleotide substitutions).
FT /FTId=VAR_002395.
FT VARIANT 38 38 R -> S (in Detroit-1).
FT /FTId=VAR_002396.
FT VARIANT 39 39 V -> D (in Canterbury).
FT /FTId=VAR_010730.
FT VARIANT 66 66 S -> T.
FT /FTId=VAR_002398.
FT VARIANT 160 160 R -> S (in Lima).
FT /FTId=VAR_002399.
FT VARIANT 331 331 T -> A (in dbSNP:rs6050).
FT /FTId=VAR_011610.
FT VARIANT 446 446 K -> E (in dbSNP:rs6052).
FT /FTId=VAR_014168.
FT VARIANT 453 453 S -> N (in Caracas-2).
FT /FTId=VAR_002400.
FT VARIANT 456 456 T -> A (in dbSNP:rs2070031).
FT /FTId=VAR_011611.
FT VARIANT 545 545 E -> V (in AMYL8).
FT /FTId=VAR_010731.
FT VARIANT 573 573 R -> C (in Dusart/Paris-5).
FT /FTId=VAR_002401.
FT VARIANT 573 573 R -> L (in AMYL8).
FT /FTId=VAR_010732.
FT CONFLICT 177 177 I -> V (in Ref. 4; BAF83248).
FT CONFLICT 184 184 C -> W (in Ref. 9; AAA52426).
FT CONFLICT 215 216 SR -> RS (in Ref. 10; AA sequence).
FT CONFLICT 299 299 S -> G (in Ref. 10; AA sequence).
FT CONFLICT 304 304 S -> G (in Ref. 10; AA sequence).
FT CONFLICT 317 318 GT -> SG (in Ref. 11; AA sequence).
FT TURN 27 31
FT STRAND 57 60
FT STRAND 63 65
FT HELIX 67 92
FT HELIX 94 111
FT HELIX 116 129
FT TURN 133 135
FT TURN 139 141
FT HELIX 142 178
FT TURN 179 183
FT STRAND 184 186
FT HELIX 195 209
FT STRAND 337 343
FT STRAND 673 681
FT HELIX 689 694
FT HELIX 711 718
FT STRAND 723 729
FT STRAND 735 744
FT TURN 747 751
FT STRAND 753 762
FT TURN 765 768
FT TURN 771 773
FT HELIX 775 778
FT STRAND 793 797
FT HELIX 799 803
FT STRAND 810 812
FT STRAND 814 816
FT STRAND 823 826
FT HELIX 829 831
FT STRAND 840 843
FT HELIX 844 847
FT STRAND 854 861
SQ SEQUENCE 866 AA; 94973 MW; EA73A81204D8AEC4 CRC64;
MFSMRIVCLV LSVVGTAWTA DSGEGDFLAE GGGVRGPRVV ERHQSACKDS DWPFCSDEDW
NYKCPSGCRM KGLIDEVNQD FTNRINKLKN SLFEYQKNNK DSHSLTTNIM EILRGDFSSA
NNRDNTYNRV SEDLRSRIEV LKRKVIEKVQ HIQLLQKNVR AQLVDMKRLE VDIDIKIRSC
RGSCSRALAR EVDLKDYEDQ QKQLEQVIAK DLLPSRDRQH LPLIKMKPVP DLVPGNFKSQ
LQKVPPEWKA LTDMPQMRME LERPGGNEIT RGGSTSYGTG SETESPRNPS SAGSWNSGSS
GPGSTGNRNP GSSGTGGTAT WKPGSSGPGS TGSWNSGSSG TGSTGNQNPG SPRPGSTGTW
NPGSSERGSA GHWTSESSVS GSTGQWHSES GSFRPDSPGS GNARPNNPDW GTFEEVSGNV
SPGTRREYHT EKLVTSKGDK ELRTGKEKVT SGSTTTTRRS CSKTVTKTVI GPDGHKEVTK
EVVTSEDGSD CPEAMDLGTL SGIGTLDGFR HRHPDEAAFF DTASTGKTFP GFFSPMLGEF
VSETESRGSE SGIFTNTKES SSHHPGIAEF PSRGKSSSYS KQFTSSTSYN RGDSTFESKS
YKMADEAGSE ADHEGTHSTK RGHAKSRPVR DCDDVLQTHP SGTQSGIFNI KLPGSSKIFS
VYCDQETSLG GWLLIQQRMD GSLNFNRTWQ DYKRGFGSLN DEGEGEFWLG NDYLHLLTQR
GSVLRVELED WAGNEAYAEY HFRVGSEAEG YALQVSSYEG TAGDALIEGS VEEGAEYTSH
NNMQFSTFDR DADQWEENCA EVYGGGWWYN NCQAANLNGI YYPGGSYDPR NNSPYEIENG
VVWVSFRGAD YSLRAVRMKI RPLVTQ
//

MIM 105200
*RECORD*
*FIELD* NO
105200
*FIELD* TI
#105200 AMYLOIDOSIS, FAMILIAL VISCERAL
;;AMYLOIDOSIS VIII;;
OSTERTAG TYPE AMYLOIDOSIS;;
read moreGERMAN TYPE AMYLOIDOSIS;;
AMYLOIDOSIS, FAMILIAL RENAL;;
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
*FIELD* TX
A number sign (#) is used with this entry because of the evidence that
systemic nonneuropathic amyloidosis is the result of mutation in the
apolipoprotein A1 gene (APOA1; 107680), the fibrinogen alpha-chain gene
(FGA; 134820), the lysozyme gene (LYZ; 153450), or the gene encoding
beta-2-microglobulin (B2M; 109700).

CLINICAL FEATURES

Ostertag (1932, 1950) reported on a family with visceral amyloidosis. A
woman, 3 of her children, and 1 of her grandchildren were affected with
chronic nephropathy, arterial hypertension, and hepatosplenomegaly.
Albuminuria, hematuria and pitting edema were early signs. The age of
onset was variable. Death occurred about 10 years after onset. The
visceral involvement by amyloid was found to be extensive.

Maxwell and Kimbell (1936) described 3 brothers who died of visceral,
especially renal, amyloidosis in their 40s. Chronic weakness, edema,
proteinuria, and hepatosplenomegaly were features. McKusick (1974)
followed up on the family reported by Maxwell and Kimbell (1936). The
father of the 3 affected brothers died at age 72 after an automobile
accident and their mother died suddenly at age 87 after being in
apparent good health. A son of one of the brothers had frequent bouts of
unexplained fever in childhood (as did his father and 2 uncles),
accompanied at times by nonspecific rash. At the age of 35, proteinuria
was discovered and renal amyloidosis was diagnosed by renal biopsy. For
2 years thereafter he displayed the nephrotic syndrome, followed in the
next 2 years by uremia from which he died at age 39. Autopsy revealed
amyloidosis, most striking in the kidneys but also involving the adrenal
glands and spleen. Although some features of the family of Maxwell and
Kimbell (1936) are similar to those of urticaria, deafness and
amyloidosis (191900), no deafness was present in their family. Weiss and
Page (1974) reported a family with 2 definite and 4 probable cases in 3
generations.

Mornaghi et al. (1981, 1982) reported rapidly progressive biopsy-proved
renal amyloidosis in 3 brothers, aged 49, 52 and 55, of Irish-American
origin. None had evidence of a plasma cell dyscrasia, a monoclonal serum
or urine protein, or any underlying chronic disease. Immunoperoxidase
staining of 1 pulmonary and 1 renal biopsy specimen was negative for
amyloid A (AA), amyloid L (AL) and prealbumin. The authors concluded
that the disorder in the 3 brothers closely resembled that described by
Ostertag (1932).

Studying the proband of a kindred with the familial amyloidosis of
Ostertag, Lanham et al. (1982) demonstrated permanganate-sensitive
congophilia of the amyloid but found no immunofluorescent staining for
amyloid A or prealbumin. They concluded that this amyloid may be
chemically distinct from previously characterized forms.

Libbey and Talbert (1987) described a case of nephropathic amyloidosis,
presumably of the Ostertag type. In their case, the amyloid showed no
staining for light chains or prealbumin. Involvement of the liver was
associated with cholestasis. In the kindred reported by Lanham et al.
(1982), 6 members in 2 generations showed the onset of renal disease
between ages 23 and 45 years. The deposition of amyloid is
characteristically interstitial rather than glomerular as seen in other
forms of amyloidosis. The proband had the sicca syndrome. The details of
their patient's family history were not given by Libbey and Talbert
(1987).

Zalin et al. (1991) described yet another family with the Ostertag type
of familial nephropathic nonneuropathic amyloidosis. Petechial skin rash
was a striking feature, and petechial hemorrhages were induced by
minimal abrasion. Extensive amyloid deposition in the lungs was
illustrated. Zalin et al. (1991) reported that the amyloid deposits
contained apolipoprotein A-I; however, it was later shown that the
disorder in this family was caused by a mutation in lysozyme (see
153450.0001).

Vella et al. (2002) reported 2 patients with glaucoma due to primary
nonneuropathic amyloidosis. Glaucoma complicating amyloidosis had been
documented previously in familial amyloidotic polyneuropathy, and in
association with primary localized orbital amyloidosis. One of their
patients developed orbital amyloidoma and secondary glaucoma. After a
sudden worsening of visual acuity, papilledema was found and
(nonarteritic) anterior ischemic optic neuropathy was diagnosed. Tumor
debulking and orbital decompression were performed. Tumor histology
showed massive deposits of amyloid containing lambda chains.
Postoperatively, glaucoma was controllable with topical therapy. The
other patient had a 2-year history of weakness, persistent abdominal
pain, paresthesias, and weight loss, and a 20-year history of open-angle
glaucoma. This patient was found to have primary systemic amyloidosis on
liver and rectal biopsies. Echocardiography showed restrictive
cardiomyopathy with a diffuse hyperrefractile 'granular sparkling
appearance.' Intraocular pressure was normal on topical therapy and
ocular fundus examination showed hard drusen-like deposits bilaterally.
The patient's course improved after 15 cycles of melphalan-prednisone
treatment over 24 months. The authors stated that the incidence of
primary amyloidosis-associated glaucoma might be underestimated because
glaucoma in Western Europe and North America is less commonly treated
surgically.

MOLECULAR GENETICS

In the family with hereditary nonneuropathic systemic amyloidosis
previously studied by Zalin et al. (1991) and in another unrelated
English family with the disease, Pepys et al. (1993) identified
heterozygosity for 2 missense mutations in the LYZ gene, respectively
(153450.0001 and 153450.0002).

