title: Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.
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.
authors.affiliation: Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Rost
authors.forename: Andreas
authors.initials: A
authors.lastname: Fregin
authors.forename: Vytautas
authors.initials: V
authors.lastname: Ivaskevicius
authors.forename: Ernst
authors.initials: E
authors.lastname: Conzelmann
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Pelz
authors.forename: Knut
authors.initials: K
authors.lastname: Lappegard
authors.forename: Erhard
authors.initials: E
authors.lastname: Seifried
authors.forename: Inge
authors.initials: I
authors.lastname: Scharrer
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Müller
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002874:Chromosome Mapping; D020147:Coagulation Protein Disorders / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases