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

  title={Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2},
  author={Simone Rost and Andreas Fregin and V Iva{\vs}kevi{\vc}ius and Ernst Conzelmann and Konstanze H{\"o}rtnagel and H. J. Pelz and Knut Tore Lappeg{\aa}rd and Erhard Seifried and Inge Scharrer and Edward G. D. Tuddenham and Clemens R. Müller and Tim Matthias Strom and Johannes Oldenburg},
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 γ-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have… 
Vitamin K‐induced modification of coagulation phenotype in VKORC1 homozygous deficiency
Modification of coagulation phenotypes in VKCFD2 after vitamin K supplementation was clinically beneficial, and provided valuable patterns of factor specific biosynthesis, half‐life and decay.
The genetics of vitamin K antagonists
Coumarins are effective rodenticides, causing fatal bleeding in coumarin-naı̈ve rodents, and the action of vitamin K epoxide reductase, whose gene (VKOR) has been newly discovered by two independent teams.
THROMBOSIS AND HEMOSTASIS Human VKORC 1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces
Inhibition of VKORC1 by 4-hydroxycoumarins, including warfarin, results in decreased availability of KH2 for g-glutamyl carboxylase and, subsequently,results in increased levels of noncarboxylated, inactive vitamin K-dependent protein coagulation factors.
VKORC1 pharmacogenomics summary.
A number of large-scale randomized clinical trials are now in progress to develop a globally applicable dosing strategy for warfarin, and it is shown that polymorphisms in the VKORC1 gene were associated with both high and low-warfarin dose phenotypes in humans.
Pharmacogenetics of Target Genes Across the Warfarin Pharmacological Pathway
Understanding the causal relationship of polygenic influences on warfarin dose requirements in patients of different ethnicity may be vital in reducing inter-patient variability and optimising anticoagulant therapy.
Confirmation of warfarin resistance of naturally occurring VKORC1 variants by coexpression with coagulation factor IX and in silico protein modelling
A cell culture-based system reflects the warfarin resistance status of VKORC1 mutations from anticoagulant resistant rodents more closely than the traditional DTT-driven enzyme assay.
Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1.
The association between a nucleotide transition in VKorC1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC1 is the site of action of warfarIn and indicates thatVKORC 1 sequence is an important determinant of the warfar in dose response.
Familial deficiency of vitamin K‐dependent clotting factors
  • B. Weston, P. Monahan
  • Biology, Medicine
    Haemophilia : the official journal of the World Federation of Hemophilia
  • 2008
Recent molecular studies have the potential to further the understanding of vitamin K metabolism, γ‐carboxylation, and the functional role this post‐translational modification has for other proteins.
Human VKORC1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces.
Half maximal inhibitory concentrations (IC50) results for 21 further hVKORC1 mutations obtained using a recently validated cell-based assay are presented, and all mutations exhibited basal VKOR activity and warfarin IC50 values that correspond well to patient OACR phenotypes.
VKORC1: molecular target of coumarins
Preliminary studies indicate that concomitant application of low‐dose vitamin K and warfarin significantly improves INR stability and time of INR within the therapeutic range, and co‐expression of VKORC1 leads to a more efficient production of recombinant vitamin K‐dependent coagulation factors such as FIX and FVII.


Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex.
A detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors and the finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex.
A molecular mechanism for genetic warfarin resistance in the rat
A novel model for genetic warfarin resistance in the rat is proposed, whereby the concentration of calumenin in liver determines resistance, andCalumenin was shown to inhibit the overall activity of the complete vitamin K‐dependent γ‐carboxylation system.
Assembly of the Warfarin-sensitive Vitamin K 2,3-Epoxide Reductase Enzyme Complex in the Endoplasmic Reticulum Membrane*
An in vitro γ-carboxylation test system is designed and it is proposed that formation of VKOR in the endoplasmic reticulum membrane resembles formation of the lipoxygenase enzyme complex where the glutathioneS-transferase-related FLAP protein binds cytosolic lip oxygengenase to form a membrane enzyme complex.
The biochemical basis of warfarin therapy.
  • J. Suttie
  • Biology
    Advances in experimental medicine and biology
  • 1987
Vitamin K is required for a liver microsomal enzyme that catalyzes the posttranslational conversion of specific glutamyl residues in precursors of the vitamin K-dependent clotting factors to
Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16.
A genome-wide linkage analysis was performed and significant linkage of FMFD to chromosome 16 was found and conserved synteny between human and mouse linkage groups would restrict the candidate gene interval to the centromeric region of the short arm of chromosome 16.
Characterization and purification of the vitamin K1 2,3 epoxide reductases system from rat liver.
The attempted purification of the vitamin K1 2,3 epoxide reductase complex from rat liver microsomes by ion exchange and size exclusion chromatography techniques yielded a purified protein that was insensitive to R,S-warfarin inhibition at concentrations up to 5 mM.
Vitamin K-dependent carboxylation and vitamin K metabolism in liver. Effects of warfarin.
A vitamin K-dependent carboxylation system is described that allows both pathways to support the car boxylation reaction with reduced vitamin K1 cofactor and is consistent with the current model for the mechanism of action of coumarin anticoagulant drugs in the rat.
Warfarin inhibition of vitamin K 2,3-epoxide reductase in rat liver microsomes.
It is concluded that dithiothreitol reduces either directly or indirectly a critical disulfide within the reductase that it reoxidized during reduction of the epoxide substrate, and warfarin and vitamin K 2,3-epoxide are not competitive with respect to one another, and Warfarin binding, which produces inhibition, occurs solely to the disulfides form of the reduCTase.