RBCC Red Blood Cell Collection

FGB [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Fibrinogen beta chain; Fibrinopeptide B; Fibrinogen beta chain; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02675
ID FIBB_HUMAN Reviewed; 491 AA.
AC P02675; B2R7G3; Q3KPF2;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1993, sequence version 2.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Fibrinogen beta chain;
DE Contains:
DE RecName: Full=Fibrinopeptide B;
DE Contains:
DE RecName: Full=Fibrinogen beta chain;
DE Flags: Precursor;
GN Name=FGB;
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 / MRNA].
RX PubMed=6688356; DOI=10.1021/bi00282a032;
RA Chung D.W., Que B.G., Rixon M.W., Mace M. Jr., Davie E.W.;
RT "Characterization of complementary deoxyribonucleic acid and genomic
RT deoxyribonucleic acid for the beta chain of human fibrinogen.";
RL Biochemistry 22:3244-3250(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
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 [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Chung D.W., Harris J.E., Davie E.W.;
RT "Nucleotide sequences of the three genes coding for human
RT fibrinogen.";
RL (In) Liu C.Y., Chien S. (eds.);
RL Fibrinogen, thrombosis, coagulation and fibrinolysis, pp.39-48, Plenum
RL Press, New York (1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-100; HIS-170;
RP LEU-265 AND LYS-478.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
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 [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-60.
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 [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-38.
RX PubMed=3029722; DOI=10.1093/nar/15.4.1615;
RA Huber P., Dalmon J., Courtois G., Laurent M., Assouline Z.,
RA Marguerie G.;
RT "Characterization of the 5'-flanking region for the human fibrinogen
RT beta gene.";
RL Nucleic Acids Res. 15:1615-1625(1987).
RN [10]
RP PROTEIN SEQUENCE OF 31-491.
RX PubMed=420779; DOI=10.1021/bi00568a011;
RA Watt K.W.K., Takagi T., Doolittle R.F.;
RT "Amino acid sequence of the beta chain of human fibrinogen.";
RL Biochemistry 18:68-76(1979).
RN [11]
RP PROTEIN SEQUENCE OF 31-491, AND GLYCOSYLATION AT ASN-394.
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 [12]
RP PROTEIN SEQUENCE OF 31-148, AND 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 [13]
RP PROTEIN SEQUENCE OF 31-44.
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 [14]
RP PROTEIN SEQUENCE OF 45-53.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [15]
RP PROTEIN SEQUENCE OF 54-72; 164-178 AND 225-239, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [16]
RP REVIEW, AND DISULFIDE BONDS.
RX PubMed=6575689; DOI=10.1111/j.1749-6632.1983.tb23232.x;
RA Henschen A., Lottspeich F., Kehl M., Southan C.;
RT "Covalent structure of fibrinogen.";
RL Ann. N. Y. Acad. Sci. 408:28-43(1983).
RN [17]
RP DISULFIDE BONDS.
RX PubMed=891553; DOI=10.1111/j.1432-1033.1977.tb11704.x;
RA Gaardlund B., Hessel B., Marguerie G., Murano G., Blombaeck B.;
RT "Primary structure of human fibrinogen. Characterization of disulfide-
RT containing cyanogen-bromide fragments.";
RL Eur. J. Biochem. 77:595-610(1977).
RN [18]
RP DISULFIDE BONDS.
RA Doolittle R.F., Takagi T., Watt K.W.K., Bouma H. III, Cottrell B.A.,
RA Cassman K.G., Goldbaum D.M., Doolittle L.R., Friezner S.J.;
RT "The structures of fibrinogen and fibrin.";
RL (In) Magnusson S., Ottesen M., Foltmann B., Dano K., Neurath H.
RL (eds.);
RL Regulatory proteolytic enzymes and their inhibitors, pp.163-172,
RL Pergamon Press, New York (1978).
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 INTERACTION WITH FBLN1.
RX PubMed=7642629; DOI=10.1074/jbc.270.33.19458;
RA Tran H., Tanaka A., Litvinovich S.V., Medved L.V., Haudenschild C.C.,
RA Argraves W.S.;
RT "The interaction of fibulin-1 with fibrinogen. A potential role in
RT hemostasis and thrombosis.";
RL J. Biol. Chem. 270:19458-19464(1995).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-394, 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 [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [23]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-394, 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 [24]
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 [25]
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 [26]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 164-491.
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 [27]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 164-491.
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 [28]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 164-491.
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 [29]
RP VARIANT BALTIMORE-2 LYS-478.
RX PubMed=3194892; DOI=10.1016/0049-3848(88)90096-5;
RA Schmelzer C.H., Ebert R.F., Bell W.R.;
RT "A polymorphism at B beta 448 of fibrinogen identified during
RT structural studies of fibrinogen Baltimore II.";
RL Thromb. Res. 52:173-177(1988).
RN [30]
RP VARIANT ISE ARG-45.
RX PubMed=2018836;
RA Yoshida N., Wada H., Morita K., Hirata H., Matsuda M., Yamazumi K.,
RA Asakura S., Shirakawa S.;
RT "A new congenital abnormal fibrinogen Ise characterized by the
RT replacement of B beta glycine-15 by cysteine.";
RL Blood 77:1958-1963(1991).
RN [31]
RP VARIANT NAPLES THR-98.
RX PubMed=1634610; DOI=10.1172/JCI115841;
RA Koopman J., Haverkate F., Lord S.T., Grimbergen J., Mannucci P.M.;
RT "Molecular basis of fibrinogen Naples associated with defective
RT thrombin binding and thrombophilia. Homozygous substitution of B beta
RT 68 Ala-->Thr.";
RL J. Clin. Invest. 90:238-244(1992).
RN [32]
RP VARIANTS IJMUIDEN CYS-44 AND NIJMEGEN CYS-74.
RX PubMed=1565641; DOI=10.1073/pnas.89.8.3478;
RA Koopman J., Haverkate F., Grimbergen J., Engesser L., Novakova I.,
RA Kerst A.F.J.A., Lord S.T.;
RT "Abnormal fibrinogens IJmuiden (B beta Arg14-->Cys) and Nijmegen (B
RT beta Arg44-->Cys) form disulfide-linked fibrinogen-albumin
RT complexes.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:3478-3482(1992).
RN [33]
RP VARIANT NEW YORK-1 39-GLY--LEU-102 DEL.
RX PubMed=3156856;
RA Liu C.Y., Koehn J.A., Morgan F.J.;
RT "Characterization of fibrinogen New York 1. A dysfunctional fibrinogen
RT with a deletion of B beta(9-72) corresponding exactly to exon 2 of the
RT gene.";
RL J. Biol. Chem. 260:4390-4396(1985).
RN [34]
RP VARIANTS GLU-2; LEU-265 AND LYS-478.
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 [35]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [36]
RP VARIANTS CONGENITAL AFIBRINOGENEMIA ARG-383 AND ASP-430.
RX PubMed=10666208;
RA Duga S., Asselta R., Santagostino E., Zeinali S., Simonic T.,
RA Malcovati M., Mannucci P.M., Tenchini M.L.;
RT "Missense mutations in the human beta fibrinogen gene cause congenital
RT afibrinogenemia by impairing fibrinogen secretion.";
RL Blood 95:1336-1341(2000).
RN [37]
RP VARIANT CONGENITAL AFIBRINOGENEMIA CYS-196.
RX PubMed=11468164; DOI=10.1182/blood.V98.3.661;
RA Lounes K.C., Lefkowitz J.B., Henschen-Edman A.H., Coates A.I.,
RA Hantgan R.R., Lord S.T.;
RT "The impaired polymerization of fibrinogen Longmont
RT (Bbeta166Arg-->Cys) is not improved by removal of disulfide-linked
RT dimers from a mixture of dimers and cysteine-linked monomers.";
RL Blood 98:661-666(2001).
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 (By similarity).
CC -!- INTERACTION:
CC P27958:- (xeno); NbExp=4; IntAct=EBI-1034445, EBI-6377335;
CC -!- SUBCELLULAR LOCATION: Secreted.
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: 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 -!- 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 Patients with congenital fibrinogen abnormalities can manifest
CC different clinical pictures. Some cases are clinically silent,
CC some show a tendency toward bleeding and some show a
CC predisposition for thrombosis with or without bleeding.
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/FGB";
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;=FGB";
