Fibrinogen Columbus II: A novel c.1075G>T mutation in the FGG gene causing hypodysfibrinogenemia and thrombosis in an adolescent male

Abstract

Hypodysfibrinogenemia, the least frequently reported congenital fibrinogen disorder is characterized by low circulating levels of a dysfunctional protein, and is associated with phenotypic features of both hypo‐ and dysfibrinogenemia. Herein, we report an adolescent male with unprovoked venous thromboembolism and hypodysfibrinogenemia. Patient had recurrent, progressive thrombosis despite therapeutic anticoagulation with both low molecular weight heparin and warfarin. He had clinical and radiological improvement after transition to a direct thrombin inhibitor. Sequencing of the FGG gene identified a novel heterozygous mutation, c.1075G>T. Structural visualization of the identified variant was pursued and suggested that the mutation likely destabilizes the Ca2+‐binding site of fibrinogen resulting in pathogenicity.

Novel variant fibrinogen γp.C352R produced hypodysfibrinogenemia leading to a bleeding episode and failure of infertility treatment

“…Fibrinolysis occurs when t-PA binds to γp.338-350 (312-324, mature protein nomenclature) region [32] on the fibrin surface. In this region, two thrombotic variants, γp.S358C [34] and G359C [35], have been reported. In the latter case, the proximity of the γp.G359C mutation to the Cys 352 -Cys 365 disulfide bond may disrupt this disulfide bond [35], resulting in thrombotic manifestation.…”

“…In this region, two thrombotic variants, γp.S358C [34] and G359C [35], have been reported. In the latter case, the proximity of the γp.G359C mutation to the Cys 352 -Cys 365 disulfide bond may disrupt this disulfide bond [35], resulting in thrombotic manifestation. These reports suggested that amino acid substitutions from or to Cys around γp.352 are prone to arouse thrombotic complications.…”