Alternative titles; symbols
HGNC Approved Gene Symbol: FGA
SNOMEDCT: 154818001, 439145006, 66451004; ICD10CM: D68.2;
Cytogenetic location: 4q31.3 Genomic coordinates (GRCh38): 4:154,583,126-154,590,742 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.3 | Afibrinogenemia, congenital | 202400 | Autosomal recessive | 3 |
| Amyloidosis, familial visceral | 105200 | Autosomal dominant | 3 | |
| Dysfibrinogenemia, congenital | 616004 | 3 | ||
| Hypodysfibrinogenemia, congenital | 616004 | 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).
Fu et al. (1992) showed that FGA, like FGB and FGG, has a sixth exon, which encodes 236 amino acids, and is used in a minor isoform of the alpha subunit referred to as alpha(E). Fu et al. (1995) compared exon VI sequence from chicken, rabbit, rat, and baboon with the human sequence and showed that it is highly conserved, implying an important physiologic function.
Henry et al. (1984) isolated clones of each fibrinogen chain (A-alpha, B-beta, and gamma) from a human liver cDNA library and showed by Chinese hamster-human somatic cell hybrids that all 3 are located on chromosome 4, thus confirming the assignment of gamma fibrinogen by linkage with MN (111300). All 3, which are coordinately expressed, are syntenic. Direct gene-dosage studies in 2 patients with unbalanced rearrangements of chromosome 4 permitted regional assignment to 4q2.
Kant and Crabtree (1983) used cDNA probes for the alpha, beta, and gamma chains of rat fibrinogen to isolate the corresponding genes from 2 rat genomic libraries constructed in bacteriophage Charon 4A. A single copy of each gene was found. Mapping of greater than 92 kilobases of rat genomic DNA showed that the gamma and alpha chains are directly linked in a 5-prime-3-prime direction. Rats defibrinated with Malayan pit viper venom showed a rapid and substantial increase in the relative abundance of hepatic RNAs for all 3 chains (Crabtree and Kant, 1982).
The genes for the 3 chains are transcribed as separate mRNAs (Uzan et al., 1982; Kant and Crabtree, 1983). Using a cDNA probe, Humphries et al. (1984) localized FGA to 4q29-q31. In somatic cell hybrids carrying a translocation involving chromosome 4 with a breakpoint at 4q26, all 3 fibrinogen genes segregated with the 4q26-qter segment. By in situ hybridization, Marino et al. (1986) located the fibrinogen gene cluster to 4q31.
By means of one or more RFLPs at each locus, Aschbacher et al. (1985) studied linkage disequilibrium in the fibrinogen cluster. They concluded that the likely order is gamma-alpha-beta. This agrees with the order suggested by Kant et al. (1985). Thomas et al. (1994) demonstrated linkage disequilibrium using restriction polymorphisms of the FGA and FGB genes detected by PCR.
Akassoglou et al. (2002) reported that fibrin inhibits peripheral nerve remyelination by regulating Schwann cell differentiation. Using immunocytochemistry and Western blot analysis to follow fibrin deposition during nerve regeneration, the authors observed that fibrin is deposited after sciatic nerve crush and that its clearance is correlated with nerve repair after sciatic nerve injury in normal mice. Using experiments to quantitate myelinating axons, they revealed that fibrin(ogen)-deficient mice showed an increase in myelinated axons after sciatic nerve injury compared to normal mice. The authors observed that fibrin induced ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and production of p75 nerve growth factor low-affinity receptor (NGFR; 162010) in Schwann cells; fibrin maintained ERK1 and NGFR in a nonmyelinating state, suppressed fibronectin production, and prevented synthesis of myelin proteins. Akassoglou et al. (2002) hypothesized that regulation of fibrin clearance and/or deposition is a regulatory mechanism for Schwann cell differentiation after nerve damage.
