Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2

摘要: Coumarin derivatives such as warfarin represent the therapy of choice for long-term treatment and prevention thromboembolic events. Coumarins target blood coagulation by inhibiting vitamin K epoxide reductase multiprotein complex (VKOR). This recycles 2,3-epoxide to hydroquinone, a cofactor that is essential post-translational gamma-carboxylation several factors. Despite extensive efforts, components VKOR have not been identified. The has proposed be involved in two heritable human diseases: combined deficiency vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance Man (OMIM) 607473), resistance coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, using linkage information from three species, gene subunit 1 (VKORC1), which encodes small transmembrane protein endoplasmic reticulum. VKORC1 contains missense mutations both disorders warfarin-resistant rat strain. Overexpression wild-type VKORC1, but carrying VKCFD2 mutation, leads marked increase activity, sensitive inhibition.