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Thromb Haemost 2001; 86(01): 154-163
DOI: 10.1055/s-0037-1616213
Research Article
Schattauer GmbH

The Molecular Basis of Inherited Afibrinogenaemia

Marguerite Neerman-Arbez
1   Division of Medical Genetics, University Medical School, Geneva, Switzerland
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Publication History

Publication Date:
12 December 2017 (online)

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Summary

This article reviews the substantial progress made in understanding the molecular basis of inherited afibrinogenaemia (or congenital afibrinogenaemia), an autosomal recessive disorder characterised by the complete absence of detectable fibrinogen. The identification in 1999 of the first genetic defect, recurrent homozygous deletions of approximately 11 kb of the fibrinogen alpha-chain (FGA) gene, revealed that the disease was caused by defective fibrinogen synthesis, and led to the subsequent analysis of the three fibrinogen genes in other affected individuals with the identification of numerous causative mutations. Combined analyses of more than thirty unrelated afibrinogenaemia families from various ethnic groups have shown that the majority of patients have truncating mutations in the FGA gene although intuitively all three fibrinogen genes might be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy.

Key words

Fibrinogen - mutations - recurrence - splicing - geographical distribution
 

  • References

  • 1 Rabe F, Salomon E. Ueber-faserstoffmangel im Blute bei einem Falle von Hämophilie. Arch Int Med 1920; 95: 2-14.
    PubMedGoogle Scholar
  • 2 Martinez J. Congenital Dysfibrinogenemia. Curr Opin Hemat 1997; 4: 357-65.
    PubMedGoogle Scholar
  • 3 Crabtree GR. The Molecular Biology of Fibrinogen. In: The Molecular Basis of Blood Diseases. Stamatoyannopoulos G, Nienhuis AW, Leder P, Majerus PW. eds. Philadelphia: Saunders; 1987: 631-61.
    Google Scholar
  • 4 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999; 107: 204-6.
    CrossrefPubMedGoogle Scholar
  • 5 Peyvandi F, Mannucci PM. Rare coagulation disorders. Thromb Haemost 1999; 82: 1207-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM, De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet aggregation as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986; 77: 1272-7.
    CrossrefPubMedGoogle Scholar
  • 7 Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106: 385-92.
    CrossrefPubMedGoogle Scholar
  • 8 Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ. et al. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 1998; 93: 61-70.
    CrossrefPubMedGoogle Scholar
  • 9 Doolittle RF. Fibrinogen and fibrin. Annu Rev Biochem 1984; 53: 195-229.
    CrossrefPubMedGoogle Scholar
  • 10 Mosesson MW. The roles of fibrinogen and fibrin in hemostasis and thrombosis. Semin Hematol 1992; 29: 177-188. Semin Hematol 1992; 29: 177-88.
    PubMedGoogle Scholar
  • 11 Kant JA, Fornace Jr AJ, Saxe D, Simon MI, McBride OW, Crabtree GR. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci USA 1985; 82: 2344-8.
    CrossrefPubMedGoogle Scholar
  • 12 Fowlkes DM, Mullis NT, Comeau CM, Crabtree GR. Potential basis for regulation of the coordinately expressed fibrinogen genes: homology in the 5′ flanking regions. Proc Natl Acad Sci USA 1984; 81: 2313-6.
    CrossrefPubMedGoogle Scholar
  • 13 Huber P, Laurent M, Dalmon J. Human beta-fibrinogen gene expression. Upstream sequences involved in its tissue specific expression and its dexamethasone and interleukin 6 stimulation. J Biol Chem 1990; 265: 5695-701.
    PubMedGoogle Scholar
  • 14 Liu Z, Fuller GM. Detection of a novel transcription factor for the A alpha fibrinogen gene in response to interleukin-6. J Biol Chem 1995; 270: 7580-6.
    CrossrefPubMedGoogle Scholar