In a Peruvian family in which a brother and sister and the son of the
brother died from renal amyloidosis, Benson et al. (1993) identified a
mutation in the fibrinogen A alpha polypeptide gene (FGA; 134820.0012).

In 2 large American kindreds of Irish descent with nephrotic syndrome
due to renal amyloidosis, Uemichi et al. (1993, 1994) identified a
missense mutation in the FGA gene (E526V; 134820.0013).

In an American kindred with hereditary renal amyloidosis, Uemichi et al.
(1996) identified a 1-bp deletion in the FGA gene (134820.0016), causing
a frameshift and termination sequence at codon 548.

In a French kindred with autosomal dominant hereditary renal
amyloidosis, Asl et al. (1997) identified a different 1-bp deletion in
the FGA gene, also resulting in termination at codon 548 (134820.0018).

Systemic amyloidosis is the diagnosis in 2.5% of all renal biopsies,
according to Davison (1985), and is the cause of death in more than 1 in
1,500 persons in the United Kingdom annually. Acquired monoclonal
immunoglobulin light-chain amyloidosis (AL; see 254500), formerly known
as primary amyloidosis, is the most common form of systemic amyloidosis
and can respond to chemotherapy directed at the underlying plasma cell
dyscrasia. Lachmann et al. (2002) studied 350 patients with systemic
amyloidosis in whom a diagnosis of the AL type of the disorder had been
suggested by clinical and laboratory data and by the apparent absence of
a family history. They identified amyloidogenic mutations in 34 (9.7%)
of the patients, all of whom had the diagnosis of hereditary amyloidosis
confirmed by additional investigations. In 18 (5.1%) of the 350
patients, the E526V mutation in the FGA gene was identified; 13 of the
patients had missense mutations in the transthyretin gene (176330); 2
patients had missense mutations in the APOA1 gene (107680); and 1
patient had the D67H mutation in the lysozyme gene (153450.0002). All 18
patients with the FGA E526V mutation were of northern European ancestry,
and although none was aware of any relevant family history, genealogic
studies revealed that 2 were cousins and that ancestors of 2 other
patients lived in adjacent villages. A fifth patient retrospectively
ascertained that her dizygotic twin had died of renal failure at the age
of 76 years. The median age of the 18 patients at the time of
presentation was 59 years; the youngest was in her thirties and the
oldest was 78 years old. All presented with isolated renal dysfunction
and proteinuria, and most had moderate hypertension; all had renal
amyloid deposits, and splenic amyloid was present in all but 1 of the
patients. Spontaneous splenic rupture occurred in 2 patients.

Granel et al. (2005) described a patient diagnosed with systemic
digestive and 'medullar' amyloidosis. (Grateau (2006) stated that the
term 'medullar' referred to the involvement of bone marrow.) Primary
(AL) amyloidosis was initially suspected, but results of
immunohistochemical staining were negative for immunoglobulin
kappa/lambda light chains. The results of a complementary search for
lysozyme amyloidosis were positive in colonic mucosa. A missense
mutation, a T-to-A transversion at the first nucleotide of codon 64
(W64R; 153450.0005), was found in the LYZ gene. Granel et al. (2005)
pointed out that an incorrect diagnosis could have been made if complete
analysis of the amyloid deposits had not been performed, and that
amyloidoses of different types, i.e., AA, AL, transthyretin, lysozyme,
or fibrinogen, can produce similar visceral involvement, but prognosis
and treatment are completely different.

In 4 affected members of a family with autosomal dominant visceral
amyloidosis, Valleix et al. (2012) identified a heterozygous mutation in
the B2M gene (D76N; 109700.0002). Studies on the recombinant D76N
protein showed reduced stability of the fully folded mutant protein and
significantly increased conversion of the mutant protein into fibrils
with amyloid-like properties under physiologic conditions, whereas the
wildtype protein did not aggregate at all. In mid-adult life, the
patients developed slowly progressive chronic diarrhea with weight loss
and sicca syndrome. One had sensorimotor axonal polyneuropathy and
orthostatic hypotension and 2 had severe autonomic neuropathy.
Postmortem examination of 1 patient, who died at age 70 years, showed
extensive B2M-containing amyloid deposits in the spleen, liver, heart,
salivary glands, and nerves. Colonic biopsy from another affected
individual also contained B2M-containing amyloid deposits. Amyloid
scinotography of 2 patients showed a heavy visceral amyloid burden in
the spleen and adrenal glands, but not in heart. Valleix et al. (2012)
noted that the amyloid deposition in this family was different from that
observed in dialysis-related amyloidosis, in which B2M-amyloid
accumulates around bones and joints. In addition, serum B2M was not
increased in the patients with familial disease, whereas it is increased
in those with dialysis-related amyloidosis.

CLINICAL MANAGEMENT

Bodin et al. (2010) demonstrated that administration of anti-human serum
amyloid P component (SAP; 104770) antibodies to mice with amyloid
deposits containing human SAP triggers a potent, complement-dependent,
macrophage-derived giant cell reaction that swiftly removes massive
visceral amyloid deposits without adverse effects. Anti-SAP antibody
treatment is clinically feasible because circulating human SAP can be
depleted in patients by the bis-D-proline compound CPHPC, thereby
enabling injected anti-SAP antibodies to reach residual SAP in the
amyloid deposits.

*FIELD* SA
Alexander and Atkins (1975); Weiss and Page (1973)
*FIELD* RF
1. Alexander, F.; Atkins, E. L.: Familial renal amyloidosis: case
reports, literature review and classification. Am. J. Med. 59: 121-128,
1975.

2. Asl, L. H.; Liepnieks, J. J.; Uemichi, T.; Rebibou, J.-M.; Justrabo,
E.; Droz, D.; Mousson, C.; Chalopin, J.-M.; Benson, M. D.; Delpech,
M.; Grateau, G.: Renal amyloidosis with a frame shift mutation in
fibrinogen A(alpha)-chain gene producing a novel amyloid protein. Blood 90:
4799-4805, 1997.

3. Benson, M. D.; Liepnieks, J.; Uemichi, T.; Wheeler, G.; Correa,
R.: Hereditary renal amyloidosis associated with a mutant fibrinogen
alpha-chain. Nature Genet. 3: 252-255, 1993.

4. Bodin, K.; Ellmerich, S.; Kahan, M. C.; Tennent, G. A.; Loesch,
A.; Gilbertson, J. A.; Hutchinson, W. L.; Mangione, P. P.; Gallimore,
J. R.; Millar, D. J.; Minogue, S.; Dhillon, A. P.; Taylor, G. W.;
Bradwell, A. R.; Petrie, A.; Gillmore, J. D.; Bellotti, V.; Botto,
M.; Hawkins, P. N.; Pepys, M. B.: Antibodies to human serum amyloid
P component eliminate visceral amyloid deposits. Nature 468: 93-97,
2010.

5. Davison, A. M.: The United Kingdom Medical Research Council's
glomerulonephritis registry. Contrib. Nephrol. 48: 24-35, 1985.

6. Granel, B.; Serratrice, J.; Disdier, P.; Weiller, P.-J.; Valleix,
S.; Grateau, G.; Droz, D.: Underdiagnosed amyloidosis: amyloidosis
of lysozyme variant. Am. J. Med. 118: 321-323, 2005.

7. Grateau, G.: Personal Communication. Paris, France 1/16/2006.

8. Lachmann, H. J.; Chir, B.; Booth, D. R.; Booth, S. E.; Bybee, A.;
Gilbertson, J. A.; Gillmore, J. D.; Pepys, M. B.; Hawkins, P. N.:
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New
Eng. J. Med. 346: 1786-1791, 2002.

9. Lanham, J. G.; Meltzer, M. L.; de Beer, F. C.; Hughes, G. R. V.;
Pepys, M. B.: Familial amyloidosis of Ostertag. Quart. J. Med. 51:
25-32, 1982.

10. Libbey, C. A.; Talbert, M. L.: A 43-year-old woman with hepatic
failure after renal transplantation because of amyloidosis. New Eng.
J. Med. 317: 1520-1531, 1987.

11. Maxwell, E. S.; Kimbell, I.: Familial amyloidosis with case reports. Med.
Bull. Vet. Admin. 12: 365-369, 1936.

12. McKusick, V. A.: Personal Communication. Baltimore, Md. 1974.

13. Mornaghi, R.; Rubinstein, P.; Franklin, E. C.: Studies of the
pathogenesis of a familial form of renal amyloidosis. Trans. Assoc.
Am. Phys. 94: 211-216, 1981.

14. Mornaghi, R.; Rubinstein, P.; Franklin, E. C.: Familial renal
amyloidosis: case reports and genetic studies. Am. J. Med. 73: 609-614,
1982.

15. Ostertag, B.: Demonstration einer eigenartigen familiaeren Paramyloidose. Zbl.
Path. 56: 253-254, 1932.

16. Ostertag, B.: Familiaere Amyloid-erkrankung. Z. Menschl. Vererb.
Konstitutionsl. 30: 105-115, 1950.

17. Pepys, M. B.; Hawkins, P. N.; Booth, D. R.; Vigushin, D. M.; Tennent,
G. A.; Soutar, A. K.; Totty, N.; Nguyen, O.; Blake, C. C. F.; Terry,
C. J.; Feest, T. G.; Zalin, A. M.; Hsuan, J. J.: Human lysozyme gene
mutations cause hereditary systemic amyloidosis. Nature 362: 553-557,
1993.

18. Uemichi, T.; Liepnieks, J. J.; Benson, M. D.: Fibrinogen Indianapolis:
a fibrinogen A-alpha chain associated with hereditary amyloidosis.
(Abstract) Clin. Res. 41: 133 only, 1993.

19. Uemichi, T.; Liepnieks, J. J.; Benson, M. D.: Hereditary renal
amyloidosis with a novel variant fibrinogen. J. Clin. Invest. 93:
731-736, 1994.

20. Uemichi, T.; Liepnieks, J. J.; Yamada, T.; Gertz, M. A.; Bang,
N.; Benson, M. D.: A frame shift mutation in the fibrinogen A-alpha
chain gene in a kindred with renal amyloidosis. Blood 87: 4197-4203,
1996.

