Impact of Novel Missense Mutation (p. Arg510Cys) in the FGA Gene Resulting in Dysfibrinogenemia

Introduction Inherited dysfibrinogenemia is a qualitative defect of fibrinogen (FG) predicted by various mutations in the FGA, FGB, or in FGG genes. Dysfibrinogenemia is associated with an increased venous thrombosis risk. Here, we report a 31-year-old female with dysfibrinogenemia who experienced sinus venous thrombosis (SVT) after a plane flight and under oral (estrogen) contraceptives.

Methods Coagulation tests were done using standard procedures. FG genes were screened using direct genomic DNA sequencing. The structural–functional implications of the mutation (p. Arg510Cys) were analyzed in silico. Since the region on which the mutation occurs is missing in the crystal structure, it was modeled on the ab initio Quark server and fitted onto the crystal structure.

Results and Discussion Dysfibrinogenemia was diagnosed in a 31-year-old Caucasian female. She experienced SVT after a flight of > 6 hours and under oral contraceptives. Her father experienced unprovoked pulmonary embolism twice, in his 50s. The patients’ FG levels (Clauss method) were mildly decreased (129–138 mg/dL, normal range being 180–355 mg/dL) and the FG antigen being within normal range (276–301 mg/dL). Thrombin time (TT) and reptilase time (RT) were slightly prolonged, 24.9–28.6 s and 22.8–23.4 s (normal ranges for both parameters: <20.5 s), respectively. Approximately 12 months after the SVT, she discontinued warfarin use and switched to SC administration of enoxaparin (4,000 IU daily) and became pregnant within a few months. Interestingly, in the second trimester, functional FG was normalized (178 mg/dL) and the immunologic FG remained stable (278 mg/dL). TT and RT were normalized too. Genetic analysis revealed a heterozygous missense mutation in the terminal part of the FGA gene (c.1528C>T, p. Arg510Cys) encoding the alpha C domain. Our in silico analysis showed that the affected residue Arg510 was located on a surface-exposed randomly ordered loop connecting two helices. The surface-exposed character of the wild-type Arg510 suggests that the mutated cysteine could form nonnative disulfide bonds with surface-exposed reactive cysteine from other plasma proteins like albumin leading to formation of aggregates and possibly thrombosis.

Conclusion This mutation may play (especially in a combination with other risk factors, e.g., long trips, oral contraceptives) a significant role in development of venous thrombosis requiring long-term anticoagulation in affected individuals, also in pregnancy.

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Publikationsverlauf

Artikel online veröffentlicht:
13. November 2020