Ahn et al. (2014) noted that fibrinogen is a cerebrovascular risk factor in Alzheimer disease (AD; 104300) that specifically binds beta-amyloid (see 104760), thereby altering fibrin clot structure and delaying clot degradation. Using a high-throughput screen, they identified RU-505 as an inhibitor of the interaction between beta-amyloid and fibrinogen. RU-505 restored beta-amyloid-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Long-term treatment with RU-505 significantly reduced vascular amyloid deposition and microgliosis in cortex and improved cognitive impairment in mouse models of AD. Ahn et al. (2014) proposed that inhibitors of the interaction between beta-amyloid and fibrinogen may be useful in AD therapy.
Hamsten et al. (1987) concluded that a substantial portion of the variance of the plasma fibrinogen level (51%) is accounted for by genetic heritability. The combined effect of obesity and smoking was found to explain 3% of the variance. Serum transaminase levels were slightly elevated.
Afbrinogenemia, Hypofibrogenemia, and Dysfibrinogenemia
Olaisen et al. (1982) stated that molecular fibrinogen variants of apparent genetic origin had been described in more than 40 persons. Gralnick and Finlayson (1972) and Ratnoff and Bennett (1973) provided tabulations of fibrinogen variants. The distinctness of all the types (over 50 as of 1981) had not been proven. Most of the variants had been detected on coagulation tests in which plasma fibrinogen is converted to fibrin (thrombin time, reptilase test, prothrombin time). The times are prolonged or infinite (i.e., no clot is formed). Chemical or immunologic assays for fibrinogen are usually normal, however. Although the variants may be asymptomatic, abnormal bleeding, abnormal clotting, and wound dehiscence in isolation or in some combination has been observed. The defect in conversion of fibrinogen to fibrin occurs, in a few of the variants, at the first step, that of removal of fibrinopeptides A and B by thrombin to form fibrin monomer. The majority, however, have the defect in the second step, that of aggregation of fibrin monomer to form a fibrin gel. (The third step is covalent cross-linking of fibrin, catalyzed by activated factor XIII, to form an insoluble clot.)
Wehinger et al. (1983) described a variant of hypofibrinogenemia (see 202400) that they concluded was due to defective fibrinogen release from hepatocytes. The outstanding feature was massive deposition of fibrinogen/fibrin within hepatocytes, faintly visible in routine microscopic sections but clearly demonstrable by immunohistologic techniques. All 3 chains of circulating fibrinogen showed normal electrophoretic mobility. Seemingly, there were no ill effects on liver function.
Using clones from the alpha, beta, and gamma fibrinogen genes, Uzan et al. (1984) studied DNA from normal individuals and 2 patients with afibrinogenemia (202400). The results indicated that the single-copy fibrinogen genes were grossly intact in afibrinogenemic DNA.
Rupp and Beck (1984) reviewed all the fibrinogen variants. Information on variant human fibrinogens was cataloged by Ebert (1990). Galanakis (1993) reviewed inherited dysfibrinogenemia (616004), correlating abnormal structure with pathologic and nonpathologic dysfunction.
In patients with congenital afibrinogenemia, a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen, Neerman-Arbez et al. (1999) demonstrated mutations in the FGA gene (134820.0019-134820.0020).
In a study of 8 afibrinogenemic probands with very low plasma levels of immunoreactive fibrinogen, Asselta et al. (2001) found 4 novel point mutations and 1 previously reported mutation. All mutations, localized within the first 4 exons of the FGA gene, were null mutations predicted to produce severely truncated A-alpha chains because of the presence of premature termination codons. Further study indicated that all the identified null mutations escaped nonsense-mediated mRNA decay. Other analyses at the protein level demonstrated that the presence of each mutation was sufficient to abolish fibrinogen secretion.
Familial Visceral Amyloidosis
In a Peruvian family in which a brother and sister and the son of the brother died from renal amyloidosis (105200), Benson et al. (1993) identified a missense mutation in the FGA gene (R554L; 134820.0012).
In 2 large American kindreds of Irish descent with nephrotic syndrome due to renal amyloidosis, Uemichi et al. (1993, 1994) identified a missense mutation in the FGA gene (E526V; 134820.0013).