21. Valleix, S.; Gillmore, J. D.; Bridoux, F.; Mangione, P. P.; Dogan,
A.; Nedelec, B.; Boimard, M.; Touchard, G.; Goujon, J.-M.; Lacombe,
C.; Lozeron, P.; Adams, D.; and 14 others: Hereditary systemic
amyloidosis due to asp76asn variant beta-2-microglobulin. New Eng.
J. Med. 366: 2276-2283, 2012.

22. Vella, F. S.; Simone, B.; Giannelli, G.; Sisto, D.; Sborgio, C.;
Antonaci, S.: Glaucoma in primary amyloidosis: a fortuitous or causative
association? (Letter) Am. J. Med. 113: 252-254, 2002.

23. Weiss, S. W.; Page, D. L.: Amyloid nephropathy of Ostertag with
special reference to renal glomerular giant cells. Am. J. Path. 72:
447-460, 1973.

24. Weiss, S. W.; Page, D. L.: Amyloid nephropathy of Ostertag: report
of a kindred. Birth Defects Orig. Art. Ser. X(4): 67-68, 1974.

25. Zalin, A. M.; Jones, S.; Fitch, N. J. S.; Ramsden, D. B.: Familial
nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry
and chemistry. Quart. J. Med. 81: 945-956, 1991.

*FIELD* CS

GI:
Hepatomegaly;
Cholestasis;
Splenomegaly

GU:
Nephropathy with hematuria;
Nephrotic syndrome;
Uremia

Endocrine:
Hypertension

Skin:
Pitting edema;
Petechial skin rash

Neuro:
Nonneuropathic

Misc:
Chronic weakness

Lab:
Generalized amyloid deposition;
Proteinuria;
Hematuria

Inheritance:
Autosomal dominant

*FIELD* CN
Cassandra L. Kniffin - updated: 6/14/2012
Ada Hamosh - updated: 1/4/2011
Marla J. F. O'Neill - updated: 1/8/2009
Victor A. McKusick - updated: 2/1/2006
Jane Kelly - updated: 3/20/2003
Victor A. McKusick - updated: 1/12/2001

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

*FIELD* ED
alopez: 06/14/2012
ckniffin: 6/14/2012
alopez: 1/4/2011
terry: 1/4/2011
carol: 1/8/2009
carol: 2/1/2006
terry: 2/1/2006
wwang: 3/23/2005
wwang: 3/16/2005
cwells: 3/20/2003
carol: 9/11/2002
cwells: 1/18/2001
terry: 1/12/2001
carol: 4/6/1994
mimadm: 3/11/1994
carol: 5/17/1993
carol: 5/12/1993
carol: 5/6/1993
carol: 3/22/1993

MIM 134820
*RECORD*
*FIELD* NO
134820
*FIELD* TI
+134820 FIBRINOGEN, A ALPHA POLYPEPTIDE; FGA
;;FIBRINOGEN--ALPHA POLYPEPTIDE CHAIN
read moreDYSFIBRINOGENEMIA CAUSING RECURRENT THROMBOSIS, INCLUDED
*FIELD* TX
Fibrinogen is a plasma glycoprotein synthesized in the liver. It is
composed of 3 structurally different subunits: alpha (FGA), beta (FGB;
134830), and gamma (FGG; 134850). Thrombin (176930) causes a limited
proteolysis of the fibrinogen molecule, during which fibrinopeptides A
and B are released from the N-terminal regions of the alpha and beta
chains, respectively. The enzyme cleaves arginine-glycine linkages so
that glycine is left as the N-terminal amino acid on both chains.
Thrombin also activates fibrin-stabilizing factor (see 134570 and
134580), which in its activated form is a transpeptidase catalyzing the
formation of epsilon-(gamma-glutamyl)-lysine crosslinks in fibrin.
Fibrinopeptides, which have been sequenced in many species, may have a
physiologic role as vasoconstrictors and may aid in local hemostasis
during blood clotting. By amino acid sequencing, Doolittle et al. (1970)
could find no variation of fibrinopeptides A and B from 125 persons.

Fu et al. (1992) showed that FGA, like FGB (134830) and FGG (134850),
has a sixth exon, which encodes 236 amino acids, and is used in a minor
isoform of the alpha subunit referred to as alpha(E). Fu et al. (1995)
compared exon VI sequence from chicken, rabbit, rat, and baboon with the
human sequence and showed that it is highly conserved, implying an
important physiologic function.

Olaisen et al. (1982) stated that molecular fibrinogen variants of
apparent genetic origin had been described in more than 40 persons.
Gralnick and Finlayson (1972) and Ratnoff and Bennett (1973) provided
tabulations of fibrinogen variants. The distinctness of all the types
(over 50 as of 1981) is not proved. Most of the variants have been
detected on coagulation tests in which plasma fibrinogen is converted to
fibrin (thrombin time, reptilase test, prothrombin time). The times are
prolonged or infinite (i.e., no clot is formed). Chemical or immunologic
assays for fibrinogen are usually normal, however. Although the variants
may be asymptomatic, abnormal bleeding, abnormal clotting, and wound
dehiscence in isolation or in some combination have been observed. The
defect in conversion of fibrinogen to fibrin is, in a few of the
variants, at the first step, that of removal of fibrinopeptides A and B
by thrombin to form fibrin monomer. The majority, however, have the
defect in the second step, that of aggregation of fibrin monomer to form
a fibrin gel. (The third step is covalent cross-linking of fibrin,
catalyzed by activated factor XIII, to form an insoluble clot.)

Dominant inheritance of dysfibrinogenemia and hypofibrinogenemia is
indicated by the pedigree patterns of many families. The presence of
abnormal and normal molecules indicate 'autosomal codominant' as the
appropriate designation for the type of inheritance. Dysfibrinogenemia
may exemplify one mechanism for dominant inheritance: the mutant
polypeptide may not participate normally as a subunit in the aggregate
that is fibrinogen (Vogel and Motulsky, 1979). An unstable aggregate
molecule results. Homozygotes have been observed for fibrinogen Metz
(Soria et al., 1972) as well as for some others, including fibrinogen
Detroit (Blomback et al., 1968). Homozygosity was more likely to be
accompanied by bleeding. Venous and arterial thrombosis has been seen
particularly with rapidly clotting fibrinogens (e.g., Oslo I) or,
paradoxically, with slowly clotting fibrinogens (e.g., New York I).
Abnormal wound healing and postoperative wound dehiscence were clinical
symptoms of those dysfibrinogenemias in which fibrin crosslinking was
deficient (e.g., Paris I; 134850.0011). Repeated spontaneous abortions
may be a feature (e.g., Metz and Bethesda III). Hamsten et al. (1987)
concluded that a substantial portion of the variance of the plasma
fibrinogen level (51%) is accounted for by genetic heritability. The
combined effect of obesity and smoking was found to explain 3% of the
variance. Serum transaminase levels were slightly elevated.

Henry et al. (1984) isolated clones of each fibrinogen chain (A-alpha,
B-beta, and gamma) from a human liver cDNA library and showed by Chinese
hamster-human somatic cell hybrids that all 3 are located on chromosome
4, thus confirming the assignment of gamma fibrinogen by linkage with MN
(111300). Interestingly, the 3, which are coordinately expressed, are
syntenic. Direct gene-dosage studies in 2 patients with unbalanced
rearrangements of chromosome 4 permitted regional assignment to 4q2.
Kant and Crabtree (1983) used cDNA probes for the alpha, beta, and gamma
chains of rat fibrinogen to isolate the corresponding genes from 2 rat
genomic libraries constructed in bacteriophage Charon 4A. A single copy
of each gene was found. Mapping of greater than 92 kilobases of rat
genomic DNA showed that the gamma and alpha chains are directly linked
in a 5-prime-3-prime direction. Rats defibrinated with Malayan pit viper
venom showed a rapid and substantial increase in the relative abundance
of hepatic RNAs for all 3 chains (Crabtree and Kant, 1982). The genes
for the 3 chains are transcribed as separate mRNAs (Uzan et al., 1982;
Kant and Crabtree, 1983). Using a cDNA probe, Humphries et al. (1984)
localized FGA to 4q29-q31. In somatic cell hybrids carrying a
translocation involving chromosome 4 with a breakpoint at 4q26, all 3
fibrinogen genes segregated with the 4q26-qter segment. By in situ
hybridization, Marino et al. (1986) located the fibrinogen gene cluster
to 4q31. By means of one or more RFLPs at each locus, Aschbacher et al.
(1985) studied linkage disequilibrium in the fibrinogen cluster. They
concluded that the likely order is gamma-alpha-beta. This agrees with
the order suggested by Kant et al. (1985). Thomas et al. (1994)
demonstrated linkage disequilibrium using restriction polymorphisms of
the FGA and FGB genes detected by PCR.

Using clones from the alpha, beta, and gamma genes, Uzan et al. (1984)
studied DNA from normal individuals and 2 patients with afibrinogenemia.
The results indicated that the single-copy fibrinogen genes were grossly
intact in afibrinogenemic DNA. In addition to afibrinogenemia (a
recessive, 202400), fibrinogen may be functionally abnormal. The first
example of a qualitatively abnormal fibrinogen (subsequently called
fibrinogen Parma) was that described by Imperato and Dettori (1958); the
first demonstration of inheritance was given by Menache (1963) for the
fibrinogen subsequently called Paris I (134850.0011). In a family of
Hungarian extraction, von Felton et al. (1966) described a clotting
disturbance, characterized by delayed aggregation of fibrin monomers, in
father and son. Chemical studies suggested a molecular abnormality of
fibrinogen. Forman et al. (1968) described fibrinogen Cleveland which is
immunoelectrophoretically distinct from fibrinogen Baltimore (described
by Beck et al., 1965). Operative wounds showed dehiscence in 2 persons
with the abnormal fibrinogen. The plasma in their 8 related persons of
both sexes showed abnormally slow coagulation when thrombin was added.
The fibrinogen described by Blomback et al. (1968) and Mammen et al.
(1969) and called fibrinogen Detroit had characteristics different from
fibrinogen Baltimore and fibrinogen Cleveland. Fibrinogen Oklahoma
appears to have a structural defect such that cross-linkage is
defective. Martinez et al. (1974) described an abnormal fibrinogen
associated with hypercatabolism. This so-called fibrinogen Philadelphia
was noted in 2 sisters and the son of one of them. Only 1 sister was
symptomatic, with excessive bleeding. In a potentially instructive
family, Kohn et al. (1983) observed a correlation between a balanced
7p;12q translocation and hypofibrinogenemia. The proband experienced
first-trimester abortions. Normal clotting factors are necessary for
placentation. Wehinger et al. (1983) described a variety of
hypofibrinogenemia that they concluded was due to defective fibrinogen
release from hepatocytes. The outstanding feature was massive deposition
of fibrinogen/fibrin within hepatocytes, faintly visible in routine
microscopic sections but clearly demonstrable by immunohistologic
techniques. All 3 chains of circulating fibrinogen showed normal
electrophoretic mobility. Seemingly, there were no ill effects on liver
function.

