Alternative titles; symbols
HGNC Approved Gene Symbol: FGG
SNOMEDCT: 154818001, 439145006; ICD10CM: D68.2;
Cytogenetic location: 4q32.1 Genomic coordinates (GRCh38): 4:154,604,136-154,612,656 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q32.1 | Afibrinogenemia, congenital | 202400 | Autosomal recessive | 3 |
| Dysfibrinogenemia, congenital | 616004 | 3 | ||
| Hypodysfibrinogenemia | 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), 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 (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 (summary by Dayhoff, 1972).
In its essential role in the adhesion and aggregation of platelets, fibrinogen binds to specific receptor sites on platelets. Hawiger et al. (1982) showed that the gamma and to a lesser extent the alpha chains carry the main sites for interaction with the platelet receptor.
In a variety of species, including rodents and man, the fibrinogen gamma chain occurs in 2 forms, called gamma-A and gamma-B, or gamma and gamma-prime. In the rat, these 2 fibrinogen gamma chains arise by translation of 2 mRNAs of 1,700 and 2,200 nucleotides, which are produced from a single gene by alternative splice patterns (Crabtree and Kant, 1982). The more abundant gamma-A mRNA encodes a protein that is 83% homologous with the human gamma-A chain. The gamma-B mRNA is identical with the gamma-A sequence with the exception of a 53-bp insert located 202 bp from the poly(A) extension. This 53-bp insert is identical to the seventh and final intron of the gamma-A gene and is located 4 codons before the termination codon for the gamma-A chain. Translocation into the inserted sequence produces a unique 12-amino acid C terminus in the rat gamma-B polypeptide that is homologous with the known C terminus of the human gamma-B chain.
Olaisen et al. (1982) assigned the FGG locus to chromosome 4 by linkage to MN (111300). Using separate DNA clones for each in hybrid cell studies, Henry et al. (1984) found that all 3 fibrinogen genes map to chromosome 4.
Liu et al. (2006) studied the mechanical properties of single fibrin fibers using an atomic force-fluorescence microscopy technique. They determined the extensibility and elastic limit of fibers formed in the presence and absence of factor XIIIa (134570). Factor XIIIa induces covalent crosslinks between gamma chains (along the fiber axis) and between the alpha (134820) chains. Samples without factor XIIIa showed no crosslinking. Uncrosslinked fibers extended 226 +/- 52%, and crosslinked fibers extended 332 +/- 71%, or 4.32 times their original length. The most extreme fibers could be extended over 6 times their length. These extensibilities are the largest of any protein fiber. Liu et al. (2006) tested the elastic limit by stretching fibers to a certain strain and releasing the applied force. Uncrosslinked fibers could be stretched 2.2 times their length and recover elastically. Crosslinked fibers could be stretched over 2.8 times their length (180% strain) and still recover without permanent damage. Liu et al. (2006) concluded that the effect of crosslinking is unusual in fibrin. In collagen, spider silk, and keratin fibers, crosslinking makes fibers stiffer and less extensible. The increased extensibility and elasticity observed for crosslinked fibrin indicates the crosslinks are directional, along the fiber axis. Thus, Liu et al. (2006) concluded that in physiologic conditions, the fast-forming gamma-gamma crosslinks along the axis may enhance elasticity and prevent rupture of the nascent fibers. These data suggested that clot rupture does not arise from the rupture of individual fibers, as had been assumed; rather, the branch points of the network forming the clot yield first.
The defect in the dysfibrinogenemia (616004) described by Fernandez et al. (1989), fibrinogen Sevilla, has not been precisely defined. It was found in a 64-year-old Spanish woman with no history of hemorrhagic or thrombotic diathesis. The same abnormal fibrinogen was present in a daughter and a grandson, who also had no clotting abnormality.
Cote et al. (1998) analyzed the molecular structure-function relationships of naturally occurring mutations in the gamma chain of human fibrinogen. They tabulated 19 separate mutations, 17 of which were missense mutations. In general, mutations within the gamma chain of fibrinogen are not associated with serious bleeding disorders. Two patients, one with Baltimore-1 (G292V; 134850.0003) and the other with Giessen-4 (D318G; 134850.0015), who experienced mild bleeding symptoms, also suffered from thrombotic tendencies. The only gamma-dysfibrinogenemia associated with a serious bleeding diathesis was Asahi (M310T; 134850.0006). Cote et al. (1998) suggested that in this instance bleeding symptoms were probably related to the extra glycosylation resulting from the M310T substitution. Hypoglycosylation increases the rate and extent of clotting. Therefore, Cote et al. (1998) speculated that hyperglycosylation could decrease the clotting rate and thereby cause a bleeding disorder.