In an American kindred with hereditary renal amyloidosis, Uemichi et al. (1996) identified a 1-bp deletion in the FGA gene (134820.0016), causing a frameshift and termination sequence at codon 548. The authors stated that this was the first description of a kindred with renal amyloidosis and low plasma fibrinogen, and the first report of amyloidosis caused by a frameshift mutation.
In a French kindred with autosomal dominant hereditary renal amyloidosis, Hamidi Asl et al. (1997) identified a different 1-bp deletion in the FGA gene, also resulting in termination at codon 548 (134820.0018).
Lachmann et al. (2002) studied 350 patients with systemic amyloidosis and identified heterozygosity for the E526V mutation in 18 (5.1%) of the patients.
To examine directly the role of fibrin(ogen) in atherogenesis, Xiao et al. (1998) crossed fibrinogen-deficient mice with atherosclerosis-prone apolipoprotein E (apoE)-deficient mice. Both apoE -/- mice and mice that were doubly deficient in apoE and fibrinogen developed lesions throughout the entire aortic tree, ranging in appearance from simple fatty streaks to complex fibrous plaques. Furthermore, remarkably little difference in lesion size and complexity was observed within the aortas of age- and gender-matched, singly and doubly deficient mice. These results indicated that the contribution of fibrin(ogen) to intimal mass and local cell adhesion, migration, and proliferation is not strictly required for the development of advanced atherosclerotic disease in mice with a severe defect in lipid metabolism.
Fibrin(ogen) has been proposed to play an important role in tissue repair by providing an initial matrix that can stabilize wound fields and support local cell proliferation and migration. Consistent with this is the observation that abnormal wound healing and postoperative wound dehiscence were clinical symptoms of those with dysfibrinogenemias (616004) in which fibrin crosslinking was deficient (e.g., Paris I; 134850.0011). Drew et al. (2001) investigated the effect of fibrinogen deficiency on cutaneous tissue repair in mice using incisional and excisional wounds. The time required to heal wounds was similar in fibrinogen-deficient (Fib -/-) and control mice, but histologic evaluation showed distinct differences in the repair process, including an altered pattern of epithelial cell migration and increased epithelial hyperplasia. Furthermore, granulation tissue failed to close the wound gap adequately, resulting in persistent open wounds or partially covered sinus tracts. The tensile strength of these wounds was also reduced compared with control mice. In knockout mice with fibrinogen deficiency, Suh et al. (1995) had previously shown that spontaneous bleeding events resolved but that pregnancies failed.
The first example of a qualitatively abnormal fibrinogen (subsequently called fibrinogen Parma) was that described by Imperato and Dettori (1958); the first demonstration of inheritance was given by Menache (1963) for the fibrinogen subsequently called Paris I (134850.0011). In a family of Hungarian extraction, von Felton et al. (1966) described a clotting disturbance, characterized by delayed aggregation of fibrin monomers, in father and son. Chemical studies suggested a molecular abnormality of fibrinogen. Forman et al. (1968) described fibrinogen Cleveland, which was immunoelectrophoretically distinct from fibrinogen Baltimore (described by Beck et al., 1965). Operative wounds showed dehiscence in 2 individuals with the abnormal fibrinogen. The plasma in 8 related individuals of both sexes showed abnormally slow coagulation when thrombin was added. The fibrinogen described by Blomback et al. (1968) and Mammen et al. (1969) called fibrinogen Detroit had characteristics different from fibrinogen Baltimore and fibrinogen Cleveland. Fibrinogen Oklahoma appears to have a structural defect such that cross-linkage is defective.
By amino acid sequencing, Doolittle et al. (1970) could find no variation of fibrinopeptides A and B from 125 persons.
Kohn et al. (1983) observed a correlation between a balanced 7p;12q translocation and hypofibrinogenemia. The proband experienced first-trimester abortions. Normal clotting factors are necessary for placentation.