Akassoglou et al. (2002) reported that fibrin inhibits peripheral nerve
remyelination by regulating Schwann cell differentiation. Using
immunocytochemistry and Western blot analysis to follow fibrin
deposition during nerve regeneration, the authors observed that fibrin
is deposited after sciatic nerve crush and its clearance is correlated
with nerve repair after sciatic nerve injury in normal mice. Using
experiments to quantitate myelinating axons, they revealed that
fibrin(ogen)-deficient mice showed an increase in myelinated axons after
sciatic nerve injury compared to normal mice. The authors observed that
fibrin induced ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and production
of p75 NGF low-affinity receptor (162010) in Schwann cells and
maintained them in a nonmyelinating state, suppressed fibronectin
production, and prevented synthesis of myelin proteins. Akassoglou et
al. (2002) hypothesized that regulation of fibrin clearance and/or
deposition is a regulatory mechanism for Schwann cell differentiation
after nerve damage.

MOLECULAR GENETICS

Rupp and Beck (1984) reviewed all the fibrinogen variants. Information
on variant human fibrinogens was cataloged by Ebert (1990). The alpha
dysfibrinogenemias all have missense mutations as indicated in the list
of variants. Galanakis (1993) reviewed inherited dysfibrinogenemia,
correlating abnormal structure with pathologic and nonpathologic
dysfunction.

In patients with congenital afibrinogenemia (202400), a rare autosomal
recessive disorder characterized by complete absence of detectable
fibrinogen, Neerman-Arbez et al. (1999) demonstrated mutations in the
FGA gene (134820.0019-134820.0020).

In a study of 8 afibrinogenemic probands, with very low plasma levels of
immunoreactive fibrinogen, Asselta et al. (2001) found 4 novel point
mutations and 1 previously reported mutation. All mutations, localized
within the first 4 exons of the FGA gene, were null mutations predicted
to produce severely truncated A-alpha chains because of the presence of
premature termination codons. Further study indicated that all the
identified null mutations escaped nonsense-mediated mRNA decay. Other
analyses at the protein level demonstrated that the presence of each
mutation was sufficient to abolish fibrinogen secretion.

- Familial Visceral Amyloidosis

In a Peruvian family in which a brother and sister and the son of the
brother died from renal amyloidosis (105200), Benson et al. (1993)
identified a missense mutation in the FGA gene (R554L; 134820.0012).

In 2 large American kindreds of Irish descent with nephrotic syndrome
due to renal amyloidosis, Uemichi et al. (1993, 1994) identified a
missense mutation in the FGA gene (E526V; 134820.0013).

In an American kindred with hereditary renal amyloidosis, Uemichi et al.
(1996) identified a 1-bp deletion in the FGA gene (134820.0016), causing
a frameshift and termination sequence at codon 548. The authors stated
that this was the first description of a kindred with renal amyloidosis
and low plasma fibrinogen, and the first report of amyloidosis caused by
a frameshift mutation.

In a French kindred with autosomal dominant hereditary renal
amyloidosis, Asl et al. (1997) identified a different 1-bp deletion in
the FGA gene, also resulting in termination at codon 548 (134820.0018).

Lachmann et al. (2002) studied 350 patients with systemic amyloidosis
and identified heterozygosity for the E526V mutation in 18 (5.1%) of the
patients.

ANIMAL MODEL

To examine directly the role of fibrin(ogen) in atherogenesis, Xiao et
al. (1998) crossed fibrinogen-deficient mice with atherosclerosis-prone
apolipoprotein E (apoE)-deficient mice. Both apoE -/- mice and mice that
were doubly deficient in apoE and fibrinogen developed lesions
throughout the entire aortic tree, ranging in appearance from simple
fatty streaks to complex fibrous plaques. Furthermore, remarkably little
difference in lesion size and complexity was observed within the aortas
of age- and gender-matched singly and doubly deficient mice. These
results indicated that the contribution of fibrin(ogen) to intimal mass
and local cell adhesion, migration, and proliferation is not strictly
required for the development of advanced atherosclerotic disease in mice
with a severe defect in lipid metabolism.

Fibrin(ogen) has been proposed to play an important role in tissue
repair by providing an initial matrix that can stabilize wound fields
and support local cell proliferation and migration. Consistent with this
is the observation that abnormal wound healing and postoperative wound
dehiscence were clinical symptoms of those dysfibrinogenemias in which
fibrin crosslinking was deficient (e.g., Paris I; 134850.0011). Drew et
al. (2001) investigated the effect of fibrinogen deficiency on cutaneous
tissue repair in mice using incisional and excisional wounds. The time
required to heal wounds was similar in fibrinogen-deficient (Fib -/-)
and control mice, but histologic evaluation showed distinct differences
in the repair process, including an altered pattern of epithelial cell
migration and increased epithelial hyperplasia. Furthermore, granulation
tissue failed to close the wound gap adequately, resulting in persistent
open wounds or partially covered sinus tracts. The tensile strength of
these wounds was also reduced compared with control mice. In knockout
mice with fibrinogen deficiency, Suh et al. (1995) had previously shown
that spontaneous bleeding events resolved but there was failure of
pregnancy.

*FIELD* AV
.0001
FIBRINOGEN LILLE 1
FGA, ASP7ASN

See Morris et al. (1981).

.0002
FIBRINOGEN ROUEN 1
FGA, GLY12VAL

See Soria et al. (1985).

.0003
FIBRINOGEN BERGAMO 1
FIBRINOGEN HERSHEY 2;;
FIBRINOGEN HOMBURG 2;;
FIBRINOGEN HOMBURG 3;;
FIBRINOGEN KAWAGUCHI 1;;
FIBRINOGEN LEOGAN;;
FIBRINOGEN METZ 1;;
FIBRINOGEN NEW ALBANY;;
FIBRINOGEN OSAKA 1;;
FIBRINOGEN SCHWARZACH 1;;
FIBRINOGEN STONY BROOK 1;;
FIBRINOGEN ZURICH 1;;
FIBRINOGEN TORINO 1;;
FIBRINOGEN LEDYARD;;
FIBRINOGEN HERSHEY 3;;
FIBRINOGEN MILANO XII, DIGENIC, INCLUDED
FGA, ARG16CYS

The change in fibrinogen Metz is arginine to cysteine at position 16 in
the alpha chain (Henschen et al., 1981). Galanakis et al. (1989) stated
that 52 dysfibrinogens had been structurally characterized and that most
were single amino acid substitutions with a high frequency of
substitutions at arg positions A-alpha-16, A-alpha-19, B-beta-14, and
gamma-275. Galanakis et al. (1989) described an A-alpha-16 arg-to-cys
(R16C) substitution in fibrinogen Stony Brook and described the
functional characteristics of the variant. See also Southan et al.
(1982), Henschen et al. (1983), Reber et al. (1985), Miyashita et al.
(1985), and Miyata et al. (1987). According to Galanakis (1993), this
mutation has been identified in 15 unrelated families. In 2 of these,
arg16-to-his (134820.0004) was demonstrated by both DNA and protein
sequencing. Lee et al. (1991) found the R16C variant, which they called
fibrinogen Ledyard, in a 10-year-old boy with a history of mild bleeding
whose father had the same defect and a history of bleeding after
surgery. Both patients were heterozygous.

Bolliger-Stucki et al. (2001) described an anomalous fibrinogen called
Milano XII in an asymptomatic Italian woman, and demonstrated that its
basis was double heterozygosity for the R16C mutation in exon 2 of the
FGA gene, and a G165R mutation in the FGG gene (134850.0018). The woman
was discovered when routine coagulation test results showed a prolonged
thrombin time. Fibrinogen levels in functional assays were considerably
lower than levels in immunologic assays. Bolliger-Stucki et al. (2001)
concluded that the FGA mutation was mainly responsible for the
coagulation abnormalities, whereas the change in the FGG gene was
responsible for a conformational change in the D3 fragment.

The R16C mutation of the FGA gene is a common cause of dysfibrinogenemia
and is associated with both bleeding and thrombosis. Flood et al. (2006)
undertook to understand the mechanism of the thrombotic phenotype. A
young patient with dysfibrinogenemia (fibrinogen Hershey III) was found
to be heterozygous for the R16C mutation. Functional assays were
performed on purified fibrinogen to characterize clot formation and
lysis with plasmin and trypsin. Consistent with previous results, clot
formation was diminished, but unexpectedly, fibrinolysis was also
delayed. When clot lysis was assayed with trypsin substituted for
plasminogen, a significant delay was also observed, indicating that
defective binding to plasminogen could not explain the fibrinolytic
resistance. The results suggested that the defective fibrinolysis is due
to increased proteolytic resistance, most likely reflecting changes in
clot structure.

Flood et al. (2006) stated that the R16C mutation is the most common
fibrinogen mutation in humans. Although about 30% of the reported cases
of the R16C mutation in humans are associated with hemorrhage, some 15%
of reported cases are associated with thrombosis (Hanss and Biot, 2001).