Congenital afibrinogenemia (202400) is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. Asselta et al. (2000) and Margaglione et al. (2000) identified mutations in the FGG gene in patients with afibrinogenemia (134820.0016-134820.0017).
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 (P265L) variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene SNPs FGB rs1800787 (134830.0014) and FGG rs2066861, which were significantly associated with fibrinogen in European Americans, were prevalent in African Americans and showed consistent associations. Several fibrinogen locus SNPs that were associated with lower fibrinogen were exclusive to African Americans.
Ebert (1990) cataloged fibrinogen variants. All dysfibrinogenemias due to gamma-chain defects had missense mutations except fibrinogen Vlissingen-1 (134850.0007), which had a 2-amino acid deletion.
Fibrinogen Tokyo-2 has also been called fibrinogen Baltimore-4, Morioka-1, Osaka-2, Tochigi-1.
In 4 persons in 3 generations of a Japanese family ascertained through routine presurgical coagulation studies which showed markedly prolonged thrombin time, Matsuda et al. (1983) described an abnormal fibrinogen tentatively designated 'Tokyo II.' No unusual bleeding or thrombosis was noted in the family.
Another dysfibrinogenemia, fibrinogen Baltimore IV, was found by Ebert and Bell (1985) in a 56-year-old white man who came to their attention during routine clinical laboratory assessment prior to surgery. Despite extensive trauma in the past, he had never experienced abnormal bleeding and had had no transfusions. The family history was negative for bleeding diathesis. Clinical laboratory tests showed only a slightly prolonged prothrombin time. Detailed studies indicated that about half of isolated fibrinogen monomers polymerized normally, whereas the remainder polymerized at approximately 2% of the normal rate.
Yoshida et al. (1988) found that abnormal fibrinogen Tochigi has a replacement of arginine at gamma-275 by cysteine (R275C). The propositus was found to have hypofibrinogenemia during routine hematologic study, and neither he nor his 2 daughters, who had the same abnormal fibrinogen, had any history of thrombosis or hemorrhage. Terukina et al. (1988) identified replacement of arginine by cysteine at position 275 of the gamma chain in fibrinogen Osaka II; thus, it is identical to fibrinogen Tochigi. See Schmelzer et al. (1989) and Terukina et al. (1988).
Mosesson et al. (1995) demonstrated that Tokyo II fibrinogen has a functionally abnormal D:D self-association site, and that a normal D:D site interaction is required, in addition to D:E, for normal fibrin or fibrinogen assembly.
Fibrinogen Haifa-1 has also been called fibrinogen Bergamo-2, Essen-1, Osaka-3, Perugia-1, and Saga-1.
Reber et al. (1986) described the same substitution, namely, arginine-to-histidine at gamma-275 (R275H), in the abnormal fibrinogen from 3 unrelated persons. In 1 family, there was a thrombotic tendency (616004). The substitution appears to be the same as that in fibrinogen Haifa (Brook et al., 1983), which was found in a patient with peripheral arterial thrombosis. See Siebenlist et al. (1989) and Yamazumi et al. (1988). Yoshida et al. (1992) demonstrated that fibrinogen Osaka III has the same mutational change.
Beck et al. (1965) demonstrated an anomalous fibrinogen in a patient with increased tendency to thrombosis and, paradoxically, a mild hemorrhagic diathesis (616004). Three daughters by 2 different husbands were similarly affected. The group referred to the anomalous protein as fibrinogen Baltimore. Brown and Crowe (1975) concluded that fibrinogen Baltimore has a defect in the alpha chain; later work disproved this. Bantia et al. (1990) demonstrated that glycine-292 in the gamma-chain was replaced by valine (G292V). Direct nucleotide sequencing of a PCR product containing this portion of the gamma chain demonstrated that the defect was a change in codon GGC to GTC. The molecular defect of fibrinogen Baltimore-1 lies in a region of the gamma chain required for fibrin polymerization, suggesting that the integrity of gly292 is critical for fibrin assembly.
In a propositus and his 2 daughters, Yoshida et al. (1986) discovered a new gamma-chain variant, which they called fibrinogen Kyoto. All 3 subjects had hypofibrinogenemia but normal coagulation studies, and the variant probably had little clinical consequence. Yoshida et al. (1988) demonstrated replacement of asparagine-308 by lysine (N308K) in the FGG gene in fibrinogen Kyoto-1.
Ebert and Bell (1988) identified Baltimore-3 as a congenital abnormal fibrinogen with defective fibrin monomer polymerization. Bantia et al. (1990) demonstrated an asn308-to-ile mutation (N308I). Polymerization is also affected by N308K (134850.0004).
