ABSTRACT
INTRODUCTION: Causative mutations leading to congenital quantitative fibrinogen are frequently clustered in FGA encoding the fibrinogen Aα-chain. Mutations of FGB encoding the Bß-chain are less common and of interest since the Bß-chain is considered the rate-limiting factor in the hepatic production of the fibrinogen hexamer. METHOD: Four novel FGB mutations were identified in two afibrinogenemic (one new-born and one 30 years old male) and hypofibrinogenemic (a 49 years old female) patient, with heterogeneous thrombotic and bleeding phenotype. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed in SwissPdbViewer 4.1 and POV-Ray 3.7. RESULTS: The FGB c.895T>C p.Y299H (numbering from the initiator Met) and the FGB c.1415G>T p.G472V were predicted to be deleterious by SIFT analysis. The first replaces an uncharged aromatic amino acid side chain by a positively charged side chain modifying the balance in the distribution of hydrophobic and hydrophilic of the 10 Å neighbourhood residues. The second replaces one non-charged aliphatic side chain by another without any changes for the 10 Å surrounding region. The FGB c.352C>T p.Q118X leads to a severe premature termination codon and the FGB intron 4: IVS4-1G>C (c719-1G>C) leads to skipping of exon 5 or usage of a cryptic acceptor site located upstream or downstream of the normal site. CONCLUSIONS: The continuous characterization of novel molecular defects responsible for fibrinogen deficiency combined with modelling of mutant proteins will continue to provide a better comprehension of the complexity of fibrinogen synthesis and physiology.