See Morris et al. (1981).
See Soria et al. (1985).
Fibrinogen Metz has also been called fibrinogen Bergamo-1, Hershey-2, Hershey-3, Homburg-2, Homburg-3, Kawaguchi-1, Ledyard, Leogan, New Albany, Osaka-1, Schwarzach-1, Stony Brook-1, Torino-1, Zurich-1, and Milano XII digenic.
Fibrinogen Metz is an arg16-to-cys (R16C) substitution in the fibrinogen alpha chain (Henschen et al., 1981). See also Southan et al. (1982), Henschen et al. (1983), Reber et al. (1985), Miyashita et al. (1985), and Miyata et al. (1987). Galanakis et al. (1989) stated that 52 dysfibrinogens had been structurally characterized and that most were single amino acid substitutions with a high frequency of substitutions at arg positions A-alpha-16, A-alpha-19, B-beta-14, and gamma-275. Galanakis et al. (1989) described an R16C substitution in fibrinogen Stony Brook and described the functional characteristics of the variant. According to Galanakis (1993), this mutation has been identified in 15 unrelated families. In 2 of these, an arg16-to-his (R16H; 134820.0004) mutation was detected by both DNA and protein sequencing. Lee et al. (1991) found the R16C variant, which they called fibrinogen Ledyard, in a 10-year-old boy with a history of mild bleeding whose father had the same defect and a history of bleeding after surgery. Both patients were heterozygous.
Bolliger-Stucki et al. (2001) described an anomalous fibrinogen called Milano XII in an asymptomatic Italian woman, and demonstrated that its basis was double heterozygosity for the R16C mutation in exon 2 of the FGA gene, and a G165R mutation in the FGG gene (134850.0018). The woman's condition was discovered when routine coagulation test results showed a prolonged thrombin time. Fibrinogen levels in functional assays were considerably lower than levels in immunologic assays. Bolliger-Stucki et al. (2001) concluded that the FGA mutation was mainly responsible for the coagulation abnormalities, whereas the change in the FGG gene was responsible for a conformational change in the D3 fragment.
The R16C mutation of the FGA gene is a common cause of dysfibrinogenemia (616004) and is associated with both bleeding and thrombosis. Flood et al. (2006) proposed to understand the mechanism of the thrombotic phenotype. They studied a young patient with dysfibrinogenemia (fibrinogen Hershey III) who was found to be heterozygous for the R16C mutation. Functional assays were performed on purified fibrinogen to characterize clot formation and lysis with plasmin and trypsin. Consistent with previous results, clot formation was diminished, but unexpectedly, fibrinolysis was also delayed. When clot lysis was assayed with trypsin substituted for plasminogen, a significant delay was also observed, indicating that defective binding to plasminogen could not explain the fibrinolytic resistance. The results suggested that the defective fibrinolysis is due to increased proteolytic resistance, most likely reflecting changes in clot structure.
Flood et al. (2006) stated that the R16C mutation is the most common fibrinogen mutation in humans. Although about 30% of the reported cases of the R16C mutation in humans are associated with hemorrhage, some 15% of reported cases are associated with thrombosis (Hanss and Biot, 2001).
Fibrinogen Petoskey-1 has also been called fibrinogen Amiens-1, Amiens-2, Bergamo-3, Bern-2, Bicetre-1, Birmingham-1, Chapel Hill-2, Clermont-Ferrand-1, Giessen-1, Leitchfield, Long Beach-1, Louisville-1, Manchester-1, Paris-6, Petoskey-1, Seattle-2, Sheffield-2, Sydney-1, Sydney-2, and White Marsh-1.
In fibrinogen Petoskey (named for Petoskey, Michigan, the site of the hospital where the blood samples were collected), Higgins and Shafer (1981) detected replacement of arg-A(alpha)16 by a histidyl residue (R16H). In an abnormal fibrinogen associated with excessive postpartum bleeding and called fibrinogen White Marsh for the Virginia town of the patient's residence, Qureshi et al. (1983) also found the R16H mutation in the alpha chain. Carrell et al. (1983) gave the name fibrinogen Chapel Hill to a fibrinogen variant associated with thrombotic disease. Fibrinogen Manchester also exhibits the R16H mutation. Southan et al. (1985) found that platelet fibrinogen expresses the heterozygous R16H phenotype, thus supporting the view that the A-alpha chains of platelet and plasma fibrinogen are produced by a single genetic locus. Alving and Henschen (1987) reported that a patient homozygous for fibrinogen Giessen I had a substitution of histidine for arginine at position 16. Although this patient had had excessive postpartum bleeding, she had normal hemostasis throughout several minor surgical procedures and during hysterectomy. Reber et al. (1987) described 2 fibrinogen variants in which there was a substitution for arginine-16 in the alpha chain by histidine in one and by cysteine in the other; these were designated fibrinogen Bergamo III and fibrinogen Torino (134820.0003), respectively. See also Galanakis et al. (1983), Ebert et al. (1986), and Siebenlist et al. (1988).
According to Galanakis (1993), the R16H mutation had been identified in 22 unrelated families, making it the most frequent form of dysfibrinogenemia. Together with R16C, it represented the majority of the mutations characterized, 37 out of 63.
See Southan et al. (1982).
The first specific amino acid substitution was found in fibrinogen Detroit (Blomback et al., 1968); serine is substituted for arginine as the 19th residue of the alpha chain (R19S) (Blomback and Blomback, 1970).
See Blomback et al. (1988).
In a 27-year-old woman with a bleeding diathesis, Yoshida et al. (1991) found heterozygosity for a substitution of leucine for proline-18 (P18L) in the A-alpha chain. Studies of the P18L mutation indicated that P18 is an important part of the polymerization site in the NH2-end of the fibrin alpha chain.
Fibrinogen Caracas II is a congenital dysfibrinogen which was originally found in an asymptomatic girl who had prolonged thrombin clotting. She and her father were heterozygotes. Maekawa et al. (1991) described a unique N-glycosylated asparagine substitution for serine-434 (S434N) of the A-alpha chain. This dysfibrinogen was characterized by impaired fibrin monomer aggregation.
Arocha-Pinango et al. (1990) described a 10-year-old girl from Lima, Peru, who had an apparently homozygous dysfibrinogenemia with impaired fibrin polymerization. The parents were first cousins and were thought to have the same type of dysfibrinogen in the heterozygous form. Although transient hematuria was noted in the patient, there was no history of bleeding or thrombosis related to this abnormality in the family. The abnormality of fibrinogen was discovered by the discrepancy between the plasma fibrinogen level determined by the thrombin time method and the gravimetric method. Similar but less remarkable discrepancies were noted in the levels of plasma fibrinogen in her parents. In the patient reported by Arocha-Pinango et al. (1990), Maekawa et al. (1992) identified a substitution of serine for arginine-141 (R141S) in fibrinogen A-alpha. The point mutation created a new glycosylation sequence. See 300841.0065 and 300841.0066 for examples of 2 mutations in factor VIII that introduce new N-glycosylation sites and result in CRM-positive hemophilia A.
Koopman et al. (1992) identified fibrinogen Marburg in a 20-year-old woman who suffered a uterine hemorrhage after delivery of her first child by cesarean section. Pulmonary embolism and deep pelvic thrombosis (616004) occurred thereafter. The patient's mother had died of apoplexy after a long period of hypertension. All other family members were asymptomatic, although the father and 5 sibs were heterozygous and 3 other sibs had only normal fibrinogen. The proposita was homozygous for an A-to-T transversion that changed codon 461 from AAA (lys) to TAA (stop).
This variant has also been called fibrinogen Paris I.
