1. Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany
2. Institute of Human Genetics, GSF National Research Center, Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany
3. Institute of Transfusion Medicine and Immune Haematology of the DRK Blood Donor Service, Sandhofstrasse 1, Johann Wolfgang Goethe-Universität, 60526 Frankfurt, Germany
4. Department of Physiological Chemistry II, University of Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany
5. Federal Biological Research Center for Agriculture and Forestry, Institute for Nematology and Vertebrate Research, Toppheideweg 88, 48161 Münster, Germany
6. Department of Medicine, Nordland Hospital, 8092 Bodo, Norway
7. Center of Internal Medicine, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60528 Frankfurt, Germany
8. MRC Clinical Sciences Centre, Imperial College, London W12 ONN, UK
9. Institute of Human Genetics, Klinikum rechts der Isar, Technical University, 81675 München, Germany
10. These authors contributed equally to this work

Correspondence to: Johannes Oldenburg^1,3 Email: joldenburg@bsdhessen.de
The sequences are deposited in GenBank under accession codes AY423042, AY423043, AY423044, AY423045, AY423046, AY423047 and AY423048

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 -carboxylation of several blood coagulation factors^{2, 3}. Despite extensive efforts, the components of the VKOR complex have not been identified^{4, 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.

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