A novel fibrinogen Bβ chain frameshift mutation in a patient with severe congenital hypofibrinogenaemia

Summary

Congenital afibrinogenemia and severe hypofibrinogenemia are severe bleeding disorders characterized by either undetectable or very low levels of fibrinogen in patients’ plasma and platelets. A majority of the reported cases are caused by mutations in the fibrinogen Aα chain. In this study, we identified a genetic defect in the fibrinogen Bβ-chain (FGB) underlying severe hypofibrinogenemia. The propositus frequently displayed bleeding episodes with a prolonged blood-clotting time (thrombin time > 180 s,activated partial thromboplastin time > 300 s, prothrombin time > 120 s) and had a very low level of plasma fibrinogen (1.7–1.8 mg/dl). His parents had a consanguineous marriage, and their functional and immunological fibrinogen was approximately half of the normal level.The platelet fibrinogen level of the propositus could not be detected by western blotting, and his platelet aggregation was severely impaired. DNA screening of the whole fibrinogen gene revealed a homozygous GGGG→GGG mutation at nucleotide 7969–7972 in his FGB gene. The propositus’ parents are both heterozygous for this mutation. This mutation contributes to Gly419→Val, and the 419–434 codons are frame shifted, and a stop codon is formed at codon 435.The predicted truncated Bβ-chain is 27 amino acids shorter than the normal Bβ-chain and a central β-strand in the globular βC domain is absent,which may lead to destabilization of the entire β-domain. To the best of our knowledge, this is the first report of such a mutation which is associated with severe hypofibrinogenemia.

Keywords

Congenital hypofibrinogenemia / afibrinogenemia - fibrinogen / fibrin - gene mutation - platelet aggregation

• References

• 1 Maghzal GJ. et al. The molecular mechanisms of congenital hypofibrinogenaemia. Cell Mol Life Sci 2004; 61: 1427-38.
• 2 Neerman-Arbez M. 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; 108: 237-40.
• 3 Vu D. et al. Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood 2003; 102: 4413-5.
• 4 Duga S. et al. Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion. Blood 2000; 95: 1336-41.
• 5 Asselta R. et al. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bβ-chain gene causing afibrinogenemia. Haematologica 2002; 87: 855-9.
• 6 Wu S. et al. A novel nonsense mutation in the FGA gene in a Chinese family with congenital afibrinogenaemia. Blood Coagul Fibrinolysis 2005; 16: 221-6.
• 7 Spena S. et al. Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bβ-chain gene causing activation of cryptic splice sites. Blood 2002; 100: 4478-84.
• 8 Reheman A. et al. Vitronectin stabilizes thrombi and vessel occlusion but plays a dual role in platelet aggregation. J Thromb Haemost 2005; 03: 875-83.
• 9 Hodivala-Dilke KM. et al. β3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 1999; 103: 229-38.
• 10 George JN. et al. Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood 1990; 75: 1383-95.
• 11 Ni H. et al. Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen gamma chain. Blood 2003; 102: 3609-14.
• 12 De Marco L. et al. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986; 77: 1272-7.
• 13 Ni H. et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106: 385-92.
• 14 Ni H, Freedman J. Platelets in hemostasis and thrombosis: Role of integrins and their ligands. Transfus Apheresis Sci 2003; 28: 257-64.
• 15 Ni H. Unveiling new face of fibronectin in thrombosis and haemostasis. J Thromb Haemost 2006; 04: 940-2.
• 16 Zhang JZ, Redman CM. Identification of Bβ chain domains involved in human fibrinogen assembly. J Biol Chem 1992; 267: 21727-32.
• 17 Neerman-Arbez M. et al. Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood 2003; 101: 3492-4.
• 18 Spena S. et al. Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bβ-chain gene. Biochim Biophys Acta 2003; 1639: 87-94.
• 19 Vu D. et al. Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia. Hum Mol Genet 2005; 14: 3271-80.
• 20 Yakovlev S. et al. Role of the beta-strand insert in the central domain of the fibrinogen gamma-module. Biochemistry 2000; 39: 15721-9.
• 21 Spraggon G. et al. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin. Nature 1997; 389: 455-62.
• 22 Lord ST, Gorkun OV. Insight from studies with recombinant fibrinogens. Ann NY Acad Sci 2001; 936: 101-16.