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/fgb/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J00129; AAA52429.1; -; mRNA.
DR EMBL; J00131; AAA98115.1; -; Genomic_DNA.
DR EMBL; J00130; AAA98115.1; JOINED; Genomic_DNA.
DR EMBL; J00132; AAA98116.1; -; Genomic_DNA.
DR EMBL; J00133; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; M64983; AAA18024.2; -; Genomic_DNA.
DR EMBL; AF388026; AAK62470.1; -; Genomic_DNA.
DR EMBL; AK312972; BAG35810.1; -; mRNA.
DR EMBL; CH471056; EAX04932.1; -; Genomic_DNA.
DR EMBL; BC106760; AAI06761.1; -; mRNA.
DR EMBL; AH002694; AAA52445.1; -; Genomic_DNA.
DR EMBL; X05018; CAA28674.1; -; Genomic_DNA.
DR PIR; B43568; FGHUB.
DR RefSeq; NP_001171670.1; NM_001184741.1.
DR RefSeq; NP_005132.2; NM_005141.4.
DR UniGene; Hs.300774; -.
DR PDB; 1FZA; X-ray; 2.90 A; B/E=164-491.
DR PDB; 1FZB; X-ray; 2.90 A; B/E=164-491.
DR PDB; 1FZC; X-ray; 2.30 A; B/E=164-491.
DR PDB; 1FZE; X-ray; 3.00 A; B/E=164-491.
DR PDB; 1FZF; X-ray; 2.70 A; B/E=164-491, M/N/S/T=45-48.
DR PDB; 1FZG; X-ray; 2.50 A; B/E=164-491, M/N/S/T=45-48.
DR PDB; 1LT9; X-ray; 2.80 A; B/E=179-491.
DR PDB; 1LTJ; X-ray; 2.80 A; B/E=179-491.
DR PDB; 1N86; X-ray; 3.20 A; B/E=164-491, I/J=45-51.
DR PDB; 1N8E; X-ray; 4.50 A; B/E=164-491.
DR PDB; 1RE3; X-ray; 2.45 A; B/E=179-491.
DR PDB; 1RE4; X-ray; 2.70 A; B/E=179-491.
DR PDB; 1RF0; X-ray; 2.81 A; B/E=179-491.
DR PDB; 1RF1; X-ray; 2.53 A; B/E=179-491.
DR PDB; 2A45; X-ray; 3.65 A; H/K=45-135.
DR PDB; 2FFD; X-ray; 2.89 A; B/E=179-491.
DR PDB; 2H43; X-ray; 2.70 A; B/E=164-491.
DR PDB; 2HLO; X-ray; 2.60 A; B/E=164-491.
DR PDB; 2HOD; X-ray; 2.90 A; B/E/H/K=164-491.
DR PDB; 2HPC; X-ray; 2.90 A; B/E/H/K=164-491.
DR PDB; 2OYH; X-ray; 2.40 A; B/E=179-491.
DR PDB; 2OYI; X-ray; 2.70 A; B/E=179-491.
DR PDB; 2Q9I; X-ray; 2.80 A; B/E=164-491.
DR PDB; 2XNX; X-ray; 3.30 A; B/E/H/K=164-491.
DR PDB; 2XNY; X-ray; 7.50 A; B/E=164-491.
DR PDB; 2Z4E; X-ray; 2.70 A; B/E=164-489.
DR PDB; 3BVH; X-ray; 2.60 A; B/E=191-488.
DR PDB; 3E1I; X-ray; 2.30 A; B/E=164-491.
DR PDB; 3GHG; X-ray; 2.90 A; B/E/H/K=31-491.
DR PDB; 3H32; X-ray; 3.60 A; B/E=31-488.
DR PDB; 3HUS; X-ray; 3.04 A; B/E=179-491.
DR PDBsum; 1FZA; -.
DR PDBsum; 1FZB; -.
DR PDBsum; 1FZC; -.
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; 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; 3BVH; -.
DR PDBsum; 3E1I; -.
DR PDBsum; 3GHG; -.
DR PDBsum; 3H32; -.
DR PDBsum; 3HUS; -.
DR ProteinModelPortal; P02675; -.
DR SMR; P02675; 88-488.
DR DIP; DIP-385N; -.
DR IntAct; P02675; 15.
DR STRING; 9606.ENSP00000306099; -.
DR BindingDB; P02675; -.
DR ChEMBL; CHEMBL2364709; -.
DR DrugBank; DB00364; Sucralfate.
DR PhosphoSite; P02675; -.
DR DMDM; 399492; -.
DR DOSAC-COBS-2DPAGE; P02675; -.
DR OGP; P02675; -.
DR REPRODUCTION-2DPAGE; IPI00298497; -.
DR REPRODUCTION-2DPAGE; P02675; -.
DR SWISS-2DPAGE; P02675; -.
DR UCD-2DPAGE; P02675; -.
DR PaxDb; P02675; -.
DR PeptideAtlas; P02675; -.
DR PRIDE; P02675; -.
DR Ensembl; ENST00000302068; ENSP00000306099; ENSG00000171564.
DR GeneID; 2244; -.
DR KEGG; hsa:2244; -.
DR UCSC; uc003ioa.4; human.
DR CTD; 2244; -.
DR GeneCards; GC04P155484; -.
DR HGNC; HGNC:3662; FGB.
DR HPA; CAB008624; -.
DR HPA; HPA001900; -.
DR HPA; HPA001901; -.
DR MIM; 134830; gene.
DR MIM; 202400; phenotype.
DR neXtProt; NX_P02675; -.
DR Orphanet; 98880; Familial afibrinogenemia.
DR Orphanet; 98881; Familial dysfibrinogenemia.
DR Orphanet; 248408; Familial hypodysfibrinogenemia.
DR Orphanet; 101041; Familial hypofibrinogenemia.
DR PharmGKB; PA163; -.
DR eggNOG; NOG277105; -.
DR HOGENOM; HOG000059561; -.
DR HOVERGEN; HBG005707; -.
DR InParanoid; P02675; -.
DR KO; K03904; -.
DR OMA; TIHNGMF; -.
DR OrthoDB; EOG7X9G60; -.
DR PhylomeDB; P02675; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; FGB; human.
DR EvolutionaryTrace; P02675; -.
DR GeneWiki; Fibrinogen_beta_chain; -.
DR GenomeRNAi; 2244; -.
DR NextBio; 9079; -.
DR PMAP-CutDB; P02675; -.
DR PRO; PR:P02675; -.
DR ArrayExpress; P02675; -.
DR Bgee; P02675; -.
DR CleanEx; HS_FGB; -.
DR Genevestigator; P02675; -.
DR GO; GO:0072562; C:blood microparticle; IEA:Ensembl.
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; IPR020837; Fibrinogen_CS.
DR Pfam; PF08702; Fib_alpha; 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; Blood coagulation; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hemostasis; Polymorphism; Pyrrolidone carboxylic acid;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1 30
FT PEPTIDE 31 44 Fibrinopeptide B.
FT /FTId=PRO_0000009070.
FT CHAIN 45 491 Fibrinogen beta chain.
FT /FTId=PRO_0000009071.
FT DOMAIN 232 488 Fibrinogen C-terminal.
FT REGION 45 47 Beta-chain polymerization, binding distal
FT domain of another fibrin.
FT COILED 157 222 Potential.
FT SITE 44 45 Cleavage; by thrombin; to release
FT fibrinopeptide B.
FT SITE 152 153 Cleavage; by plasmin; to break down
FT fibrin clots.
FT SITE 160 161 Cleavage; by hementin; to prevent blood
FT coagulation.
FT SITE 163 164 Cleavage; by plasmin; to break down
FT fibrin clots.
FT MOD_RES 31 31 Pyrrolidone carboxylic acid.
FT CARBOHYD 394 394 N-linked (GlcNAc...).
FT DISULFID 95 95 Interchain (with C-55 in alpha chain).
FT DISULFID 106 106 Interchain (with C-68 in alpha chain).
FT DISULFID 110 110 Interchain (with C-45 in gamma chain).
FT DISULFID 223 223 Interchain (with C-184 in alpha chain).
FT DISULFID 227 227 Interchain (with C-161 in gamma chain).
FT DISULFID 231 316
FT DISULFID 241 270
FT DISULFID 424 437
FT VARIANT 2 2 K -> E (in dbSNP:rs6053).
FT /FTId=VAR_014169.
FT VARIANT 39 102 Missing (in New York-1).
FT /FTId=VAR_002402.
FT VARIANT 44 44 R -> C (in Christchurch-2, Seattle-1 and
FT Ijmuiden).
FT /FTId=VAR_002403.
FT VARIANT 45 45 G -> R (in Ise).
FT /FTId=VAR_002404.
FT VARIANT 74 74 R -> C (in Nijmegen).
FT /FTId=VAR_002405.
FT VARIANT 98 98 A -> T (in Naples and Milano-2;
FT associated with defective thrombin
FT binding and thrombophilia).
FT /FTId=VAR_002406.
FT VARIANT 100 100 P -> S (in dbSNP:rs2227434).
FT /FTId=VAR_013091.
FT VARIANT 170 170 N -> H (in dbSNP:rs2227409).
FT /FTId=VAR_013092.
FT VARIANT 196 196 R -> C (in congenital afibrinogenemia;
FT variant Longmont).
FT /FTId=VAR_016908.
FT VARIANT 265 265 P -> L (in dbSNP:rs6054).
FT /FTId=VAR_013093.
FT VARIANT 365 365 A -> T (in Pontoise-2).
FT /FTId=VAR_002407.
FT VARIANT 383 383 L -> R (in congenital afibrinogenemia;
FT abolishes fibrinogen secretion).
FT /FTId=VAR_016909.
FT VARIANT 430 430 G -> D (in congenital afibrinogenemia;
FT abolishes fibrinogen secretion).
FT /FTId=VAR_016910.
FT VARIANT 478 478 R -> K (in Baltimore-2; dbSNP:rs4220).
FT /FTId=VAR_002408.
FT CONFLICT 138 139 SQ -> QS (in Ref. 11; AA sequence and 12;
FT AA sequence).
FT CONFLICT 145 146 FQ -> QF (in Ref. 10; AA sequence, 11; AA
FT sequence and 12; AA sequence).
FT CONFLICT 192 192 P -> A (in Ref. 1; AAA52429).
FT TURN 100 102
FT HELIX 109 145
FT HELIX 147 167
FT HELIX 172 180
FT TURN 182 189
FT HELIX 190 222
FT STRAND 224 226
FT STRAND 233 235
FT STRAND 238 240
FT HELIX 241 246
FT STRAND 253 257
FT STRAND 261 263
FT STRAND 266 271
FT HELIX 274 276
FT STRAND 279 288
FT HELIX 296 301
FT STRAND 302 304
FT STRAND 306 308
FT STRAND 311 315
FT STRAND 321 323
FT HELIX 326 334
FT STRAND 335 337
FT STRAND 339 345
FT STRAND 347 349
FT STRAND 351 361
FT HELIX 364 366
FT STRAND 370 379
FT HELIX 382 385
FT STRAND 388 390
FT HELIX 392 396
FT STRAND 404 407
FT STRAND 408 410
FT HELIX 420 422
FT TURN 424 428
FT STRAND 435 437
FT STRAND 439 441
FT STRAND 448 451
FT TURN 454 456
FT STRAND 457 461
FT STRAND 464 467
FT HELIX 468 471
FT STRAND 473 475
FT STRAND 478 485
SQ SEQUENCE 491 AA; 55928 MW; B92FFB9976AB53C5 CRC64;
MKRMVSWSFH KLKTMKHLLL LLLCVFLVKS QGVNDNEEGF FSARGHRPLD KKREEAPSLR
PAPPPISGGG YRARPAKAAA TQKKVERKAP DAGGCLHADP DLGVLCPTGC QLQEALLQQE
RPIRNSVDEL NNNVEAVSQT SSSSFQYMYL LKDLWQKRQK QVKDNENVVN EYSSELEKHQ
LYIDETVNSN IPTNLRVLRS ILENLRSKIQ KLESDVSAQM EYCRTPCTVS CNIPVVSGKE
CEEIIRKGGE TSEMYLIQPD SSVKPYRVYC DMNTENGGWT VIQNRQDGSV DFGRKWDPYK
QGFGNVATNT DGKNYCGLPG EYWLGNDKIS QLTRMGPTEL LIEMEDWKGD KVKAHYGGFT
VQNEANKYQI SVNKYRGTAG NALMDGASQL MGENRTMTIH NGMFFSTYDR DNDGWLTSDP
RKQCSKEDGG GWWYNRCHAA NPNGRYYWGG QYTWDMAKHG TDDGVVWMNW KGSWYSMRKM
SMKIRPFFPQ Q
//

