Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder

Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and structural analysis of 4 novel variants located in the FGB gene coding for fibrinogen B beta chain-heterozygous missense B beta Y416C and B beta A68S, homozygous nonsense B beta Y345*, and heterozygous nonsense B beta W403* mutations. The cases were identified by coagulation screening tests and further investigated by various methods. Fibrin polymerization had abnormal development with decreased maximal absorbance in all patients. Plasmin-induced fibrin degradation revealed different lytic phases of B beta Y416C and B beta W403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of B beta A68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of B beta Y416C, B beta A68S, and B beta W403*, and in the fiber density of B beta Y416C and B beta W403*. Finally, homology modeling of B beta A68S showed that mutation caused negligible alternations in the protein structure. In conclusion, all mutations altered the correct fibrinogen function or structure that led to congenital fibrinogen disorders.