  • 15 Uzan G, Courtois G, Besmond C, Frain M, Sala-Trepat J, Kahn A, Marguerie G. Analysis of fibrinogen genes in patients with congenital afibrinogenemia. Biochem Biophys Res Commun 1984; 120: 376-83.
    CrossrefPubMedGoogle Scholar
  • 16 Galanakis DK. Inherited dysfibrinogenemia: emerging abnormal structure associations with pathologic and nonpathologic dysfunctions. Semin Thromb Hemost 1993; 19: 386-95.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Neerman-Arbez M, Honsberger A, Antonarakis SE, Morris MA. Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital afibrinogenemia. J Clin Invest 1999; 103: 215-8.
    CrossrefPubMedGoogle Scholar
  • 18 Suh TT, Holmback K, Jensen NJ, Daugherty CC, Small K, Simon DI, Potter S, Degen JL. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 9: 2020-33.
    CrossrefPubMedGoogle Scholar
  • 19 Neerman-Arbez M, Antonarakis SE, Honsberger A, Morris MA. The 11kb FGA deletion responsible for congenital afibrinogenaemia is mediated by a short direct repeat in the fibrinogen gene cluster. Eur J Hum Genet 1999; 7: 897-902.
    CrossrefPubMedGoogle Scholar
  • 20 SantaLucia Jr. J. A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. Proc Natl Acad Sci USA 1998; 95: 1460-5.
    CrossrefPubMedGoogle Scholar
  • 21 Cooper DN, Krawczak M. Human Gene Mutation. Oxford: BIOS Scientific; 1993
    Google Scholar
  • 22 Ottolenghi S, Giglioni B. The deletion in a type of delta 0-beta 0-thalassaemia begins in an inverted AluI repeat. Nature 1982; 300: 770-1.
    CrossrefPubMedGoogle Scholar
  • 23 Lehrman MA, Schneider WJ, Sudhof TC, Brown MS, Goldstein JL, Russell DW. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 1985; 227: 140-6.
    CrossrefPubMedGoogle Scholar
  • 24 Lakich D, Kazazian Jr HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993; 5: 236-41.
    CrossrefPubMedGoogle Scholar
  • 25 Phillips JA, Vik TA, Scott AF, Young KE, Kazazian Jr HH, Smith KD, Fairbanks VF, Koenig HM. Unequal crossing-over: a common basis of single alpha-globin genes in Asians and American blacks with hemoglobin-H disease. Blood 1980; 55: 1066-9.
    PubMedGoogle Scholar
  • 26 Neerman-Arbez M, de Moerloose P, Bridel C, Honsberger A, Schonborner A, Rossier C, Peerlinck K, Claeyssens S, Di Michele D, d‘Oiron R. et al. Mutations in the fibrinogen A gene account for the majority of cases of congenital afibrinogenemia. Blood 2000; 96: 149-152.
    PubMedGoogle Scholar
  • 27 Neerman-Arbez M, de Moerloose P, Honsberger A, Parlier G, Arnuti B, Biron C, Borg JY, Eber S, Meili E, d‘Oiron R. et al. Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: novel truncating mutations in the FGA and FGG genes. Hum Genet. 2001 in press.
    PubMedGoogle Scholar
  • 28 Fu Y, Weissbach L, Plant PW, Oddoux C, Cao Y, Liang TJ, Roy SN, Redman CM, Grieninger G. Carboxy-terminal-extended variant of the human fibrinogen alpha subunit: a novel exon conferring marked homology to beta and gamma subunits. Biochemistry 1992; 31: 11968-72.
    CrossrefPubMedGoogle Scholar
  • 29 Grieninger G, Lu X, Cao Y, Fu Y, Kudryk BJ, Galanakis DK, Hertzberg KM. Fib420, the novel fibrinogen subclass: newborn levels are higher than adult. Blood 1997; 90: 2609-14.
    PubMedGoogle Scholar
  • 30 Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat 1998; 11: 1-3.
    CrossrefPubMedGoogle Scholar
  • 31 den Dunnen JT, Antonarakis SE, den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000; 15: 7-12.
    CrossrefPubMedGoogle Scholar
  • 32 Fellowes AP, Brennan SO, Holme R, Stormorken H, Brosstad FR, George PM. Homozygous truncation of the fibrinogen Aalpha chain within the coiled coil causes congenital afibrinogenemia. Blood 2000; 96: 773-5.
    PubMedGoogle Scholar