MIM 134830
*RECORD*
*FIELD* NO
134830
*FIELD* TI
*134830 FIBRINOGEN, B BETA POLYPEPTIDE; FGB
;;FIBRINOGEN--BETA POLYPEPTIDE CHAIN
*FIELD* TX
read moreSee fibrinogen--alpha polypeptide chain (FGA; 134820) and gamma chain
(FGG; 134850). Humphries et al. (1987) used RFLPs of fibrinogen genes to
demonstrate a strong association between polymorphism detected with a
beta-fibrinogen probe and the enzyme BclI. Genetic variation at the
fibrinogen locus accounted for 15% of the total variance in fibrinogen
level. Meyer et al. (1988) discovered an abnormality of the beta chain
incidentally in the course of electrophoretic protein studies of normal
blood samples. The 29-year-old blood donor had no symptoms of bleeding
tendency or thrombosis. A sister was similarly affected. The mother, who
may have had the variant, called Erfurt I, was deceased. Divelbiss et
al. (1989) studied a balanced de novo translocation between chromosomes
2 and 4 with a breakpoint at 4q31.1. Using RFLPs for both GYPA (111300)
and GYPB (111740), they found that a paternal allele from the
chromosomally normal father had not been inherited. This result was
interpreted as indicating loss of genetic material at the site of the
GYPA and GYPB genes presumably related to the de novo translocation. No
evidence was found for rearrangement of gamma or beta fibrinogen. By in
situ hybridization using probes for GYPA and for FGB, no hybridization
was found on the derived chromosome 2, which contained most of 4q31.
These data were interpreted as indicating that the fibrinogen locus is
proximal to the GYPA/GYPB loci. In a Norwegian population, Berg and
Kierulf (1989) were unable to confirm an association between RFLP
markers at either the alpha-fibrinogen or beta-fibrinogen locus and
plasma fibrinogen concentration, a finding that had been reported by
Humphries et al. (1987). They also found little evidence from a twin
study of heritability of fibrinogen level. The study was of interest
because of a growing body of evidence suggesting an important
association between plasma fibrinogen level and coronary artery disease
risk.

