ZHU Liqing,ZHANG Haiyue,LUO Shasha, et al. Phenotypic and genetic analysis of congenital hypofibrinogenemia associated with a novel heterozygous mutation in fibrinogen β Chain[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2019, 49(5): 339-343.
Abstract：Objective: To identify the genetic defect underlying congenital hypofibrinogenamia in a Chinese pedigree. Methods: Totally 6 family members were enrolled in this study. Routine coagulation tests, including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT), D-Dimer (DD) and fibrinogen degradation products (FDPs) were determined. The activity of fibrinogen (Fg:C) was measured using Clauss method and fibrinogen antigen (Fg:Ag) was measured using immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain gene were amplified using PCR, followed by direct sequencing. Suspected mutation was further confirmed by reverse sequencing. The mutant fibrinogen was analyzed by the Swiss-PdbViewer, ClustalX-2.1-win and other online software. Results: PT and TT were prolonged in the proband. Her functional fibrinogen (Fg:C) and antigen fibrinogen (Fg:Ag) levels were reduced, which was 0.82 g/L and 1.19 g/L, respectively. Genetic analysis revealed a heterozygous T>G change at nucleotide 425 in exon 3 of FGB gene in the proband, predicting a novel Leu121Arg mutation. This mutation was also found in her father and son. Model analysis showed that the Leu121Arg mutation added a hydrogen bonding among Try117, Met118, Trp125 and Leu121. Moreover, the mutation also changed the mutual electrostatic forces, affecting the folding and instability of the mutant fibrinogen. Conclusion: The heterozygous Leu121Arg mutation leading to the hypofibrinogenemia in this pedigree.
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