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- Title
Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.
- Authors
Rost, Simone; Fregin, Andreas; Ivaskevicius, Vytautas; Conzelmann, Ernst; Hörtnagel, Konstanze; Pelz, Hans-Joachim; Lappegard, Knut; Seifried, Erhard; Scharrer, Inge; Tuddenham, Edward G D; Müller, Clemens R; Strom, Tim M; Oldenburg, Johannes
- Abstract
Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have not been identified. The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wild-type VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition.
- Publication
Nature, 2004, Vol 427, Issue 6974, p537
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature02214