Petzelbauer et al. (2005) demonstrated that the FGB(15-42) peptide
fragment competes with the fibrin fragment N-terminal disulfide knot-II
for binding to vascular endothelial cadherin (CDH5; 601120) and thus
prevents transmigration of leukocytes across endothelial cell
monolayers. In acute and chronic rat models of myocardial
ischemia-reperfusion injury, FGB(15-42) substantially reduced leukocyte
infiltration, infarct size, and subsequent scar formation. Petzelbauer
et al. (2005) concluded that the interplay of fibrin fragments,
leukocytes, and CDH5 contributes to the pathogenesis of myocardial
damage and reperfusion injury.

Fowkes et al. (1992) concluded that there is an association between
peripheral atherosclerosis and the presence in homozygous or
heterozygous state of an allele at the FGB locus, the 4.2-kb allele with
BclI digestion. The allele frequency was 0.197 in cases and 0.097 in
controls (p = less than 0.005). In a large study in Copenhagen,
Tybjaerg-Hansen et al. (1997) found that the -455G-A polymorphism in the
FGB promoter (134830.0008) is associated with an increase in plasma
fibrinogen in both genders, but does not appear to cause ischemic heart
disease.

Ebert (1990) cataloged the variant human fibrinogens. Except for New
York-1, which has a large deletion, the beta-dysfibrinogenemias show a
fibrinogen with an amino acid substitution.

Duga et al. (2000) pointed to the 11-kb deletion involving the FGA gene
(134820.0019) that results in congenital afibrinogenemia (202400). They
hypothesized that since patients with afibrinogenemia showing no gross
alteration within the fibrinogen cluster had been reported, mechanisms
other than deletion of a fibrinogen gene are likely to exist. In 2
families, 1 Italian and 1 Iranian, the authors identified homozygous
missense mutations in exons 7 and 8 of the FGB gene (134830.0009,
134830.0010).

Spena et al. (2002) stated that 25 mutations in fibrinogen had been
identified in afibrinogenemia: 17 in FGA, 6 in FGG, and only 2 in FGB.
They reported 2 additional mutations in the FGB gene as the cause of
afibrinogenemia (134830.0012-134830.0013).

O'Donnell et al. (2001) studied the heritability of platelet aggregation
responses in 2,413 participants in the Framingham Heart Study. The
threshold concentrations of epinephrine and ADP required to produce
biphasic platelet aggregation and collagen lag time were determined.
After accounting for environmental covariates, the adjusted sib
correlations for epinephrine, ADP, and collagen lag time were 0.24,
0.22, and 0.31, respectively (P of 0.0001 for each). In contrast,
adjusted correlations for spouse pairs were -0.01, 0.05, and -0.02,
respectively (P greater than 0.30 for each). The estimated
heritabilities were 0.48, 0.44, and 0.62, respectively. Measured
covariates accounted for only 4 to 7% of the overall variance in
platelet aggregation, and heritable factors accounted for 20 to 30%. The
Pl(A2) variant of platelet glycoprotein IIIa (173470.0006) and the
fibrinogen HindIII beta-148 polymorphism (134830.0014) contributed less
than 1% of the overall variance.

