Congenital dysfibrinogenemia caused by γAla327Val mutation: structural abnormality of D region

Abstract

ABSTRACT Background : Congenital dysfibrinogenemia (CD) is a coagulation disorder caused by mutations in the fibrinogen genes, which result in abnormal fibrinogen function. However, the precise pathogenesis underlying it remains unclear. Methods : In this study, we identified a novel heterozygous mutation in an asymptomatic patient with CD caused by γ Ala327Val mutation. Aimed to investigate the pathogenesis, functional studies of fibrinogen isolated from the proband and her family members were performed, such as coagulation function, fibrinogen aggregation test, and fibrin clot lysis test. 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. Results : The fibrinogen activity concentration in patients with CD was significantly lower than that in healthy individuals, indicating that fibrinogen activity was low. Proband’s fibrinogen activity concentration was 0.75 g/L(Clauss method) and antigen concentration (immune turbidimetry method) was 1.59 g/L(normal reference range for both parameters: 2.0–4.0 g/L). Thromboelastography showed that the K value of patients with CD was higher than that of healthy individuals and Angle values were decreased, indicating that mutation impaired fibrinogen function. Compared to fibrinogen from healthy individuals, fiber network structure of the proband was loose, pore size was increased, and fiber branch nodes were increased. Conclusions : Ala327Val heterozygous missense mutation leads to changes in the structure of fibrinogen D region and impairs the aggregation function of fibrinogen. This mutation is reported here for the first time.