Alternative titles; symbols
HGNC Approved Gene Symbol: FGB
SNOMEDCT: 154818001, 439145006; ICD10CM: D68.2;
Cytogenetic location: 4q31.3 Genomic coordinates (GRCh38): 4:154,562,980-154,572,807 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.3 | Afibrinogenemia, congenital | 202400 | Autosomal recessive | 3 |
| Dysfibrinogenemia, congenital | 616004 | 3 | ||
| Hypofibrinogenemia, congenital | 202400 | Autosomal recessive | 3 |
Fibrinogen, the soluble precursor of fibrin, is a plasma glycoprotein synthesized in the liver. It is composed of 3 structurally different subunits: alpha (FGA; 134820), beta, 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 (factor XIII; 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 (summary by Dayhoff, 1972).
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 (617922) and GYPB (617923), 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.
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.
Meyer et al. (1988) incidentally discovered an abnormality of the beta chain 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.
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 (134830.0008). Genetic variation at the fibrinogen locus accounted for 15% of the total variance in fibrinogen level.
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.
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 3 Italian sibs with dysbetafibrinogenemia with thrombosis, Koopman et al. (1992) identified a homozygous mutation in the FGB gene (134830.0007).
In 2 families with congenital afibrinogenemia, 1 Italian and 1 Iranian, Duga et al. (2000) 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 (rs6054) associated with lower fibrinogen. Common fibrinogen gene SNPs FGB rs1800787 (134830.0014) and FGG rs2066861, which are 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.
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.
Ebert (1990) cataloged the variant human fibrinogens. Except for New York-1 (134830.0001), which had a large deletion, the beta-dysfibrinogenemias showed a fibrinogen with an amino acid substitution.
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.
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 (R14C) 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.)
This variant has also been called fibrinogen Seattle I.
See Kaudewitz et al. (1986).
This substitution is a polymorphism, i.e., the fibrinogen is not dysfunctional (Schmelzer et al., 1988).
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 (G15C) (Yoshida et al., 1991).
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 (R44C) 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.
This variant has also been called fibrinogen Milano-2.
In 3 sibs of an Italian family, the offspring of a first-cousin marriage, with congenital dysfibrinogenemia (616004), Koopman et al. (1992) found a homozygous mutation 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 (A68T). 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.
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.
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; his first-cousin parents were each heterozygous, as were sibs of each, 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 necessitated 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.
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 L353R mutation (134830.0009), impairment of fibrinogen secretion could be demonstrated in vitro.
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.
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 premature termination, supporting the importance of the C-terminal domain of the B-beta chain for fibrinogen assembly and secretion.
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 premature termination.
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.
Asselta et al. (2004) studied a 57-year-old Italian woman with severe hypofibrinogenemia (202400). She was compound heterozygous 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.
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.
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. [PubMed: 15070683] [Full Text: https://doi.org/10.1182/blood-2003-10-3725]
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. [PubMed: 12161363]
Berg, K., Kierulf, P. DNA polymorphisms at fibrinogen loci and plasma fibrinogen concentration. Clin. Genet. 36: 229-235, 1989. [PubMed: 2572363] [Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb03195.x]
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. [PubMed: 6688356] [Full Text: https://doi.org/10.1021/bi00282a032]
Dayhoff, M. O. Atlas of Protein Sequence and Structure. Fibrinogen and fibrinopeptides. Vol. 5. Washington: National Biomedical Research Foundation (pub.) 1972. Pp. D87-D97.
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.
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. [PubMed: 10666208]
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. [PubMed: 6580646] [Full Text: https://doi.org/10.1073/pnas.80.23.7318]
Ebert, R. F. Index of Variant Human Fibrinogens. Rockville, Md.: Privately published (pub.) 1990.
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. [PubMed: 1347581] [Full Text: https://doi.org/10.1016/0140-6736(92)90596-u]
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. [PubMed: 2885451] [Full Text: https://doi.org/10.1016/s0140-6736(87)92205-7]
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.
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.
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. [PubMed: 1565641] [Full Text: https://doi.org/10.1073/pnas.89.8.3478]
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. [PubMed: 1634610] [Full Text: https://doi.org/10.1172/JCI115841]
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. [PubMed: 3156856]
Lord, S. T. Personal Communication. Chapel Hill, N. C. 5/27/1992.
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. [PubMed: 11468164] [Full Text: https://doi.org/10.1182/blood.v98.3.661]
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. [PubMed: 3388290]
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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.
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. [PubMed: 3194892] [Full Text: https://doi.org/10.1016/0049-3848(88)90096-5]
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. [PubMed: 12393540] [Full Text: https://doi.org/10.1182/blood-2002-06-1647]
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. [PubMed: 9185528] [Full Text: https://doi.org/10.1172/JCI119499]
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