In an abnormal fibrinogen with severely impaired polymerization of fibrin monomers, Yamazumi et al. (1989) identified a met310-to-thr (M310T) substitution in the FGG gene. Furthermore, asp308 was found to be N-glycosylated due to a newly formed consensus sequence, asp308-gly309-thr310 (D308-G309-T310).
Koopman et al. (1989) demonstrated a 6-basepair deletion resulting in absence of asparagine-319 (N319) and aspartic acid-320 (D320) and a fibrinogen molecule with defective interaction with calcium. Koopman et al. (1991) found this congenitally abnormal fibrinogen in a young woman with massive pulmonary embolism. In 50% of the fragments corresponding to exon 8, the 6-bp deletion removed N319 and D320 from the normal gamma chain.
See Miyata et al. (1989).
See Terukina et al. (1989).
Fibrinogen Milano-1 has also been called fibrinogen Ales.
Reber et al. (1986) found that fibrinogen Milano I has a substitution of valine for aspartic acid at gamma-330 (D330V). The variant was discovered in a father and daughter from northern Italy during routine studies of blood coagulation. There was no bleeding or thrombosis in either. Fibrin polymerization was impaired in this mutation.
Lounes et al. (2000) identified the D330V mutation in the FGG gene in homozygous state in a case of congenital dysfibrinogenemia (616004), which they referred to as fibrinogen Ales. The proband had a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The polymerization defect was characterized by a defective site 'a,' resulting in an absence of interaction between sites A and a. The amino acid change resulted from an A-to-T transversion in exon 8 of the FGG gene. His sister was likewise homozygous for the mutation but was asymptomatic. The parents were cousins, were heterozygous for the mutation, and were asymptomatic, as were heterozygotes in the family reported by Reber et al. (1986). Another mutation in codon 330 is fibrinogen Kyoto-3 (134850.0009). It is also characterized by impaired fibrin polymerization.
The proband of Lounes et al. (2000) had been hospitalized in the past with multiple traumas during which there were no signs of unusual bleeding or thrombotic tendency. As an explanation for the arterial thrombosis leading to strokes, the authors suggested that, because clotting by thrombin was dramatically delayed in the patient, thrombin was not trapped in fibrin, allowing platelet aggregation to occur. Thrombophilia in association with congenital dysfibrinogenemia was reported with fibrinogen Naples (134830.0007), a defect of the beta chain of fibrinogen. Defective thrombin binding to the clot was also identified in that instance.
Menache (1964) described this fibrinogen variant in a father and son. Budzynski et al. (1974) showed that the gamma polypeptide chain in fibrinogen Paris I is abnormally long at the C-terminal end. A terminator mutation, analogous to that found in Hb Constant Spring, was thought to be responsible for it (Marder, 1974); however, Rosenberg et al. (1993) demonstrated an A-to-G transition at nucleotide 6588 within intron 8 of the FGG gene, leading to the insertion of a 45-bp segment between exons 8 and 9 in the mature FGG mRNA, and a 15-amino acid insert in the protein after amino acid 350. Alternative splicing of this region from intron 8 into the mature mRNA also resulted after translation into a substitution of serine for glycine at position 351 (G351S). Rosenberg et al. (1993) concluded that the insertion of this amino acid sequence, with 2 additional cysteines, led to a conformationally altered and dysfunctional gamma chain in Paris I fibrinogen. See also Mosesson et al. (1976).
Olaisen et al. (1982) identified a fibrinogen gamma-chain variant by 2-dimensional electrophoresis in plasma samples from a Norwegian kindred (EB-25) with an inherited skin disorder. Brosstad et al. (1983) stated that the variant was designated fibrinogen Oslo III.
Rupp and Beck (1984) stated that the gamma chain of fibrinogen Oslo-3 is elongated at the C-terminal end. The mutation had not been identified.
Heterozygosity for the abnormal fibrinogen Osaka V is characterized by correction of defective fibrinogen clotting with physiologic concentrations of calcium; lack of protective effect of calcium on fibrinogen or crosslinked fibrin against further plasmic digestion; and defective calcium binding to high-affinity sites. Yoshida et al. (1992) demonstrated substitution of glycine for arginine at position gamma-375 (R375G), presumably arising from a CGG-to-GGG change in that codon.