.0004
FIBRINOGEN AMIENS 1
FIBRINOGEN AMIENS 2;;
FIBRINOGEN BERGAMO 3;;
FIBRINOGEN BERN 2;;
FIBRINOGEN BICETRE 1;;
FIBRINOGEN BIRMINGHAM 1;;
FIBRINOGEN CHAPEL HILL 2;;
FIBRINOGEN CLERMONT-FERRAND 1;;
FIBRINOGEN GIESSEN 1;;
FIBRINOGEN LEITCHFIELD;;
FIBRINOGEN LONG BEACH 1;;
FIBRINOGEN LOUISVILLE 1;;
FIBRINOGEN MANCHESTER 1;;
FIBRINOGEN PARIS 6;;
FIBRINOGEN PETOSKEY 1;;
FIBRINOGEN SEATTLE 2;;
FIBRINOGEN SHEFFIELD 2;;
FIBRINOGEN SYDNEY 1;;
FIBRINOGEN SYDNEY 2;;
FIBRINOGEN WHITE MARSH 1
FGA, ARG16HIS

Carrell et al. (1983) gave the name fibrinogen Chapel Hill to a
fibrinogen variant associated with thrombotic disease. Higgins and
Shafer (1981) found that fibrinogen Petoskey (named for Petoskey,
Michigan, the site of the hospital where the blood samples were
collected) had replacement of arg-A(alpha)16 by a histidyl residue. In
an abnormal fibrinogen associated with excessive bleeding after
childbirth and called fibrinogen White Marsh for the Virginia town of
residence, Qureshi et al. (1983) also found substitution of histidine
for arginine at position 16 in the alpha chain. Fibrinogen Manchester
has replacement of A-alpha-16 arginine by histidine. Southan et al.
(1985) found that platelet fibrinogen expresses the heterozygous
A-alpha-16his phenotype, thus supporting the view that the A-alpha
chains of platelet and plasma fibrinogen are produced by a single
genetic locus. Alving and Henschen (1987) reported that a patient
homozygous for fibrinogen Giessen I had a substitution of histidine for
arginine at position 16. Although this patient had had excessive
postpartum bleeding, she had normal hemostasis throughout several minor
surgical procedures and during hysterectomy. Reber et al. (1987)
described 2 fibrinogen variants in which there was a substitution for
arginine 16 in the alpha chain by histidine in one and by cysteine in
the other; these were designated fibrinogen Bergamo III and fibrinogen
Torino (134820.0003), respectively. See also Galanakis et al. (1983),
Ebert et al. (1986), and Siebenlist et al. (1988). According to
Galanakis (1993), the mutation has been identified in 22 unrelated
families, making it the most frequent form of dysfibrinogenemia.
Together with arg16 to cys, it represents the majority of the mutations
characterized to date, 37 out of 63.

.0005
FIBRINOGEN MUNICH 1
FGA, ARG19ASN

See Southan et al. (1982).

.0006
FIBRINOGEN DETROIT 1
FGA, ARG19SER

The first specific amino acid substitution was found in fibrinogen
Detroit (Blomback et al., 1968); serine is substituted for arginine as
the 19th residue of the alpha chain (Blomback and Blomback, 1970).

.0007
FIBRINOGEN AARHUS 1
FGA, ARG19GLY

See Blomback et al. (1988).

.0008
FIBRINOGEN KYOTO 2
FGA, PRO18LEU

In a 27-year-old woman with a bleeding diathesis, Yoshida et al. (1991)
found heterozygosity for a substitution of leucine for proline-18 in the
A-alpha chain. Studies of the pro18-to-leu mutation indicated that
proline-18 is an important part of the polymerization site in the
NH2-end of the fibrin alpha chain.

.0009
FIBRINOGEN CARACAS-2
FGA, SER434ASN

Fibrinogen Caracas II is a congenital dysfibrinogen which was originally
found in an asymptomatic girl who had prolonged thrombin clotting. She
and her father were heterozygotes. Maekawa et al. (1991) described a
unique N-glycosylated asparagine substitution for serine-434 of the
A-alpha chain. This dysfibrinogen was characterized by impaired fibrin
monomer aggregation.

.0010
FIBRINOGEN LIMA
FGA, ARG141SER

Arocha-Pinango et al. (1990) described a 10-year-old girl from Lima,
Peru, who had an apparently homozygous dysfibrinogenemia with impaired
fibrin polymerization. The parents were first cousins and were thought
to have the same type of dysfibrinogen in the heterozygous form.
Although transient hematuria was noted in the patient, there was no
history of bleeding or thrombosis related to this abnormality in the
family. The abnormality of fibrinogen was discovered by the discrepancy
between the plasma fibrinogen level determined by the thrombin time
method and the gravimetric method. Similar but less remarkable
discrepancies were noted in the levels of plasma fibrinogen in her
parents. In the patient reported by Arocha-Pinango et al. (1990),
Maekawa et al. (1992) identified a substitution of serine for
arginine-141 in fibrinogen A-alpha. The point mutation created a new
glycosylation sequence. See 300841.0065 and 300841.0066 for examples of
2 mutations in factor VIII that introduce new N-glycosylation sites and
result in CRM-positive hemophilia A.

.0011
FIBRINOGEN MARBURG
DYSFIBRINOGENEMIA CAUSING BLEEDING DIATHESIS
FGA, LYS461TER

Koopman et al. (1992) identified fibrinogen Marburg in a 20-year-old
woman who suffered a uterine hemorrhage after delivery of her first
child by cesarean section. Pulmonary embolism and deep pelvic thrombosis
occurred thereafter. The patient's mother had died of apoplexy after a
long period of hypertension. All other family members were asymptomatic,
although the father and 5 sibs were heterozygous and 3 other sibs had
only normal fibrinogen. The proposita was homozygous for an A-to-T
transversion that changed codon 461 from AAA (lys) to TAA (stop).

.0012
AMYLOIDOSIS, FAMILIAL VISCERAL
FGA, ARG554LEU

Benson et al. (1993) studied a family in which a brother and sister and
the son of the brother died from renal amyloidosis (105200). They were
all found to share a nucleotide substitution in the FGA gene. The
predicted arginine to leucine mutation (arg554-to-leu) was proven by
amino acid sequence analysis of amyloid fibril protein isolated from
postmortem kidney of 1 of the affected persons. Direct genomic DNA
sequencing and RFLP analysis demonstrated that all 3 affected persons
had the G-to-T transversion at position 4993. This was the first
demonstration of hereditary amyloidosis associated with a variant
fibrinogen alpha-chain. The propositus was a Peruvian male who died at
age 50. At age 36 he had developed nephrotic syndrome and subsequently
azotemia due to renal amyloidosis. At age 40 he received a cadaver renal
transplant and enjoyed good health for 8 years until renal biopsy showed
diffuse amyloid involvement of glomeruli in the transplanted kidney. He
died with septicemia after receiving a second renal allograft. The
patient's sister, who had nephrotic syndrome, died at age 28. The
patient's son developed azotemia at age 24. Benson et al. (1993) pointed
to the close similarity to the Ostertag form of renal amyloidosis
(105200).

.0013
AMYLOIDOSIS, FAMILIAL VISCERAL
FGA, GLU526VAL

In 2 large American kindreds of Irish descent, Uemichi et al. (1993,
1994) found that renal amyloidosis (105200) presenting with nephrotic
syndrome was associated with an A-to-T transversion at position 1674 of
the FGA gene, predicting a glu-to-val change in amino acid residue 526.
In 1 kindred renal amyloidosis presented with nephrotic syndrome in the
late forties and death occurred by age 60; in the other kindred
nephrotic syndrome presented in the early sixties with death in the
early seventies. Neither kindred had neuropathy or cardiomyopathy.
Uemichi et al. (1996) reported 2 further kindreds, 1 Polish-Canadian and
the other Irish-American, with the glu526-to-val mutation. In these 4
kindreds, affected members developed hypertension and nephrotic syndrome
due to amyloidosis in their forties or fifties. Haplotype analysis
suggested that all 4 kindreds may have been derived from a single
founder.

In 18 patients of northern European ancestry with renal amyloidosis,
Lachmann et al. (2002) found the glu526-to-val mutation. The median age
of presentation was 59 years with a range from the thirties to 78.
Spontaneous splenic rupture occurred in 2 patients.

In a 48-year-old man with proteinuria, in whom renal biopsy revealed
amyloid deposits exclusively in the mesangium of the glomeruli and whose
mother had died of renal amyloidosis, Mourad et al. (2008) identified
the E526V mutation in the FGA gene. Four years later, the patient
required implantation of a defibrillator due to cardiac arrhythmia;
echocardiography suggested cardiac amyloidosis and the diagnosis was
confirmed by multiple myocardial biopsies showing amyloid deposits in
subendocardial and perivascular areas.

.0014
FIBRINOGEN DUSART
FIBRINOGEN PARIS 5
FGA, ARG554CYS

Fibrinogen Dusart (Paris V) is a form of dysfibrinogenemia associated
with recurrent thrombosis. Koopman et al. (1993) demonstrated that the
defect was a C-to-T transition in the FGA gene, resulting in the
substitution of cysteine for arginine-554. Electron microscopic studies
on fibrin formed from purified fibrinogen Dusart demonstrated fibers
that were much thinner than in normal fibrin. The additional cysteine
created by the mutation was involved in the formation of
fibrinogen-albumin complexes in plasma; a substantial part of the
fibrinogen Dusart molecules were disulfide-linked to albumin.

Mosesson et al. (1996) found that the abnormal Dusart chains promote
'preassembly' of fibrinogen molecules and consequent increased
cross-linking potential, a phenomenon that probably plays a causal role
in the thrombophilia that is associated with this defect.

.0015
FIBRINOGEN CANTERBURY
FGA, VAL20ASP

Fibrinogen Canterbury was detected by Brennan et al. (1995) in a
45-year-old vegetarian with type III hyperlipoproteinemia (107741) which
brought him to the attention of a lipid clinic. Fibrinogen was measured
as part of the routine panel of cardiovascular risk factors. On specific
questioning, it was found that he had a tendency to prolonged bleeding,
lasting up to 15 minutes, from even minor cuts. He denied easy bruising.
Heterozygosity for a val20-to-asp mutation of the FGA gene was found.
The molar ratio of fibrinopeptide A to B released by thrombin was
substantially reduced (0.64), suggesting either impaired cleavage or
that the majority of the variant alpha-chains lacked the A peptide. The
latter novel proposal arose from the observation that the mutation
changed the normal RGPRV sequence of amino acids 16-20 to RGPRD,
creating a potential furin cleavage site at arg19. Synthetic peptides
incorporating both sequences were tested for substrates for both
thrombin and furin (136950). There was no substantial difference in the
thrombin-catalyzed cleavage however, the variant peptide, but not the
normal, was rapidly cleaved at arg19 by furin. Predictably,
intracellular cleavage of the A-alpha-chain at arg19 would remove
fibrinopeptide A together with the GPR polymerization site. This was
confirmed by sequence analysis of fibrinogen A-alpha chains after
isolation by SDS-PAGE. The expected normal sequence was detected
together with the new sequence commencing at residue 20.