Benson et al. (1993) studied a family in which a brother and sister and the son of the brother died from renal amyloidosis (105200). They were all found to share a nucleotide substitution in the FGA gene. The predicted arg554-to-leu mutation (R554L) was proven by amino acid sequence analysis of amyloid fibril protein isolated from postmortem kidney of 1 of the affected individuals. Direct genomic DNA sequencing and RFLP analysis demonstrated that all 3 affected family members had the G-to-T transversion at position 4993. This was the first demonstration of hereditary amyloidosis associated with a variant fibrinogen alpha chain. The propositus was a Peruvian male who died at age 50. At age 36 he had developed nephrotic syndrome and subsequently azotemia due to renal amyloidosis. At age 40 he received a cadaver renal transplant and enjoyed good health for 8 years until renal biopsy showed diffuse amyloid involvement of glomeruli in the transplanted kidney. He died with septicemia after receiving a second renal allograft. The patient's sister, who had nephrotic syndrome, died at age 28. The patient's son developed azotemia at age 24. Benson et al. (1993) pointed to the close similarity to the Ostertag form of renal amyloidosis (105200).
In 2 large American kindreds of Irish descent, Uemichi et al. (1993, 1994) found that renal amyloidosis (105200) presenting with nephrotic syndrome was associated with an A-to-T transversion at position 1674 of the FGA gene, predicting a glu-to-val change in amino acid residue 526 (E526V). In 1 kindred, renal amyloidosis presented with nephrotic syndrome in the late forties and death occurred by age 60; in the other kindred, nephrotic syndrome presented in the early sixties, with death in the early seventies. Neither kindred had neuropathy or cardiomyopathy. Uemichi et al. (1996) reported 2 further kindreds, 1 Polish Canadian and the other Irish American, with the E526V mutation. In these 4 kindreds, affected members developed hypertension and nephrotic syndrome due to amyloidosis in their forties or fifties. Haplotype analysis suggested that all 4 kindreds may have been derived from a single founder.
In 18 patients of northern European ancestry with renal amyloidosis, Lachmann et al. (2002) found the E526V mutation. The median age of presentation was 59 years, with a range from the thirties to 78. Spontaneous splenic rupture occurred in 2 patients.
In a 48-year-old man with proteinuria, in whom renal biopsy revealed amyloid deposits exclusively in the mesangium of the glomeruli and whose mother had died of renal amyloidosis, Mourad et al. (2008) identified the E526V mutation in the FGA gene. Four years later, the patient required implantation of a defibrillator due to cardiac arrhythmia; echocardiography suggested cardiac amyloidosis, and the diagnosis was confirmed by multiple myocardial biopsies showing amyloid deposits in subendocardial and perivascular areas.
Fibrinogen Dusart has also been called fibrinogen Paris V.
Fibrinogen Dusart is a form of dysfibrinogenemia associated with recurrent thrombosis (616004). Koopman et al. (1993) demonstrated that the defect was a C-to-T transition in the FGA gene, resulting in the substitution of cysteine for arginine-554 (R554C). Electron microscopic studies on fibrin formed from purified fibrinogen Dusart demonstrated fibers that were much thinner than in normal fibrin. The additional cysteine created by the mutation was involved in the formation of fibrinogen-albumin complexes in plasma; a substantial part of the fibrinogen Dusart molecules were disulfide-linked to albumin.
Mosesson et al. (1996) found that the abnormal Dusart chains promote 'preassembly' of fibrinogen molecules and consequent increased cross-linking potential, a phenomenon that probably plays a causal role in the thrombophilia associated with this defect.