  • 33 Furlan M, Steinmann C, Jungo M, Bogli C, Baudo F, Redaelli R, Fedeli F, Lammle B. A frameshift mutation in Exon V of the A alpha-chain gene leading to truncated A alpha-chains in the homozygous dysfibrinogen Milano III. J Biol Chem 1994; 269: 33129-34.
    PubMedGoogle Scholar
  • 34 Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A alpha 461-610 (Lys 461 AAA stop TAA). Blood 1992; 80: 1972-9.
    PubMedGoogle Scholar
  • 35 Ridgway HJ, Brennan SO, Gibbons S, George PM. Fibrinogen Lincoln: a new truncated alpha chain variant with delayed clotting. Br J Haematol 1996; 93: 177-84.
    CrossrefPubMedGoogle Scholar
  • 36 Ridgway HJ, Brennan SO, Faed JM, George PM. Fibrinogen Otago: a major alpha chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Br J Haematol 1997; 98: 632-9.
    CrossrefPubMedGoogle Scholar
  • 37 Gorkun OV, Henschen-Edman AH, Ping LF, Lord ST. Analysis of A alpha 251 fibrinogen: the alpha C domain has a role in polymerization, albeit more subtle than anticipated from the analogous proteolytic fragment X. Biochemistry 1998; 37: 15434-41.
    CrossrefPubMedGoogle Scholar
  • 38 Wyatt J, Brennan SO, May S, George PM, Wyatt J, Brennan SO, May S, George PM. Hypofibrinogenaemia with compound heterozygosity for two gamma chain mutations – gamma 82 Ala Gly and an intron two GT AT splice site mutation. Thromb Haemost 2000; 84: 449-52.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Duga S, Asselta R, Santagostino E, Zeinali S, Simonic T, Malcovati M, Mannucci PM, Tenchini ML. Missense mutations in the humanfibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion. Blood 2000; 95: 1336-41.
    PubMedGoogle Scholar
  • 40 Iida H, Ishii E, Nakahara M, Urata M, Wakiyama M, Kurihara M, Watanabe K, Kai T, Ihara K, Kinoshita S. et al. A case of congenital afibrinogenaemia: fibrinogen Hakata, a novel nonsense mutation of the fibrinogen γ-chain gene. Thromb Haemost 2000; 84: 49-53.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Asselta R, Duga S, Simonic T, Malcovati M, Santagostino E, Giangrande PL, Mannucci PM, Tenchini ML. Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation. Blood 2000; 96: 2496-500.
    PubMedGoogle Scholar
  • 42 Margaglione M, Santacroce R, Colaizzo D, Seripa D, Vecchione G, Lupone MR, De Lucia D, Fortina P, Grandone E, Perricone C. et al. A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenemia due to abnormal RNA splicing. Blood 2000; 96: 2501-5.
    PubMedGoogle Scholar
  • 43 Krawczak M, Reiss J, Cooper DN. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992; 90: 41-54.
    PubMedGoogle Scholar
  • 44 Cooper DN, Krawczak M, Antonarakis SE. The nature and mechanisms of human gene mutation. In: The Metabolic and Molecular Bases of Inherited Disease. (7th edition) Scriver CR, Beudet AL, Sly WS, Valle D. eds. New York: McGraw-Hill Inc; 1995: 259-91.
    Google Scholar
  • 45 Wittop Koning TH, Schümperli D. RNAs and ribonucleoproteins in recognition and catalysis. Eur J Biochem 1994; 219: 29-42.
    PubMedGoogle Scholar
  • 46 Kramer A. The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem 1996; 65: 367-409.
    CrossrefPubMedGoogle Scholar
  • 47 Rogozin IB, Milanesi L. Analysis of donor splice signals in different organisms. J Mol Evol 1997; 45: 50-9.
    CrossrefPubMedGoogle Scholar
  • 48 Attanasio C, de Moerloose P, Antonarakis SE, Morris MA, Neeman-Arbez M. Activation of multiple cryptic donor splice sites by the common congenital afibrinogenemia mutation, FGA IVS4+1 G T. Blood 2001; 97: 1879-81.
    CrossrefPubMedGoogle Scholar
  • 49 Roy SN, Procyk P, Kudryk BJ, Redman CM. Assembly and secretion of recombinant human fibrinogen. J Biol Chem 1991; 266: 4758-63.
    PubMedGoogle Scholar
  • 50 Gantla S, Bakker C, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M, Roy Chowdhury J, Bosma PJ, RoyChowdhury N. Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. Am J Hum Genet 1998; 62: 585-92.
    CrossrefPubMedGoogle Scholar