A novel fibrinogen B beta chain frameshift mutation causes congenital afibrinogenaemia

Summary

Congenital afibrinogenaemia is a rare autosomal recessive disorder caused by various mutations within the fibrinogen genes FGA, FGB and FGG. Ins/del mutations in FGB are extremely rare. We report a patient with afibrinogenaemia who suffered from umbilical cord bleeding and repeated bleeding episodes. His plasma fibrinogen levels could not be detected using the Clauss method and immunological methods. Molecular analyses revealed homozygosity in a novel four bases insertion in codon 40 of FGB exon 2 (g. 2833_2834 ins GTTT), which resulted in a truncated 50-residue polypeptide that contained 11 exceptional abnormal residues. In the transient expression experiments, mutant fibrinogen could be detected at higher level than wild-type fibrinogen in COS-7 cell lysates but not in culture media. These results suggest that the homozygous mutation in FGB could be responsible for congenital afibrinogenaemia in this patient. This frameshift mutation could impair fibrinogen assembly and secretion without influencing the protein synthesis.

Keywords

Congenital afibrinogenaemia - FGB gene - frameshift mutation - fibrinogen secretion

^* Jian Zhang and Xiaojuan Zhao are co-first authors.

• References

• 1 Doolittle RF. Fibrinogen and fibrin. Ann Rev Biochem 1984; 53: 195-229.
• 2 Kent WJ, Sugnet CW, Furey TS. et al. The Human Genome Browser at UCSC. Genome Res 2002; 12: 996-1006.
• 3 Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. Ann NY Acad Sci 2001; 936: 480-495.
• 4 Hettasch JM, Bolyard MG, Lord ST. The residues AGDV of recombinant gamma of chains of human fibrinogen must be carboxy-terminal to support human platelet aggregation. Thromb Haemost 1992; 68: 701-706.
• 5 Bach TL, Barsigian C, Chalupowicz DG. et al. VE-Cadherin mediates endothelial cell capillary tube formation in fibrin and collagen gels. Exp Cell Res 1998; 238: 324-334.
• 6 Blomback B, Hessel B, Hogg D. et al. A two-step fibrinogen-fibrin transition in blood coagulation. Nature 1978; 275: 501-505.
• 7 Matsuda M, Sugo T. Hereditary disorders of fibrinogen variants. Ann NY Acad Sci 2001; 936: 65-88.
• 8 Ai-Mondhiry H, Ehman WC. Congenital afibrinogenemia. Am J Hematol 1994; 46: 343-347.
• 9 Meyer M. Molecular biology of haemostasis: fibrinogen, factor XIII. Hamostaseologie 2004; 24: 108-115.
• 10 Neerman-Arbez M, de Moerloose P. Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations. Hum Mutat 2007; 28: 540-553.
• 11 Kotlín R, Sobotková A, Suttnar J. et al. A novel fibrinogen variant: Liberec – dysfibrinogenaemia associated with gamma Tyr262Cys substitution. Eur J Haematol 2008; 81: 123-129.
• 12 Huang S, Mulvihill E, Farrell D. et al. Biosynthesis of human fibrinogen. Subunit interactions and potential intermediates in the assembly. J Biol Chem 1993; 268: 8919-8926.
• 13 Yu S, Sher B, Kudryk B. et al. Fibrinogen precursors. Order of assembly of fibrinogen chains. J Biol Chem 1984; 259: 10574-10581.
• 14 Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation and association with lipid synthesis and secretion. Ann NY Acad Sci 2001; 936: 480-495.
• 15 Brennan SO, Maghzal G, Shneider BL. et al. Novel fibrinogen gamma375 Arg➔Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia. Hepatology 2002; 36: 652-658.
• 16 Fellowes AP, Brennan SO, Holme R. et al. Homozygous truncation of the fibrinogen A alpha chain within the coiled coil causes congenital afibrinogenaemia. Blood 2000; 96: 773-775.
• 17 Duga S, Asselta R, Santagostino E. et al. Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion. Blood 2000; 95: 1336-1341.
• 18 Vu D, Bolton-Maggs PH, Parr JR. et al. Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood 2003; 102: 4413-4415.
• 19 Spena S, Asselta R, Duga S. et al. Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bbeta-chain gene. Biochim Biophys Acta 2003; 1639: 87-94.
• 20 Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. Ann NY Acad Sci 2001; 936: 480-495.