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

Simone Rost, Andreas Fregin, Vytautas Ivaskevicius, Ernst Conzelmann, Konstanze Hörtnagel, Hans-Joachim Pelz, Knut Lappegard, Erhard Seifried, Inge Scharrer, Edward G. D. Tuddenham, Clemens R. Müller, Tim M. Strom and Johannes Oldenburg ()
Additional contact information
Simone Rost: University of Würzburg, Biozentrum
Andreas Fregin: University of Würzburg, Biozentrum
Vytautas Ivaskevicius: Johann Wolfgang Goethe-Universität
Ernst Conzelmann: University of Würzburg, Biozentrum
Konstanze Hörtnagel: Institute of Human Genetics, GSF National Research Center
Hans-Joachim Pelz: Institute for Nematology and Vertebrate Research
Knut Lappegard: Nordland Hospital
Erhard Seifried: Johann Wolfgang Goethe-Universität
Inge Scharrer: Johann Wolfgang Goethe-Universität
Edward G. D. Tuddenham: Imperial College
Clemens R. Müller: University of Würzburg, Biozentrum
Tim M. Strom: Institute of Human Genetics, GSF National Research Center
Johannes Oldenburg: University of Würzburg, Biozentrum

Nature, 2004, vol. 427, issue 6974, 537-541

Abstract: 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)1. This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational γ-carboxylation of several blood coagulation factors2,3. Despite extensive efforts, the components of the VKOR complex have not been identified4,5,6,7,8. 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.

Date: 2004
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DOI: 10.1038/nature02214

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