Vu et al. (2005) showed that truncation of the 7 most C-terminal
residues (arg455 to gln461) of the B-beta chain specifically inhibited
fibrinogen secretion. Expression of additional mutants and structural
modeling suggested that neither the last 6 residues nor arg455 is
crucial per se for secretion, but prevents protein misfolding by
protecting hydrophobic residues in the B-beta C-terminal core.
Immunofluorescence and immunoelectron microscopy studies indicated that
secretion-impaired mutants were retained in a pre-Golgi compartment. In
addition, expression of FGB, FGG, and angiopoietin-2 (ANGPT2; 601922)
chimeric molecules demonstrated that the B-beta C-terminal domain
prevented the secretion of single chains and complexes, whereas the
gamma C-terminal domain allowed their secretion.

Wassel et al. (2011) used a vascular gene-centric array in 23,634
European Americans and 6,657 African American participants from 6
studies comprising the Candidate Gene Association Resource project to
examine the association of 47,539 common and lower frequency variants
with fibrinogen concentration. Wassel et al. (2011) identified a rare
pro265-to-leu variant in FGB (dbSNP rs6054) associated with lower
fibrinogen. Common fibrinogen gene SNPs FGB dbSNP rs1800787
(134830.0014) and FGG dbSNP rs2066861 significantly associated with
fibrinogen in European Americans were prevalent in African Americans and
showed consistent associations. There were several fibrinogen locus SNPs
associated with lower fibrinogen that were exclusive to African
Americans.

*FIELD* AV
.0001
FIBRINOGEN NEW YORK 1
FGB, EX2DEL

In the dysfunctional fibrinogen New York I, Liu et al. (1985)
demonstrated deletion of amino acids 9 to 72, corresponding exactly to
exon 2 of the FGB gene.

.0002
FIBRINOGEN CHRISTCHURCH 2
FIBRINOGEN SEATTLE 1;;
FIBRINOGEN IJmuiden
FGB, ARG14CYS

See Kaudewitz et al. (1986) and Pirkle et al. (1987). By sequence
analysis of PCR-amplified genomic DNA, Koopman et al. (1992)
demonstrated that the defect in fibrinogen IJmuiden is also an
arg14-to-cys substitution in the beta polypeptide. They demonstrated
that in the heterozygous individual some of the abnormal molecules were
linked by disulfide bonds to albumin. Fibrinogen-albumin and abnormally
high molecular weight fibrinogen complexes were detected in the
patient's plasma. Of the total plasma fibrinogen in the IJmuiden
patient, 20% was linked to albumin and 10% was present as high molecular
weight complexes. (According to Lord (1992), IJmuiden is the Dutch town
in which the patients with the anomalous fibrinogen lived. The double
capitals are the anglicized version of a single Dutch letter which
resembles a capital script 'Y' with a dot over each arm. The letter is
pronounced like the 'i' in life.)

.0003
FIBRINOGEN PONTOISE 2
FGB, ALA335THR

See Kaudewitz et al. (1986).

.0004
FIBRINOGEN BALTIMORE 2
FGB, ARG448LYS

This substitution is a polymorphism, i.e., the fibrinogen is not
dysfunctional (Schmelzer et al., 1988).

.0005
FIBRINOGEN ISE
FGB, GLY15CYS

During routine hematologic studies in preparation for cholecystectomy, a
50-year-old man was found to have hypofibrinogenemia by the thrombin
time method but a normal concentration of plasma fibrinogen by the
turbidimetric method. The proband's 2 sisters and a daughter were also
found to have hypofibrinogenemia by the thrombin time method but none of
the 4 had a history of thrombosis or hemorrhage. Called fibrinogen Ise,
this fibrinogen was shown to have replacement of glycine-15, the
N-terminus of the fibrin beta chain, by cysteine (Yoshida et al., 1991).

.0006
FIBRINOGEN NIJMEGEN
FGB, ARG44CYS

By sequence analysis of genomic DNA amplified by PCR, Koopman et al.
(1992) demonstrated that the defect in fibrinogen Nijmegen is an
arg44-to-cys substitution in the beta polypeptide. They demonstrated
that some of the abnormal fibrinogen in the patients (who were
heterozygous for the mutation) was linked by disulfide bonds to albumin.
In addition, abnormally high molecular weight fibrinogen complexes were
present in plasma from Nijmegen patients; 13% of fibrinogen was linked
to albumin and 15% was present as high molecular weight complexes.

.0007
FIBRINOGEN NAPLES
FIBRINOGEN MILANO 2;;
THROMBOPHILIA, DYSFIBRINOGENEMIC
FGB, ALA68THR

In an Italian family, 3 sibs, the offspring of a first-cousin marriage,
were found to be homozygous for a single base substitution (G-to-A) in
the fibrinogen B-beta chain, resulting in an amino acid substitution of
alanine by threonine at position 68 (Koopman et al., 1992). Heterozygous
individuals had no clinical symptoms. The propositus developed
postoperative deep-vein thrombosis at the age of 33 years. His sister
had a stroke at the age of 25 years due to thrombotic occlusion of the
internal carotid artery, and his brother had a stroke and thrombosis of
the abdominal aorta at the age of 21 years.

.0008
FIBRINOGEN-BETA POLYMORPHISM
FGB, PROMOTER MUTATION, -455G-A

A common mutation, a G-to-A transition at nucleotide position -455
within the promoter of the FGB gene, is associated with elevated plasma
fibrinogen levels. In a general population sample (N = 9,127) in
Copenhagen, Tybjaerg-Hansen et al. (1997) found that the A-allele
(relative frequency, 0.20) was associated with elevated fibrinogen
levels in both genders (P less than 0.001). While the effect of the
A-allele on fibrinogen level was additive in men, the effect was
dominant in postmenopausal women. The frequency of the A-allele was
similar in those with and without ischemic heart disease, and genotype
was not a predictor of disease.

