A novel missense mutation in the FGB gene (p.Gly302Arg) leading to afibrinogenemia. Predicted structure and function consequences.

Afibrinogenemia represents the rarest form of fibrinogen deficiency. Causative missense mutations occur rarely and may improve the understanding of fibrinogen structure and function.

PATIENTS AND METHODS: The propositus was a 26-year-old Argentinian with afibrinogenemia. FGA, FGB and FGG exons and flanking regions were screened by sequencing and the mutant protein was analyzed in silico.

RESULTS: A novel missense mutation in the FGB gene (Bbeta Gly272Arg, p.Gly302Arg) was identified. In silico analysis revealed its location in a highly conserved region, which preserves the core fold of the C-terminal beta-chain and is important for proper secretion. A substitution by a positively charged large Arg residue in this area would most likely disturb the core fold by additional interactions with adjacent residues (p.Asp291, p.Asp297, p.Asp311), or by forming of non-native interactions with other proteins, thereby hindering the action of molecular chaperones. Both alternatives would disturb the regular secretion of the beta-chain.

CONCLUSIONS: The novel missense mutation in the FGB gene causes afibrinogenemia most probably by affecting the secretion of the fibrinogen beta-chain.