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

Nature volume 427, pages 537–541 (2004)Cite this article

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.

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Figure 1: VKORC1 mutations in individuals with VKCFD2 and WR.
Figure 2: Amino acid sequence alignment of VKORC1 and VKORC1L1.
Figure 3: Subcellular location of VKORC1.

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Acknowledgements

We thank H. Hermann-Brackmann, W. Eberl, J. Pattinson, A.-N. Parkes and R. Jurgutis for the donation and clinical characterization of patient samples; V. Milenkovic for technical assistance and H. Höhn, T. Meitinger and T. Wienker for discussions and critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung Deutsches Zentrum für Luft- und Raumfahrt (BMBF/DLR), Baxter Germany, the Stiftung Hämotherapie-Forschung, the Gesellschaft für Thrombose- und Hämostaseforschung (GTH) and the BMBF projects German National Genome Research Network (NGFN) and Bioinformatics for the Functional Analysis of Mammalian Genomes (BFAM).

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  1. Simone Rost and Andreas Fregin: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, 97074, Würzburg, Germany

    Simone Rost, Andreas Fregin, Clemens R. Müller & Johannes Oldenburg

  2. Institute of Human Genetics, GSF National Research Center, Ingolstädter Landstrasse 1, 85764, München-Neuherberg, Germany

    Simone Rost, Konstanze Hörtnagel & Tim M. Strom

  3. Institute of Transfusion Medicine and Immune Haematology of the DRK Blood Donor Service, Johann Wolfgang Goethe-Universität, Sandhofstrasse 1, 60526, Frankfurt, Germany

    Vytautas Ivaskevicius, Erhard Seifried & Johannes Oldenburg

  4. Department of Physiological Chemistry II, University of Würzburg, Biozentrum, Am Hubland, 97074, Würzburg, Germany

    Ernst Conzelmann

  5. Federal Biological Research Center for Agriculture and Forestry, Institute for Nematology and Vertebrate Research, Toppheideweg 88, 48161, Münster, Germany

    Hans-Joachim Pelz

  6. Department of Medicine, Nordland Hospital, 8092, Bodo, Norway

    Knut Lappegard

  7. Center of Internal Medicine, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60528, Frankfurt, Germany

    Inge Scharrer

  8. MRC Clinical Sciences Centre, Imperial College, W12 ONN, London, UK

    Edward G. D. Tuddenham

  9. Institute of Human Genetics, Klinikum rechts der Isar, Technical University, 81675, München, Germany

    Tim M. Strom

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Correspondence to Johannes Oldenburg.

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Baxter Healthcare Corporation has filed a patent protecting the diagnostic and therapeutic consequences of the research described in the paper. Commercialization of the patent may result in financial benefits to the authors affiliated with the University of Würzburg and the Technical University of Munich.

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Rost, S., Fregin, A., Ivaskevicius, V. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427, 537–541 (2004). https://doi.org/10.1038/nature02214

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