.0016
AMYLOIDOSIS, FAMILIAL VISCERAL
FGA, 1-BP DEL, 4904G

In an American kindred with hereditary renal amyloidosis (105200),
Uemichi et al. (1996) found that the FGA gene had a single nucleotide
deletion at the third base of codon 524, a deletion of 4904G, that
resulted in a frameshift and premature termination of the protein at
codon 548. Antiserum was produced to a portion of the abnormal peptide
predicted by the DNA sequence and amyloid deposits were
immunohistologically proven to contain this abnormal polypeptide. Two of
the 4 children of the proposita were positive for mutant gene by RFLP
analysis based on PCR. The 2 mutant gene carriers in the second decade
of life showed no clinical symptoms of amyloidosis but had lower plasma
fibrinogen concentrations when compared with their normal sibs. Uemichi
et al. (1996) stated that this was the first description of a kindred
with renal amyloidosis and low plasma fibrinogen and the first report of
amyloidosis caused by a frameshift mutation. The proposita had onset at
age 41 years and showed no signs of involvement other than in the
kidney. She died at the age of 46 years. Her mother died at 38 years of
age and a maternal uncle died at 41 years of age, both of renal failure.
The onset of disease in the late thirties and early forties was later
than that in patients with the leu554 mutation of the FGA gene, who were
affected in their twenties or thirties, and earlier than that in
individuals with the val526 mutation of the FGA gene, who developed the
disease in the fifth through seventh decade of life. They speculated
that the abnormal fibrinogen chain in this kindred that is missing 14%
of the normal C-terminal sequence (residues 525 through 610) and has an
abnormal peptide sequence of 23 amino acid residues may be degraded much
more rapidly than the normal protein.

.0017
MOVED TO 134820.0016
.0018
AMYLOIDOSIS, FAMILIAL VISCERAL
FGA, 1-BP DEL, 4897T

Asl et al. (1997) found that a French kindred with autosomal dominant
hereditary renal amyloidosis (105200) had a novel mutation in the FGA
gene. In this kindred, renal disease appeared early in life and led to
terminal renal failure at an early age. The propositus developed
nephrotic syndrome at age 31 years; his son presented with it at age 12
years. Renal failure in the son progressed rapidly with severe
hypertension, and peritoneal dialysis was begun 1 year after the
occurrence of the nephrotic syndrome. Renal transplantation was
performed at the age of 15 years. Amyloid fibril protein isolated from
the transplanted kidney of the propositus was found to contain a novel
hybrid peptide of 49 residues whose N-terminal 23 amino acids were
identical to residues 499 to 521 of normal fibrinogen A-alpha chain. The
remaining 26 residues of the peptide represented a completely new
sequence for mammalian proteins. DNA sequencing documented that the new
sequence was the result of a single nucleotide deletion, 4897T, of the
FGA gene, creating a frameshift at codon 522 and premature termination
at codon 548. The FGA gene of the propositus's son contained the same
mutation. Liver transplantation to stop synthesis of this abnormal
liver-derived protein should be considered early in the course of this
disease.

.0019
AFIBRINOGENEMIA, CONGENITAL
FGA, 11-KB DEL

In a nonconsanguineous Swiss family with congenital afibrinogenemia
(202400), Neerman-Arbez et al. (1999) demonstrated that 4 affected males
(2 brothers and their 2 first cousins) were homozygous for a deletion of
approximately 11 kb from the FGA gene. Haplotype data suggested that
deletions occurred separately, on 3 distinct ancestral chromosomes,
implying that the FGA region is susceptible to deletion by a common
mechanism. This was said to be the first known causative mutation for
congenital afibrinogenemia.

Neerman-Arbez et al. (1999) found that all 3 deletions were identical to
the level of the basepair and probably resulted from nonhomologous
(illegitimate) recombination. The centromeric and telomeric deletion
junctions featured both a 7-bp direct repeat, AACTTTT, situated in FGA
intron 1 and in the FGA-FGB (134830) intergenic sequence, and a number
of inverted repeats that could be involved in the generation of
secondary structures. Analysis with closely linked flanking polymorphic
markers revealed the existence of at least 2 haplotypes, further
suggesting independent origins of the deletions in this family.

Neerman-Arbez et al. (2000) collected data on 13 additional unrelated
patients with congenital afibrinogenemia to identify the causative
mutations and to determine the prevalence of the 11-kb deletion. A
common recurrent mutation at the donor splice site of FGA intron 4
(IVS4G-T+1; 134820.0020) accounted for 14 of the 26 (54%) alleles. One
patient was heterozygous for the 11-kb deletion. Neerman-Arbez et al.
(2000) stated that 86% of afibrinogenemia alleles analyzed to that time
had truncating mutations of FGA, although mutations in all 3 fibrinogen
genes, FGG, FGA, and FGB, might be predicted to cause congenital
afibrinogenemia.

.0020
AFIBRINOGENEMIA, CONGENITAL
FGA, IVS4DS, G-T, +1

Neerman-Arbez et al. (2000) collected data on 13 unrelated patients with
congenital afibrinogenemia (202400). A common recurrent mutation at the
donor splice site of FGA intron 4 (IVS4G-T+1) accounted for 14 of the 26
(54%) alleles.

.0021
FIBRINOGEN NIEUWEGEIN
FGA, 1-BP INS, 453C

Collen et al. (2001) discovered fibrinogen Nieuwegein to be the cause of
congenital dysfibrinogenemia in a young man without any thromboembolic
complications or bleeding. He showed a prolonged activated partial
thrombin time, which was determined routinely before a biopsy procedure.
The abnormal fibrinogen resulted from a homozygous insertion of a single
nucleotide (C) at codon 453 (pro) of the FGA gene, resulting in deletion
of the carboxyl-terminal segment, amino acids 454-610. The ensuing
unpaired cysteine-442 generated fibrinogen-albumin complexes of
different molecular weights. Delayed clotting and a fibrin network with
a low turbidity resulted. The altered fibrin structure could not be
crosslinked by tissue transglutaminase and was less supportive for
ingrowth of endothelial cells.

.0022
MOVED TO 134820.0003
.0023
AFIBRINOGENEMIA, CONGENITAL
FGA, 1-BP INS

Vlietman et al. (2002) described congenital afibrinogenemia (202400) in
a newborn female with hemorrhagic diathesis. The pregnancy and delivery
had been uneventful. She was the first child of consanguineous parents
(first cousins). DNA analysis revealed the insertion of an extra thymine
between nucleotides 3983 and 3986 in exon 5 of FGA. The patient was
homozygous for this novel mutation. The insertion changed codon TTT
(PAG) to TAA (stop).

.0024
FIBRINOGEN KEOKUK
FGA, GLN328TER

Lefebvre et al. (2004) described a nonconsanguineous American family of
European descent in which 2 sibs with hypodysfibrinogenemia (202400) had
lifelong trauma-related bleeding. The brother had recurrent thrombosis
after cryoprecipitate infusions following surgery. The sister had 6
miscarriages. DNA analysis revealed a heterozygous CAA-to-TAA mutation
at codon 328 of the FGA gene resulting in a gln328-to-ter (Q328X) amino
acid change (fibrinogen Keokuk), which predicted a 46% truncation and
the production of a 35-kD fibrinogen A-alpha chain. The sibs and their
mother were found to be heterozygous for a second FGA mutation, a
GT-to-TT splice site mutation in intron 4 (IVS4+1G-T; 134820.0025).

.0025
HYPODYSFIBRINOGENEMIA, CONGENITAL
FGA, IVS4DS, G-T, +1

See 134820.0024 and Lefebvre et al. (2004).

.0026
VENOUS THROMBOEMBOLISM, SUSCEPTIBILITY TO
FGA, THR312ALA

Among 122 patients with deep venous thrombosis and 99 patients with
pulmonary embolism (see 188050), Carter et al. (2000) found an
association between a 4266A-G transition in the FGA gene, resulting in a
thr312-to-ala (T312A) substitution, and the development of pulmonary
embolism. Homozygosity for the ala312 allele conferred an odds ratio of
2.71 compared to homozygosity for the thr312 allele. No association was
found for venous thrombosis. The T312A polymorphism occurs close to the
alpha-fibrin/alpha-fibrin cross-linking site, which may influence the
strength of cross-linking in clots.

In a case-control study of 186 Taiwanese patients with venous
thromboembolism, Ko et al. (2006) observed an association between venous
thromboembolism and the ala312 allele. An FGA haplotype containing the
ala312 allele was also associated with venous thromboembolism, although
controls with the haplotype did not have increased plasma fibrinogen
levels.

*FIELD* SA
Aznar et al. (1974); Barthels and Sandvoss (1977); Beck et al. (1971);
Branson et al. (1977); Crabtree and Kant (1981); Crum et al. (1974);
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al. (1977); Funk and Straub (1970); Godal et al. (1978); Gralnick
et al. (1979); Gralnick et al. (1972); Gralnick et al. (1971); Hampton
and Garrison (1972); Hampton et al. (1971); Hasselback et al. (1963);
Jackson et al. (1965); Jandrot-Perrus et al. (1982); Kudryk et al.
(1976); Marder and Budzynski (1974); McDonagh et al. (1980); Menache
(1964); Neerman-Arbez et al. (1999); Samama et al. (1969); Soria et
al. (1983); Streiff et al. (1971); Uemichi et al. (1996); Verhaeghe
et al. (1974); Verstraete (1970); Winckelmann et al. (1971); Zietz
and Scott (1970)
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Society on Thrombosis and Haemostasis. Oslo: Villco Trykkeri (pub.)
1972.

44. Gralnick, H. R.; Givelber, H. M.; Shainoff, J. R.; Finlayson,
J. S.: Fibrinogen Bethesda: a congenital dysfibrinogenemia with delayed
fibrinopeptide release. J. Clin. Invest. 50: 1819-1830, 1971.

45. Hampton, J. W.; Garrison, M. S.: Fibrinogen and fibrin-stabilizing
factor. Med. Clin. N. Am. 56: 133-143, 1972.

46. Hampton, J. W.; Morton, R. O.; Bannerjee, D.; Kalmaz, E.: Defective
fibrin cross-linkages: a genetic and biochemical study of three families.
(Abstract) J. Clin. Invest. 50: 42A only, 1971.

47. Hamsten, A.; Iselius, L.; de Faire, U.; Blomback, M.: Genetic
and cultural inheritance of plasma fibrinogen concentration. Lancet 330:
988-990, 1987. Note: Originally Volume II.