.0009
AFIBRINOGENEMIA, CONGENITAL
FGB, LEU353ARG

In a 17-year-old Italian boy with congenital afibrinogenemia (202400),
Duga et al. (2000) found a T-to-G transversion in exon 7 of the FGB gene
leading to a leu353-to-arg (L353R) amino acid substitution. The patient
was homozygous; the parents, who were first cousins, were each
heterozygous as were sibs of each of them, as well as a second
unaffected child. The diagnosis of afibrinogenemia had been made at
birth because of life-threatening bleeding from the umbilical cord,
which rendered necessary transfusion with whole blood and fibrinogen
concentrates. After that, the patient had relatively mild symptoms, such
as epistaxis and posttraumatic muscle hematomas. By transient
transfection experiments with plasmids expressing wildtype and mutant
fibrinogens, Duga et al. (2000) demonstrated that the mutation was
sufficient to abolish fibrinogen secretion.

.0010
AFIBRINOGENEMIA, CONGENITAL
FGB, GLY400ASP

In a 24-year-old Iranian patient with congenital afibrinogenemia
(202400), born of a consanguineous marriage, Duga et al. (2000) found a
homozygous G-to-A transition in exon 8 of the FGB gene leading to a
gly400-to-asp (G400D) substitution. He had bled at birth from the
umbilical cord and later during circumcision, and was treated with whole
blood and fresh-frozen plasma on both occasions. Subsequently, he
suffered repeatedly from muscle hematomas and hemarthroses that occurred
spontaneously or after minor trauma. As in the case of the leu353-to-arg
mutation (134830.0009), impairment of fibrinogen secretion could be
demonstrated in vitro.

.0011
FIBRINOGEN LONGMONT
FGB, ARG166CYS

In a young woman with an episode of severe hemorrhage at childbirth and
a subsequent mild bleeding disorder, Lounes et al. (2001) identified a
novel variant of the B-beta chain of fibrinogen. The variant, denoted
fibrinogen Longmont, contains a C-to-T nucleotide substitution in exon 4
of the FGB gene, resulting in an arg166-to-cys (R166C) amino acid
change. Fibrinogen Longmont has normal release of fibrinopeptides A and
B, but protofibrils are unable to associate in the normal manner of
lateral aggregation, leading to abnormal clot formation.

.0012
AFIBRINOGENEMIA, CONGENITAL
FGB, IVS6, C-T, +13

Spena et al. (2002) described 2 probands with congenital afibrinogenemia
(202400), showing undetectable levels of functional fibrinogen, each
with a novel homozygous mutation in intron 6 or 7 of the FGB gene:
IVS6+13C-T and IVS7+1G-T (134830.0013), respectively. These were said to
represent the first FGB gene splicing mutations in this disorder. The
IVS6+13C-T mutation predicted creation of a donor splice site in intron
6, 11 nucleotides downstream of the physiologic one. The mutation was
predicted to result in truncation of the protein, supporting the
importance of the C-terminal domain of the B-beta chain for fibrinogen
assembly and secretion.

.0013
AFIBRINOGENEMIA, CONGENITAL
FGB, IVS7, G-T, +1

In a proband with congenital afibrinogenemia (202400), Spena et al.
(2002) identified an IVS7+1G-T splicing mutation of the FGB gene which
caused the disappearance of the invariant G-T dinucleotide of the intron
7 donor splice site. Assessed by semiquantitative analysis of RT-PCR
products, the IVS7+1G-T mutation resulted in multiple aberrant
splicings. It was predicted to result in truncation of the protein.

.0014
FIBRINOGEN, BETA-148 POLYMORPHISM
FGB, -148T-C

O'Donnell et al. (2001) used a modified PCR-based RFLP analysis to
detect the so-called HindIII beta-148 polymorphism of the FGB gene in a
study of genetic and environmental contributions to platelet
aggregation. The polymorphism involves a C-to-T substitution at position
-148 in the promoter region of the FGB gene. In the presence of the
HindIII restriction endonuclease recognition site that represents the
most common variant (H1), the 400-bp amplification product was cleaved
into fragments of 114 bp and 286 bp. The H2 allele was not cleaved by
HindIII. O'Donnell et al. (2001) found that the Pl(A2) polymorphism of
platelet glycoprotein IIIa (173470.0006) and the FGB HindIII beta-148
polymorphism contributed less than 1% to the overall variance in
platelet aggregability.

.0015
HYPOFIBRINOGENEMIA, CONGENITAL
FGB, LEU172GLN

Asselta et al. (2004) studied a 57-year-old Italian woman with severe
hypofibrinogenemia (202400). She was a compound heterozygote for a novel
missense mutation, leu172 to gln (L172Q), arising from a T-to-A
transversion at nucleotide 5157 in exon 4 of the FGB gene, and a
previously described nonsense mutation, arg17 to ter (R17X;
134830.0016). Studies of the L172Q mutation in COS-1 cells showed that
this mutant fibrinogen was normally assembled and secreted. Inspection
of the nucleotide sequence surrounding the mutation suggested a possible
effect on pre-mRNA splicing. Production of the mutant transcript in HeLa
cells confirmed that the mutation activates a cryptic acceptor splice
site in exon 4, resulting in a truncated fibrinogen B-beta chain lacking
approximately 70% of the C-terminal region. This was said to represent
the first exonic splicing mutation identified in fibrinogen genes. The
report demonstrated the importance of analyzing potentially pathogenetic
nucleotide variations at both the protein and the mRNA levels.

.0016
HYPOFIBRINOGENEMIA, CONGENITAL
FGB, ARG17TER

Asselta et al. (2004) described a patient with severe hypofibrinogenemia
(202400) caused by compound heterozygosity for mutations in the FGB
gene: a missense mutation (L172Q; 134830.0015) and a nonsense mutation,
arg17 to ter (R17X), previously reported in homozygous state in an
Iranian afibrinogenemic patient by Asselta et al. (2002). The R17X
mutation arose from a 3282C-T transition in exon 2.

*FIELD* SA
Chung et al. (1983); Ebert and Bell (1983); Kaudewitz et al. (1986)
*FIELD* RF
1. Asselta, R.; Duga, S.; Spena, S.; Peyvandi, F.; Castaman, G.; Malcovati,
M.; Mannucci, P. M.; Tenchini, M. L.: Missense or splicing mutation?
The case of a fibrinogen B-beta-chain mutation causing severe hypofibrinogenemia. Blood 103:
3051-3054, 2004.

2. Asselta, R.; Spena, S.; Duga, S.; Peyvandi, F.; Malcovati, M.;
Mannucci, P. M.; Tenchini, M. L.: Analysis of Iranian patients allowed
the identification of the first truncating mutation on the fibrinogen
B-beta-chain gene causing afibrinogenemia. Haematologica 87: 855-859,
2002.

