Author
Listed:
- Simone Rost
(University of Würzburg, Biozentrum
Institute of Human Genetics, GSF National Research Center)
- 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
Technical University)
- Johannes Oldenburg
(University of Würzburg, Biozentrum
Johann Wolfgang Goethe-Universität)
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.
Suggested Citation
Simone Rost & Andreas Fregin & Vytautas Ivaskevicius & Ernst Conzelmann & Konstanze Hörtnagel & Hans-Joachim Pelz & Knut Lappegard & Erhard Seifried & Inge Scharrer & Edward G. D. Tuddenham & Clemens , 2004.
"Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2,"
Nature, Nature, vol. 427(6974), pages 537-541, February.
Handle:
RePEc:nat:nature:v:427:y:2004:i:6974:d:10.1038_nature02214
DOI: 10.1038/nature02214
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Cited by:
- Zhiyuan Ma & Ping Wang & Zehui Gao & Ruobing Wang & Koroush Khalighi, 2018.
"Ensemble of machine learning algorithms using the stacked generalization approach to estimate the warfarin dose,"
PLOS ONE, Public Library of Science, vol. 13(10), pages 1-12, October.
- Da-Yun Jin & Xuejie Chen & Yizhou Liu & Craig M. Williams & Lars C. Pedersen & Darrel W. Stafford & Jian-Ke Tie, 2023.
"A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase,"
Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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