A novel fibrinogen gamma-chain mutation, p. γAla327Val, causes structural abnormality of D region and ultimately leads to congenital dysfibrinogenemia

Abstract

ABSTRACTCongenital dysfibrinogenemia (CD) is a coagulation disorder caused by mutations in the fibrinogen gene, which result in abnormal fibrinogen function. Many studies have confirmed that over half of dysfibrinogenemia cases are asymptomatic. In this study, we aimed to investigate the pathogenesis of CD caused by γ Ala327Val heterozygous mutation, a new mutation, by studying fibrinogen function. Blood samples of patients were collected and the coagulation function, fibrinogen (Fg) aggregation test, fibrin clot lysis test, and SDS-PAGE were performed. Coagulation was monitored using a thromboelastometer, and the fibrin clot network structure was observed by scanning electron microscopy. The effect of the mutation on fibrinogen structure and function was predicted by molecular modeling. The fibrinogen activity concentration in patients with CD was significantly lower than that in healthy individuals. Thromboelastography showed that the K value of patients with CD was higher than that for healthy individuals. The Angle values were also decreased. The function of fibrinogen in patients with CD was low. Compared to fibrinogen from healthy individuals, fibrin size was different, the fiber network structure was loose, the pore size was increased, and the fiber branch nodes were increased for fibrinogen isolated from the proband. The γ Ala327Val mutation led to changes in the structure of fibrinogen D region, affecting its structural stability. Ala327Val heterozygous missense mutation in exon 8 of FGG gene γ-chain thus leads to abnormal fibrinogen structure and impairs the aggregation function of fibrinogen. This mutation is reported here for the first time.