48. Hanss, M.; Biot, F.: A database for human fibrinogen variants. Ann.
New York Acad. Sci. 936: 89-90, 2001.

49. Hasselback, R.; Marion, R. B.; Thomas, J. W.: Congenital hypofibrinogenemia
in five members of a family. Canad. Med. Assoc. J. 88: 19-22, 1963.

50. Henry, I.; Uzan, G.; Weil, D.; Nicolas, H.; Kaplan, J. C.; Marguerie,
C.; Kahn, A.; Junien, C.: The genes coding for A-alpha-, B-beta-,
and gamma-chains of fibrinogen map to 4q2. Am. J. Hum. Genet. 36:
760-768, 1984.

51. Henschen, A.; Kehl, M.; Deutsch, E.: Novel structure elucidation
strategy for genetically abnormal fibrinogens with incomplete fibrinopeptide
release as applied to fibrinogen Schwarzach. Hoppe Seylers Z. Physiol.
Chem. 364: 1747-1751, 1983.

52. Henschen, A.; Southan, C.; Soria, J.; Soria, C.; Samama, M.:
Structure abnormality of fibrinogen Metz and its relation to the clotting
defect. (Abstract) Thromb. Haemost. 45: 103 only, 1981.

53. Higgins, D. L.; Shafer, J. A.: Fibrinogen Petoskey, a dysfibrinogenemia
characterized by replacement of arg-A(alpha)16 by a histidyl residue:
evidence for thrombin-catalyzed hydrolysis at a histidyl residue. J.
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54. Humphries, S. E.; Imam, A. M. A.; Robbins, T. P.; Cook, M.; Carritt,
B.; Ingle, C.; Williamson, R.: The identification of a DNA polymorphism
of the alpha fibrinogen gene, and the regional assignment of the human
fibrinogen genes to 4q26-qter. Hum. Genet. 68: 148-153, 1984.

55. Imperato, C.; Dettori, A. G.: Ipofibrinogenemia congenita con
fibrinoastenia. Helv. Paediat. Acta 13: 380-399, 1958.

56. Jackson, D. P.; Beck, E. A.; Charache, P.: Congenital disorders
of fibrinogen. Fed. Proc. 24: 816-821, 1965.

57. Jandrot-Perrus, M.; Aurousseau, M.-H.; Rabiet, M.-J.; Josso, F.
: Fibrinogen Bondy: a new case of dysfibrinogenemia. Isolation of
the abnormal fibrinogen molecules. Thromb. Res. 27: 659-670, 1982.

58. Kant, J. A.; Crabtree, G. R.: The rat fibrinogen genes: linkage
of the A-alpha and gamma chain genes. J. Biol. Chem. 258: 4666-4667,
1983.

59. Kant, J. A.; Fornace, A. J., Jr.; Saxe, D.; Simon, M. I.; McBride,
O. W.; Crabtree, G. R.: Evolution and organization of the fibrinogen
locus on chromosome 4: gene duplication accompanied by transposition
and inversion. Proc. Nat. Acad. Sci. 82: 2344-2348, 1985.

60. Ko, Y.-L.; Hsu, L.-A.; Hsu, T.-S.; Tsai, C.-T.; Teng, M.-S.; Wu,
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61. Kohn, P. H.; Cruz, A. C.; Kitchens, C. S.: Autosomal dominant
hypofibrinogenemia associated with a balanced 7p/12q translocation
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only, 1983.

62. Koopman, J.; Haverkate, F.; Grimbergen, J.; Egbring, R.; Lord,
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63. Koopman, J.; Haverkate, F.; Grimbergen, J.; Lord, S. T.; Mosesson,
M. W.; DiOrio, J. P.; Siebenlist, K. S.; Legrand, C.; Soria, J.; Soria,
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64. Kudryk, B.; Blomback, B.; Blomback, M.: Fibrinogen Detroit--an
abnormal fibrinogen with nonfunctional NH(2)-terminal polymerization
domain. Thromb. Res. 9: 25-36, 1976.

65. Lachmann, H. J.; Chir, B.; Booth, D. R.; Booth, S. E.; Bybee,
A.; Gilbertson, J. A.; Gillmore, J. D.; Pepys, M. B.; Hawkins, P.
N.: Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New
Eng. J. Med. 346: 1786-1791, 2002.

66. Lee, M. H.; Kaczmarek, E.; Chin, D. T.; Oda, A.; McIntosh, S.;
Bauer, K. A.; Clyne, L. P.; McDonagh, J.: Fibrinogen Ledyard (A-alpha
arg16-to-cys): biochemical and physiologic characterization. Blood 78:
1744-1752, 1991.

67. Lefebvre, P.; Velasco, P. T.; Dear, A.; Lounes, K. C.; Lord, S.
T.; Brennan, S. O.; Green, D.; Lorand, L.: Severe hypodysfibrinogenemia
in compound heterozygotes of the fibrinogen A-alpha-IVS4+1G-T mutation
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2571-2576, 2004.

68. Maekawa, H.; Yamazumi, K.; Muramatsu, S.; Kaneko, M.; Hirata,
H.; Takahashi, N.; Arocha-Pinango, C. L.; Rodriguez, S.; Nagy, H.;
Perez-Requejo, J. L.; Matsuda, M.: Fibrinogen Lima: a homozygous
dysfibrinogen with an A-alpha-arginine141-to-serine substitution associated
with extra N-glycosylation at A-alpha-asparagine-139--impaired fibrin
gel formation but normal fibrin-facilitated plasminogen activation
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67-76, 1992.

69. Maekawa, H.; Yamazumi, K.; Muramatsu, S.; Kaneko, M.; Hirata,
H.; Takahashi, N.; de Bosch, N. B.; Carvajal, Z.; Ojeda, A.; Arocha-Pinango,
C. L.; Matsuda, M.: An A-alpha ser-434 to N-glycosylated asn substitution
in a dysfibrinogen, fibrinogen Caracas II, characterized by impaired
fibrin gel formation. J. Biol. Chem. 266: 11575-11581, 1991.

70. Mammen, E. F.; Prasad, A. S.; Barnhart, M. I.; Au, C. C.: Congenital
dysfibrinogenemia: fibrinogen Detroit. J. Clin. Invest. 48: 235-249,
1969.

71. Marder, V. J.; Budzynski, A. Z.: Fibrinogen and its derivatives,
hereditary and acquired abnormalities. Schweiz. Med. Wschr. 104:
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72. Marino, M. W.; Fuller, G. M.; Elder, F. F. B.: Chromosomal localization
of human and rat A-alpha, B-beta, and gamma fibrinogen genes by in
situ hybridization. Cytogenet. Cell Genet. 42: 36-41, 1986.

73. Martinez, J.; Holburn, R. R.; Shapiro, S.; Erslev, A. J.: A hereditary
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74. McDonagh, R. P.; Carrell, N. A.; Roberts, H. R.; Blatt, P. M.;
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a tertiary polymerization defect. Am. J. Hemat. 9: 23-38, 1980.

75. Menache, D.: Dysfibrinogenemie constitutionnelle et familiale.
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76. Menache, D.: Constitutional and familial abnormal fibrinogen. Thromb.
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77. Miyashita, C.; Schwamborn, J.; von Blohn, G.; Wenzel, E.; Hellstern,
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78. Miyata, T.; Terukina, S.; Matsuda, M.; Kasamatsu, A.; Takeda,
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amino acid substitution of A alpha arginine-16 to cysteine which forms
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79. Morris, S.; Denninger, M. H.; Finlayson, J. S.; Menache, D.:
Fibrinogen Lille: A (alpha) 7 asp-to-asn. (Abstract) Thromb. Haemost. 46:
104 only, 1981.

80. Mosesson, M. W.; Siebenlist, K. R.; Hainfeld, J. F.; Wall, J.
S.; Soria, J.; Soria, C.; Caen, J. P.: The relationship between the
fibrinogen D domain self-association/cross-linking site (gamma-XL)
and the fibrinogen Dusart abnormality (A-alpha R554C-albumin): clues
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2342-2350, 1996. Note: Erratum: J. Clin. Invest. 98: 239 only, 1996.

81. Mourad, G.; Delabre, J.-P.; Garrigue, V.: Cardiac amyloidosis
with the E526V mutation of the fibrinogen A alpha-chain. (Letter) New
Eng. J. Med. 359: 2847-2848, 2008.

82. Neerman-Arbez, M.; Antonarakis, S. E.; Honsberger, A.; Morris,
M. A.: The 11 kb FGA deletion responsible for congenital afibrinogenaemia
is mediated by a short direct repeat in the fibrinogen gene cluster. Europ.
J. Hum. Genet. 7: 897-902, 1999.

83. Neerman-Arbez, M.; de Moerloose, P.; Bridel, C.; Honsberger, A.;
Schonborner, A.; Rossier, C.; Peerlinck, K.; Claeyssens, S.; Di Michele,
D.; d'Oiron, R.; Dreyfus, M.; Laubriat-Bianchin, M.; Dieval, J.; Antonarakis,
S. E.; Morris, M. A.: Mutations in the fibrinogen A-alpha gene account
for the majority of cases of congenital afibrinogenemia. Blood 96:
149-152, 2000.

84. Neerman-Arbez, M.; Honsberger, A.; Antonarakis, S. E.; Morris,
M. A.: Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital
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85. Olaisen, B.; Teisberg, P.; Gedde-Dahl, T., Jr.: Fibrinogen gamma
chain locus is on chromosome 4 in man. Hum. Genet. 61: 24-26, 1982.

86. Qureshi, G. D.; Evans, H. J.; Vennart, R. M.; Magnant, J. P.;
Sabau, J. M.; Willoughby, J. B.; Koehn, J. A.: Fibrinogen White Marsh--a
new human fibrinogen variant with alpha chain defect. (Abstract) Clin.
Res. 31: 321A only, 1983.

87. Ratnoff, O. D.; Bennett, B.: The genetics of hereditary disorders
of blood coagulation. Science 179: 1291-1298, 1973.

88. Reber, P.; Furlan, M.; Beck, E. A.; Barbui, T.: Fibrinogen Bergamo
III and fibrinogen Torino: two further variants with hereditary molecular
defects in fibrinopeptide A. Thromb. Res. 46: 163-167, 1987.

89. Reber, P.; Furlan, M.; Beck, E. A.; Finazzi, G.; Buelli, M.; Barbui,
T.: Fibrinogen Bergamo I (A alpha 16 arg-to-cys): susceptibility
towards thrombin following aminoethylation, methylation or carboxamidomethylation
of cysteine residues. Thromb. Haemost. 54: 390-393, 1985.

