Species Human Entrez 79001 | Human Mouse Ensembl ENSG00000167397 | |
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Aliases VKORC1, EDTP308, IMAGE3455200, MST134, MST576, VKCFD2, VKOR, vitamin K epoxide reductase complex subunit 1 External IDs MGI: 106442 HomoloGene: 11416 GeneCards: VKORC1 | ||
The human gene VKORC1 encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1. This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting. In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.
Contents
Function
Vitamin K is a family of molecules that are essential to blood clotting. Vitamin K 2,3-epoxide is activated by reduction via the VKORC enzyme. The activated form is then responsible for the carboxylation of glutamic acid residues in some blood-clotting proteins. These proteins are known as vitamin-K-dependent clotting factors.
Gene
The human gene is located on chromosome 16. Two pseudogenes have been identified on chromosome 1 and the X chromosome.
Clinical relevance
In humans, mutations in this gene are associated with deficiencies in vitamin-K-dependent clotting factors. Fatal bleeding (internal) and hemorrhage can result from a decreased ability to form clots.
The product of the VKORC1 gene encodes a subunit of the enzyme that is responsible for reducing vitamin K 2,3-epoxide to the activated form, a reduction reaction. A genetic polymorphism on the VKORC1 gene results in a patient having less available VKORC enzyme to complete this reaction.
Specifically, in the VKORC1 1639 (or 3673) single-nucleotide polymorphism, the common ("wild-type") G allele is replaced by the A allele. People with an A allele (or the "A haplotype") produce less VKORC1 than do those with the G allele (or the "non-A haplotype"). The prevalence of these variants also varies by race, with 37% of Caucasians and 14% of Africans carrying the A allele. The end result is a decreased amount of clotting factors and therefore, a decreased ability to clot.
Warfarin is an anticoagulant that opposes the procoagulant effect of vitamin K by inhibiting the VKORC enzyme. If these patients are prescribed warfarin for another medical purpose, they will require lower doses than usual because the patient is already deficient in VKORC. They may experience severe bleeding and bruising. Lower warfarin doses are needed to inhibit VKORC1 and to produce an anticoagulant effect in carriers of the A allele. Genetic testing can reveal the presence of the genetic mutation and FDA recommends lower starting doses of warfarin in these patients.
Two alternatively spliced transcripts encoding different isoforms have also been described. These isoforms result in warfarin resistance (requiring higher doses) in humans and rats, because the amount and effectiveness of the VKORC enzyme has not changed, but the ability of warfarin to exert its effect (antagonize the enzyme) has changed. These isoform mutations are rare except in Ethiopian and certain Jewish populations.