Okumura et al. (1996) identified an asp364-to-his (D364H) mutation in the gamma chain of fibrinogen in fibrinogen Matsumoto I, a dysfibrinogen found in a heterozygous individual who had a mixture of molecules with normal and variant gamma chains. Polymerization of fibrinogen Matsumoto I was markedly delayed, and this delay could be partially compensated by mixing with normal fibrinogen. During blood coagulation, soluble fibrinogen is converted to fibrin monomers that polymerize to form an insoluble clot. Polymerization had been described as a 2-step process, the formation of double-stranded protofibrils and the subsequent lateral aggregation of protofibrils into fibers. The residues tyr363 (Y363) and D364 had been shown to have a significant role in polymerization, most likely in protofibril formation. Okumura et al. (1997) found that fibrinogen containing the D364H mutation showed the same release of fibrinopeptides A and B as the normal; in contrast, polymerization was almost nonexistent for the D364H variant. Clottability of the H364 variant was substantially reduced, and fibrin gels were not formed. The data suggested that both protofibril formation and lateral aggregation were altered by these substitutions, indicating that the C-terminal domain of the gamma chain has a role in both polymerization steps.
See Haverkate and Samama (1995).
Asselta et al. (2000) reported the first example of a mutation in the gamma-chain gene as the cause of afibrinogenemia (202400). A 3-year-old Pakistani patient, born of consanguineous parents, had unmeasurable plasma levels of functional and immunoreactive fibrinogen. Sequencing of the fibrinogen genes revealed a homozygous G-to-A transition at position +5 of intron 1 of the gamma-chain gene. The predicted mutant fibrinogen gamma chain would contain the signal peptide, followed by a short stretch of aberrant amino acids, preceding a premature stop codon. No bleeding complication occurred at birth, but after 3 weeks the child presented with intracranial bleeding.
Margaglione et al. (2000) described congenital afibrinogenemia (202400) due to an FGG mutation in a 6-year-old girl whose parents were first cousins. The diagnosis of afibrinogenemia had been made at the age of 1 year because of posttraumatic and life-threatening bleeding. She was found to be homozygous for a G-to-A transition at the fifth nucleotide (nucleotide 2395) of the third intervening sequence of the FGG gene. Sequencing of the abnormal mRNA showed complete absence of exon 3. Skipping of exon 3 predicted the deletion of amino acid sequence from residue 16 to residue 75 and a frameshift at amino acid 76 with a premature stop codon within exon 4 at position 77. Thus, the truncated gamma-chain gene product would not interact with other chains to form the mature fibrinogen molecule.
In an asymptomatic Italian woman whose routine coagulation test results revealed a prolonged thrombin time, Bolliger-Stucki et al. (2001) found double heterozygosity for the R16C mutation (134820.0003) in the FGA gene and a G-to-A transition at nucleotide 4682, resulting in a gly165-to-arg (G165R) mutation in exon 6 of the FGG gene.
Mullin et al. (2002) discovered a novel gamma-chain dysfibrinogen in a 32-year-old asymptomatic man admitted to the hospital after a car accident. He presented with a low fibrinogen concentration and a prolonged thrombin clotting time. Electrophoresis revealed a gamma-chain variant with an apparently higher molecular weight. DNA sequence analysis showed a heterozygous mutation of GGC (gly) to GAC (asp) at codon 309 (G309D) of the FGG gene.
In 2 Italian sibs with congenital afibrinogenemia (202400), previously reported by Castaman and Rodeghiero (1992), Spena et al. (2007) identified a homozygous A-to-T transversion in intron 6 of the FGG gene. RT-PCR and sequencing analysis showed that the mutation was present in a cryptic splice site and resulted in an in-frame inclusion of a 75-bp pseudo-exon carrying a premature stop codon. Circulating fibrinogen was completely absent in the sibs. Spena et al. (2007) commented on the unique pathogenic genetic mechanism in this family.
Martinez et al. (1974) described an abnormal fibrinogen, designated fibrinogen Philadelphia, associated with hypercatabolism in a family with hypodysfibrinogenemia (see 616004). The proband experienced postpartum hemorrhage and had a lifelong history of excessive bleeding after minor trauma, tooth extraction, and tonsillectomy. Keller et al. (2005) performed DNA sequence analysis of the 3 fibrinogen genes in the proband of this family as well as in her son and grandson, both of whom also had hypodysfibrinogenemia, and in her unaffected granddaughter. All 3 affected individuals were found to have a heterozygous T-to-C transition in exon 9 of the FGG gene, resulting in a ser378-to-pro (S378P) substitution. The mutation was not present in the unaffected granddaughter or in 10 control individuals.
Asselta, R., Duga, S., Simonic, T., Malcovati, M., Santagostino, E., Giangrande, P. L. F., Mannucci, P. M., Tenchini, M. L. Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation. Blood 96: 2496-2500, 2000. [PubMed: 11001902]
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Miyata, T., Furukawa, K., Iwanaga, S., Takamatsu, J., Saito, H. Fibrinogen Nagoya, a replacement of glutamine-329 by arginine in the gamma-chain that impairs the polymerization of fibrin monomer. J. Biochem. 105: 10-14, 1989. [PubMed: 2738036] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a122601]
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