3. Berg, K.; Kierulf, P.: DNA polymorphisms at fibrinogen loci and
plasma fibrinogen concentration. Clin. Genet. 36: 229-235, 1989.

4. Chung, D. W.; Que, B. G.; Rixon, M. W.; Mace, M., Jr.; Davie, E.
W.: Characterization of complementary deoxyribonucleic acid and genomic
deoxyribonucleic acid for the beta chain of human fibrinogen. Biochemistry 22:
3244-3250, 1983.

5. Divelbiss, J.; Shiang, R.; German, J.; Moore, J.; Murray, J. C.;
Patil, S. R.: Refinement of the physical location of glycophorin
A and beta fibrinogen using in situ hybridization and RFLP analysis.
(Abstract) Cytogenet. Cell Genet. 51: 991 only, 1989.

6. Duga, S.; Asselta, R.; Santagostino, E.; Zeinali, S.; Simonic,
T.; Malcovati, M.; Mannucci, P. M.; Tenchini, M. L.: Missense mutations
in the human beta fibrinogen gene cause congenital afibrinogenemia
by impairing fibrinogen secretion. Blood 95: 1336-1341, 2000.

7. Ebert, R. F.: Index of Variant Human Fibrinogens. Rockville,
Md.: Privately published (pub.) 1990.

8. Ebert, R. F.; Bell, W. R.: Fibrinogen Baltimore II: congenital
hypodysfibrinogenemia with delayed release of fibrinopeptide B and
decreased rate of fibrinogen synthesis. Proc. Nat. Acad. Sci. 80:
7318-7322, 1983.

9. Fowkes, F. G. R.; Connor, J. M.; Smith, F. B.; Wood, J.; Donnan,
P. T.; Lowe, G. D. O.: Fibrinogen genotype and risk of peripheral
atherosclerosis. Lancet 339: 693-696, 1992.

10. Humphries, S. E.; Cook, M.; Dubowitz, M.; Stirling, Y.; Meade,
T. W.: Role of genetic variation at the fibrinogen locus in determination
of plasma fibrinogen concentrations. Lancet 329: 1452-1454, 1987.
Note: Originally Volume I.

11. Kaudewitz, H.; Henschen, A.; Soria, C.; Soria, J.; Bertrand, O.;
Heaton, D.: The molecular defect of the genetically abnormal fibrinogen
Christchurch II.In: Muller-Berghaus, G.; Scheefers-Borchel, V.; Selmayr,
E.; Henschen, A.: Fibrinogen and Its Derivatives. Amsterdam: Elsevier
(pub.) 1986. Pp. 31-36.

12. Kaudewitz, H.; Henschen, A.; Soria, J.; Soria, C.: Fibrinogen
Pontoise--a genetically abnormal fibrinogen with defective fibrin
polymerisation but normal fibrinopeptide release.In: Lane, D. A.;
Henschen, A.; Jasani, M. K.: Fibrinogen--Fibrin Formation and Fibrinolysis.
Berlin: W. de Gruyter (pub.) 1986. Pp. 91-96.

13. Koopman, J.; Haverkate, F.; Grimbergen, J.; Engesser, L.; Novakova,
I.; Kerst, A. F. J. A.; Lord, S. T.: Abnormal fibrinogens IJmuiden
(B-beta-arg14-to-cys) and Nijmegen (B-beta-arg44-to-cys) form disulfide-linked
fibrinogen-albumin complexes. Proc. Nat. Acad. Sci. 89: 3478-3482,
1992.

14. Koopman, J.; Haverkate, F.; Lord, S. T.; Grimbergen, J.; Mannucci,
P. M.: Molecular basis of fibrinogen Naples associated with defective
thrombin binding and thrombophilia: homozygous substitution of B-beta
68ala-to-thr. J. Clin. Invest. 90: 238-244, 1992.

15. Liu, C. Y.; Koehn, J. A.; Morgan, F. J.: Characterization of
fibrinogen New York 1: a dysfunctional fibrinogen with a deletion
of B beta(9-72) corresponding exactly to exon 2 of the gene. J. Biol.
Chem. 260: 4390-4396, 1985.

16. Lord, S. T.: Personal Communication. Chapel Hill, N. C. 5/27/1992.

17. Lounes, K. C.; Lefkowitz, J. B.; Henschen-Edman, A. H.; Coates,
A. I.; Hantgan, R. R.; Lord, S. T.: The impaired polymerization of
fibrinogen Longmont (B-beta-166arg-cys) is not improved by removal
of disulfide-linked dimers from a mixture of dimers and cysteine-linked
monomers. Blood 98: 661-666, 2001.

18. Meyer, M.; Schellenberg, I.; Vogel, G.; Bischoff, I.: A new genetic
fibrinogen variant (fibrinogen Erfurt I) structurally characterized
by an abnormal beta-chain and present both in plasma and platelets. Thromb.
Haemost. 59: 138-142, 1988.

19. O'Donnell, C. J.; Larson, M. G.; Feng, D.; Sutherland, P. A.;
Lindpaintner, K.; Myers, R. H.; D'Agostino R. A.; Levy, D.; Tofler,
G. H.: Genetic and environmental contributions to platelet aggregation:
the Framingham Heart Study. Circulation 103: 3051-3056, 2001.

20. Petzelbauer, P.; Zacharowski, P. A.; Miyazaki, Y.; Friedl, P.;
Wickenhauser, G.; Castellino, F. J.; Groger, M.; Wolff, K.; Zacharowski,
K.: The fibrin-derived peptide B-beta(15-42) protects the myocardium
against ischemia-reperfusion injury. Nature Med. 11: 298-304, 2005.

21. Pirkle, H.; Kaudewitz, H.; Henschen, A.; Theodor, I.; Simmons,
G.: Substitution of B beta 14 arginine by cyst(e)ine in fibrinogen
Seattle I.In: Lowe, G. D. O.; Douglas, J. T.; Forbes, C. D.; Henschen,
A.: Fibrinogen 2. Biochemistry, Physiology and Clinical Relevance.
Amsterdam: Elsevier (pub.) 1987. Pp. 49-52.

22. Schmelzer, C. H.; Ebert, R. F.; Bell, W. R.: A polymorphism at
B beta 448 of fibrinogen identified during structural studies of fibrinogen
Baltimore II. Thromb. Res. 52: 173-177, 1988.

