Background: In recent years it has become clear that the molecular investigation of hypofibrinogenemia provides unique insight into regions of the fibrinogen molecule that are important in molecular assembly, secretion and stability.
Objectives: To investigate a case of hypofibrinogenemia at the molecular level.
Patients and methods: The study was conducted on a 37-year-old woman from Mannheim, Germany, who had an antigenic plasma fibrinogen concentration of 0.86 g L(-1). Mutation screening was performed by DNA sequencing and the effect of the identified mutation was investigated at the protein level.
Results: Analysis of exon 8 of the fibrinogen gamma gene identified a heterozygous CAT-->TAT transition at codon 307. This novel His-->Tyr substitution was not detected when plasma fibrinogen was analyzed by electrospray ionization mass spectrometry. The mutation predicts a mass increase of 26 Da in the gamma chain, but purified gamma chains had a normal mass, indicating non-expression of the gamma(Tyr307) chain in plasma fibrinogen.
Conclusions: This work reports a novel gamma307 His-->Tyr mutation (fibrinogen Mannheim II) that causes hypofibrinogenemia. Crystal structures show that His307 is located immediately adjacent to three residues that have been implicated in fibrin polymerization at the D:D interface. However, the histidine residue appears critical in maintaining structure of the fibrinogen gammaD domain, rather than in determining function.