Fibrinogen Canterbury was detected by Brennan et al. (1995) in a 45-year-old vegetarian with type III hyperlipoproteinemia (see 107741), which brought him to the attention of a lipid clinic. Fibrinogen was measured as part of the routine panel of cardiovascular risk factors. On specific questioning, it was found that he had a tendency to prolonged bleeding, lasting up to 15 minutes, from even minor cuts. He denied easy bruising. Heterozygosity for a val20-to-asp (V20D) mutation of the FGA gene was found. The molar ratio of fibrinopeptide A to B released by thrombin was substantially reduced (0.64), suggesting either impaired cleavage or that the majority of the variant alpha-chains lacked the A peptide. The latter novel proposal arose from the observation that the mutation changed the normal RGPRV sequence of amino acids 16-20 to RGPRD, creating a potential furin cleavage site at arg19. Synthetic peptides incorporating both sequences were tested for substrates for both thrombin and furin (136950). There was no substantial difference in the thrombin-catalyzed cleavage; however, the variant peptide, but not the normal one, was rapidly cleaved at arg19 by furin. Predictably, intracellular cleavage of the A-alpha-chain at arg19 would remove fibrinopeptide A together with the GPR polymerization site. This was confirmed by sequence analysis of fibrinogen A-alpha chains after isolation by SDS-PAGE. The expected normal sequence was detected together with the new sequence commencing at residue 20.
In an American kindred with hereditary renal amyloidosis (105200), Uemichi et al. (1996) found that the FGA gene had a single nucleotide deletion at the third base of codon 524, a deletion of 4904G, that resulted in a frameshift and premature termination of the protein at codon 548. Antiserum was produced to a portion of the abnormal peptide predicted by the DNA sequence, and amyloid deposits were immunohistologically proven to contain this abnormal polypeptide. Two of the 4 children of the proposita were positive for mutant gene by RFLP analysis based on PCR. In the second decade of life, the 2 mutant gene carriers showed no clinical symptoms of amyloidosis but had lower plasma fibrinogen concentrations when compared with their normal sibs. Uemichi et al. (1996) stated that this was the first description of a kindred with renal amyloidosis and low plasma fibrinogen and the first report of amyloidosis caused by a frameshift mutation. The proposita had onset at age 41 years and showed no signs of involvement other than in the kidney. She died at the age of 46 years. Her mother died at 38 years of age and a maternal uncle died at 41 years of age, both of renal failure. The onset of disease in the late thirties and early forties was later than that in patients with the R554L mutation of the FGA gene (134820.0012), who were affected in their twenties or thirties, and earlier than that in individuals with the E526V mutation of the FGA gene (134820.0013), who developed the disease in the fifth through seventh decade of life. Uemichi et al. (1996) speculated that the abnormal fibrinogen chain in this kindred, which is missing 14% of the normal C-terminal sequence (residues 525- 610) and has an abnormal peptide sequence of 23 amino acid residues, may be degraded much more rapidly than the normal protein.
Hamidi Asl et al. (1997) found that a French kindred with autosomal dominant hereditary renal amyloidosis (105200) had a novel mutation in the FGA gene. In this kindred, renal disease appeared early in life and led to terminal renal failure at an early age. The propositus developed nephrotic syndrome at age 31 years; his son presented with it at age 12 years. Renal failure in the son progressed rapidly with severe hypertension, and peritoneal dialysis was begun 1 year after onset of nephrotic syndrome. Renal transplantation was performed at the age of 15 years. Amyloid fibril protein isolated from the transplanted kidney of the propositus was found to contain a novel hybrid peptide of 49 residues whose N-terminal 23 amino acids were identical to residues 499 to 521 of normal fibrinogen A-alpha chain. The remaining 26 residues of the peptide represented a completely new sequence for mammalian proteins. DNA sequencing documented that the new sequence was the result of a single nucleotide deletion, 4897T, of the FGA gene, creating a frameshift at codon 522 and premature termination at codon 548. The FGA gene of the propositus's son contained the same mutation. Liver transplantation to stop synthesis of this abnormal liver-derived protein should be considered early in the course of this disease.