90. Rupp, C.; Beck, E. A.: Congenital dysfibrinogenemia.In: Beck,
E. A.; Furlan, M.: Variants of Human Fibrinogen. Berne: Hans Huber
(pub.) 1984. Pp. 65-130.

91. Samama, M.; Soria, J.; Soria, C.; Bousser, J.: Dysfibrinogenemie
congenitale et familiale sans tendance hemorragique. Nouv. Rev. Franc.
Hemat. 9: 817-832, 1969.

92. Siebenlist, K. R.; Prchal, J. T.; Mosesson, M. W.: Fibrinogen
Birmingham: a heterozygous dysfibrinogenemia (A alpha 16 arg-to-his)
containing heterodimeric molecules. Blood 71: 613-618, 1988.

93. Soria, J.; Soria, C.; Bertrand, O.; Dunn, F.; Drouet, L.; Caen,
J. P.: Plasminogen Paris I: congenital abnormal plasminogen and its
incidence in thrombosis. Thromb. Res. 32: 229-238, 1983.

94. Soria, J.; Soria, C.; Hedner, U.; Nilsson, I. M.; Bergqvist, D.;
Samama, M.: Episodes of increased fibronectin level observed in a
patient suffering from recurrent thrombosis related to congenital
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727-738, 1985.

95. Soria, J.; Soria, C.; Samama, M.; Poirot, E.; Kling, C.: Fibrinogen
Troyes-fibrinogen Metz: two new cases of congenital dysfibrinogenemia. Thromb.
Diath. Haemorrh. 27: 619-633, 1972.

96. Southan, C.; Henschen, A.; Lottspeich, F.: The search for molecular
defects in abnormal fibrinogens.In: Henschen, A.; Graeff, H.; Lottspeich,
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W. de Gruyter (pub.) 1982. Pp. 153-166.

97. Southan, C.; Lane, D. A.; Knight, I.; Ireland, H.; Bottomley,
J.: Fibrinogen Manchester: detection of a heterozygous phenotype
in the intraplatelet pool. Biochem. J. 229: 723-730, 1985.

98. Streiff, F.; Alexandre, P.; Vigneron, C.; Soria, J.; Soria, C.;
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565-576, 1971.

99. Suh, T. T.; Holmback, K.; Jensen, N. J.; Daugherty, C. C.; Small,
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Dev. 9: 2020-2033, 1995.

100. Thomas, A.; Lamlum, H.; Humphries, S.; Green, F.: Linkage disequilibrium
across the fibrinogen locus as shown by five genetic polymorphisms,
G/A(-455) (HaeIII), C/T(-148) (HindIII/AluI), T/G(+1689) (AvaII),
and BclI (beta-fibrinogen) and TaqI (alpha-fibrinogen), and their
detection by PCR. Hum. Mutat. 3: 79-81, 1994.

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The molecular basis of renal amyloidosis in Irish-American and Polish-Canadian
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102. Uemichi, T.; Liepnieks, J. J.; Benson, M. D.: Fibrinogen Indianapolis:
a fibrinogen A-alpha chain associated with hereditary amyloidosis.
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731-736, 1994.

104. Uemichi, T.; Liepnieks, J. J.; Yamada, T.; Gertz, M. A.; Bang,
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1996.

105. Uemichi, T.; Liepnieks, J. J.; Yamada, T.; Gertz, M. A.; Bang,
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1996.

106. Uzan, G.; Besmond, C.; Kahn, A.; Marguerie, G.: Cell free translation
of messenger RNA for human fibrinogen. Biochem. Int. 4: 271-278,
1982.

107. Uzan, G.; Courtois, G.; Besmond, C.; Frain, M.; Sala-Trepat,
J.; Kahn, A.; Marguerie, G.: Analysis of fibrinogen genes in patients
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376-383, 1984.

108. Verhaeghe, R.; Verstraete, M.; Vermylen, J.; Vermylen, C.: Fibrinogen
'Leuven', another genetic variant. Brit. J. Haemat. 26: 421-434,
1974.

109. Verstraete, M.: Discussion. Thromb. Diath. Haemorrh. 39 (suppl.):
334-337, 1970.

110. Vlietman, J. J.; Verhage, J.; Vos, H. L.; van Wijk, R.; Remijn,
J. A.; van Solinge, W. W.; Brus, F.: Congenital afibrinogenaemia
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113. Wehinger, H.; Klinge, O.; Alexandrakis, E.; Schurmann, J.; Witt,
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114. Winckelmann, G.; Augustin, R.; Bandilla, K.: Congenital dysfibrinogenemia:
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179 only, 1970.

*FIELD* CN
Marla J. F. O'Neill - updated: 1/8/2009
Victor A. McKusick - updated: 9/19/2006
Cassandra L. Kniffin - updated: 5/17/2006
Victor A. McKusick - updated: 9/17/2004
Victor A. McKusick - updated: 10/20/2003
Dawn Watkins-Chow - updated: 11/15/2002
Victor A. McKusick - updated: 6/10/2002
Victor A. McKusick - updated: 2/15/2002
Victor A. McKusick - updated: 10/9/2001
Victor A. McKusick - updated: 8/7/2001
Victor A. McKusick - updated: 4/3/2001
Victor A. McKusick - updated: 9/27/2000
Victor A. McKusick - updated: 2/9/2000
Victor A. McKusick - updated: 3/16/1999
Victor A. McKusick - updated: 4/13/1998
Victor A. McKusick - updated: 3/26/1998
Alan F. Scott - updated: 2/12/1996

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

*FIELD* ED
terry: 12/20/2012
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mgross: 3/17/2004
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carol: 9/10/1993

MIM 202400
*RECORD*
*FIELD* NO
202400
*FIELD* TI
#202400 AFIBRINOGENEMIA, CONGENITAL
HYPOFIBRINOGENEMIA, CONGENITAL, INCLUDED;;
DYSFIBRINOGENEMIA, CONGENITAL, INCLUDED;;
read moreHYPODYSFIBRINOGENEMIA, CONGENITAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is the
result of mutation in one or another of the 3 fibrinogen genes, alpha
(FGA; 134820), beta (FGB; 134830), or gamma (FGG; 134850). Complete
absence of detectable fibrinogen, true congenital afibrinogenemia, was
first demonstrated to be due to a deletion in the FGA gene
(134820.0019). The phenotype has also been associated with missense
mutations in the FGB gene (134830.0009, 134830.0010) that result in
impaired fibrinogen secretion and with mutations in the FGG gene
(134850.0016-134850.0017).

Lefebvre et al. (2004) noted that fibrinogen abnormalities can be
classified according to whether there are low or no circulating levels
of normal protein (hypofibrinogenemia or afibrinogenemia), a mutated
species (dysfibrinogenemia), or a combination (hypodysfibrinogenemia).
Reports (e.g., Haverkate and Samama, 1995) on approximately 350 families
with dysfibrinogenemia revealed that approximately half of cases are
clinically silent, a quarter show a tendency toward bleeding, and
another quarter show a predisposition for thrombosis with or without
bleeding.

Although relatively few cases of congenital afibrinogenemia have been
reported, the high proportion with consanguineous parents and/or
affected sibs makes recessive inheritance very likely. The blood is
completely incoagulable, yet some of the affected persons have
remarkably little trouble with bleeding. In some cases the disorder was
detected at birth because of excess bleeding from the umbilical stump. A
partial deficiency of fibrinogen has been observed in parents and other
heterozygotes. In 2 brothers reported by Lemoine et al. (1963)
congenital afibrinogenemia was associated with osseous and hepatic
lesions, thought to be of hemorrhagic origin. In several Jewish
communities in Israel, the rate of consanguinity and particularly of
uncle-niece marriages is unusually high. Fried and Kaufman (1980)
studied an Iraqi Jewish sibship and a Moroccan Jewish kindred in which
10 of 27 sibs had congenital afibrinogenemia. Death occurred in 6 in
childhood. Two affected sibs were young women. Two died as neonates from
uncontrollable bleeding. Two of the survivors had suffered spontaneous
rupture of the spleen. Fitness seemed to be close to zero. Neerman-Arbez
et al. (1999) reported that patients with afibrinogenemia respond well
to fibrinogen replacement therapy, either prophylactically or on demand.

Neerman-Arbez et al. (2000) pointed out that the overwhelming majority
of cases of afibrinogenemia are due to truncating mutations of the FGA
gene. One of these mutations is a recurrent deletion of approximately 11
kb that probably results from a nonhomologous recombination mediated by
7-bp direct repeats; see 134820.0019. Another common recurrent mutation
occurs at the donor splice site of FGA intron 4 (134820.0020).

*FIELD* SA
Barbui et al. (1972); Bommer et al. (1963); Bronnimann (1954); Egbring
et al. (1971); Elseed and Karrar (1984); Girolami et al. (1971); Lawson
(1953); Montgomery and Natelson (1977); Neerman-Arbez et al. (2001);
Prichard and Vann (1954); Werder (1963)
*FIELD* RF
1. Barbui, T.; Porciello, P. I.; Dini, E.: Coagulation studies in
a case of severe congenital hypofibrinogenemia. Thromb. Diath. Haemorrh. 28:
129-134, 1972.

2. Bommer, W.; Kunzer, W.; Schroer, H.: Kongenitale Afibrinogenaemie. Ann.
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*FIELD* CS

Abdomen:
Splenic rupture

Heme:
Blood completely incoagulable;
Bleeding mild to severe;
Osseous hemorrhage;
Hepatic hemorrhage

Lab:
Afibrinogenemia

Inheritance:
Autosomal recessive

*FIELD* CN
Anne M. Stumpf - updated: 9/20/2004
Victor A. McKusick - updated: 4/6/2001
Victor A. McKusick - updated: 9/27/2000
Victor A. McKusick - updated: 7/13/2000
Victor A. McKusick - updated: 3/16/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 12/17/2012
alopez: 9/20/2004
mcapotos: 4/16/2001
mcapotos: 4/9/2001
terry: 4/6/2001
mcapotos: 10/12/2000
mcapotos: 10/10/2000
terry: 9/27/2000
alopez: 7/21/2000
terry: 7/13/2000
carol: 3/16/1999
terry: 3/16/1999
mimadm: 11/12/1995
supermim: 3/16/1992
carol: 1/17/1992
supermim: 3/20/1990
supermim: 2/8/1990
carol: 2/5/1990