23. Spena, S.; Duga, S.; Asselta, R.; Malcovati, M.; Peyvandi, F.;
Tenchini, M. L.: Congenital afibrinogenemia: first identification
of splicing mutations in the fibrinogen B-beta-chain gene causing
activation of cryptic splice sites. Blood 100: 4478-4484, 2002.

24. Tybjaerg-Hansen, A.; Agerholm-Larsen, B.; Humphries, S. E.; Abildgaard,
S.; Schnohr, P.; Nordestgaard, B. G.: A common mutation (G(-455)-to-A)
in the beta-fibrinogen promoter is an independent predictor of plasma
fibrinogen, but not of ischemic heart disease: a study of 9,127 individuals
based on the Copenhagen City Heart Study. J. Clin. Invest. 99: 3034-3039,
1997.

25. Vu, D.; Di Sanza, C.; Caille, D.; de Moerloose, P.; Scheib, H.;
Meda, P.; Neerman-Arbez, M.: Quality control of fibrinogen secretion
in the molecular pathogenesis of congenital afibrinogenemia. Hum.
Molec. Genet. 14: 3271-3280, 2005.

26. Wassel, C. L.; Lange, L. A.; Keating, B. J.; Taylor, K. C.; Johnson,
A. D.; Palmer, C.; Ho, L. A.; Smith, N. L.; Lange, E. M.; Li, Y.;
Yang, Q.; Delaney, J. A.; and 11 others: Association of genomic
loci from a cardiovascular gene SNP array with fibrinogen levels in
European Americans and African-Americans from six cohort studies:
the Candidate Gene Association Resource (CARe). Blood 117: 268-275,
2011.

27. Yoshida, N.; Wada, H.; Morita, K.; Hirata, H.; Matsuda, M.; Yamazumi,
K.; Asakura, S.; Shirakawa, S.: A new congenital abnormal fibrinogen
Ise characterized by the replacement of B-beta glycine-15 by cysteine. Blood 77:
1958-1963, 1991.

*FIELD* CN
Ada Hamosh - updated: 10/4/2011
George E. Tiller - updated: 7/21/2009
Marla J. F. O'Neill - updated: 3/29/2005
Victor A. McKusick - updated: 9/17/2004
Victor A. McKusick - updated: 10/31/2003
Victor A. McKusick - updated: 3/3/2003
Victor A. McKusick - updated: 12/5/2001
Victor A. McKusick - updated: 1/5/2001
Victor A. McKusick - updated: 7/13/2000
Victor A. McKusick - updated: 7/14/1997

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

*FIELD* ED
alopez: 10/11/2011
terry: 10/4/2011
wwang: 8/7/2009
terry: 7/21/2009
terry: 1/14/2009
wwang: 3/29/2005
terry: 10/29/2004
alopez: 9/20/2004
terry: 9/17/2004
mgross: 11/3/2003
terry: 10/31/2003
carol: 3/11/2003
tkritzer: 3/7/2003
terry: 3/3/2003
carol: 12/10/2001
mcapotos: 12/5/2001
terry: 1/5/2001
alopez: 7/21/2000
terry: 7/13/2000
dkim: 6/30/1998
mark: 8/12/1997
terry: 8/8/1997
mark: 7/14/1997
terry: 7/14/1997
mark: 6/14/1997
mimadm: 4/29/1994
terry: 4/27/1994
pfoster: 4/21/1994
warfield: 4/20/1994
carol: 7/22/1993
carol: 8/17/1992

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.
Paediat. 200: 46-59, 1963.

3. Bronnimann, R.: Kongenitale Afibrinogenamie. Acta Haemat. 11:
40-51, 1954.

4. Egbring, R.; Andrassey, K.; Egli, H.; Meyer-Linderberg, J.: Diagnostische
und therapeutische Probleme bei congenitaler Afibrinogenaemie. Blut 22:
175-201, 1971.

5. Elseed, F. A.; Karrar, Z. A.: Congenital afibrinogenaemia in a
Saudi family: a case report and family study. Acta Haemat. 71: 388-392,
1984.

6. Fried, K.; Kaufman, S.: Congenital afibrinogenemia in 10 offspring
of uncle-niece marriages. Clin. Genet. 17: 223-227, 1980.

7. Girolami, A.; Zacchello, G.; D'Elia, R.: Congenital afibrinogenemia:
a case report with some considerations on the hereditary transmission
of this disorder. Thromb. Diath. Haemorrh. 25: 460-468, 1971.

8. Haverkate, F.; Samama, M.: Familial dysfibrinogenemia and thrombophilia:
report on a study of the SSC subcommittee on fibrinogen. Thromb.
Haemost. 73: 151-161, 1995.

9. Lawson, H. A.: Congenital afibrinogenemia: report of a case. New
Eng. J. Med. 248: 552-554, 1953.

10. 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
and an A-alpha-gln328 truncation (fibrinogen Keokuk). Blood 103:
2571-2576, 2004.

11. Lemoine, P.; Harousseau, H.; Guimbretiere, J.; Lenne, Y.; Angebaud,
Y.: Afibrinemie congenitale chez deux freres avec lesions osseuses
et hepatiques. Arch. Franc. Pediat. 20: 463-483, 1963.

12. Montgomery, R.; Natelson, S. E.: Afibrinogenemia with intracerebral
hematoma: report of a successfully treated case. Am. J. Dis. Child. 131:
555-556, 1977.

13. 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.

14. Neerman-Arbez, M.; de Moerloose, P.; Honsberger, A.; Parlier,
G.; Arnuti, B.; Biron, C.; Borg, J.-Y.; Eber, S.; Meili, E.; Peter-Salonen,
K.; Ripoll, L.; Vervel, C.; d'Oiron, R.; Staeger, P.; Antonarakis,
S. E.; Morris, M. A.: Molecular analysis of the fibrinogen gene cluster
in 16 patients with congenital afibrinogenemia: novel truncating mutations
in the FGA and FGG genes. Hum. Genet. 108: 237-240, 2001.

15. Neerman-Arbez, M.; Honsberger, A.; Antonarakis, S. E.; Morris,
M. A.: Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital
afibrogenemia (sic). J. Clin. Invest. 103: 215-218, 1999. Note:
Erratum: J. Clin. Invest. 103: 759 only, 1999.

16. Prichard, R. W.; Vann, R. L.: Congenital afibrinogenaemia: report
on a child without fibrinogen and review of the literature. Am. J.
Dis. Child. 88: 703-710, 1954.

17. Werder, E. A.: Kongenitale Afibrinogenaemie. Helv. Paediat.
Acta 18: 208-229, 1963.

*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