In a nonconsanguineous Swiss family with congenital afibrinogenemia (202400), Neerman-Arbez et al. (1999) demonstrated that 4 affected males (2 brothers and their 2 first cousins) were homozygous for a deletion of approximately 11 kb from the FGA gene. Haplotype data suggested that deletions occurred separately, on 3 distinct ancestral chromosomes, implying that the FGA region is susceptible to deletion by a common mechanism. This was said to be the first known causative mutation for congenital afibrinogenemia. Neerman-Arbez et al. (1999) found that all 3 deletions were identical to the level of the basepair and probably resulted from nonhomologous (illegitimate) recombination. The centromeric and telomeric deletion junctions featured both a 7-bp direct repeat, AACTTTT, situated in FGA intron 1 and in the FGA-FGB (134830) intergenic sequence, and a number of inverted repeats that could be involved in the generation of secondary structures. Analysis with closely linked flanking polymorphic markers revealed the existence of at least 2 haplotypes, further suggesting independent origins of the deletions in this family.
Neerman-Arbez et al. (2000) collected data on 13 additional unrelated patients with congenital afibrinogenemia to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation at the donor splice site of FGA intron 4 (IVS4G-T+1; 134820.0020) accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the 11-kb deletion. Neerman-Arbez et al. (2000) stated that 86% of afibrinogenemia alleles analyzed to that time had truncating mutations of FGA, although mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.
Neerman-Arbez et al. (2000) collected data on 13 unrelated patients with congenital afibrinogenemia (202400). A common recurrent mutation at the donor splice site of FGA intron 4 (IVS4G-T+1) accounted for 14 of the 26 (54%) alleles.
Collen et al. (2001) discovered fibrinogen Nieuwegein to be the cause of congenital dysfibrinogenemia in a young man without any thromboembolic complications or bleeding. He showed a prolonged activated partial thrombin time, which was determined routinely before a biopsy procedure. The abnormal fibrinogen resulted from a homozygous insertion of a single nucleotide (C) at codon 453 (pro) of the FGA gene, resulting in deletion of the carboxyl-terminal segment, amino acids 454-610. The ensuing unpaired cysteine-442 generated fibrinogen-albumin complexes of different molecular weights. Delayed clotting and a fibrin network with a low turbidity resulted. The altered fibrin structure, which could not be cross-linked by tissue transglutaminase, was less supportive for ingrowth of endothelial cells.
Vlietman et al. (2002) described congenital afibrinogenemia (202400) in a newborn female with hemorrhagic diathesis. The pregnancy and delivery had been uneventful. She was the first child of consanguineous parents (first cousins). DNA analysis revealed the insertion of an extra thymine between nucleotides 3983 and 3986 in exon 5 of FGA. The patient was homozygous for this novel mutation. The insertion changed codon TTT (PAG) to TAA (stop).
Lefebvre et al. (2004) described a nonconsanguineous American family of European descent in which 2 sibs with hypodysfibrinogenemia (see 616004) had lifelong trauma-related bleeding. The brother had recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. DNA analysis revealed a heterozygous CAA-to-TAA mutation at codon 328 of the FGA gene resulting in a gln328-to-ter (Q328X) amino acid change (fibrinogen Keokuk), which predicted a 46% truncation and the production of a 35-kD fibrinogen A-alpha chain. The sibs and their mother were found to be heterozygous for a second FGA mutation, a GT-to-TT splice site mutation in intron 4 (IVS4+1G-T; 134820.0025).
See 134820.0024 and Lefebvre et al. (2004).
Among 122 patients with deep venous thrombosis and 99 patients with pulmonary embolism (see 188050), Carter et al. (2000) found an association between a 4266A-G transition in the FGA gene, resulting in a thr312-to-ala (T312A) substitution, and the development of pulmonary embolism. Homozygosity for the ala312 allele conferred an odds ratio of 2.71 compared to homozygosity for the thr312 allele. No association was found for venous thrombosis. The T312A polymorphism occurs close to the alpha-fibrin/alpha-fibrin cross-linking site, which may influence the strength of cross-linking in clots.
In a case-control study of 186 Taiwanese patients with venous thromboembolism, Ko et al. (2006) observed an association between venous thromboembolism and the ala312 allele. An FGA haplotype containing the ala312 allele was also associated with venous thromboembolism, although controls with the haplotype did not have increased plasma fibrinogen levels.
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