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VKORC1

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This is an old revision of this page, as edited by Boghog (talk | contribs) at 06:22, 2 October 2016 (copyedit; consistent citation formatting; removed further reading citations not specific to this gene). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

VKORC1
Identifiers
AliasesVKORC1, EDTP308, IMAGE3455200, MST134, MST576, VKCFD2, VKOR, vitamin K epoxide reductase complex subunit 1
External IDsOMIM: 608547; MGI: 106442; HomoloGene: 11416; GeneCards: VKORC1; OMA:VKORC1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

79001

27973

Ensembl

ENSG00000167397

ENSMUSG00000096145

UniProt

Q9BQB6

Q9CRC0

RefSeq (mRNA)

NM_001311311
NM_024006
NM_206824

NM_178600

RefSeq (protein)

NP_001298240
NP_076869
NP_996560

NP_848715

Location (UCSC)Chr 16: 31.09 – 31.1 MbChr 7: 127.49 – 127.49 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The human gene VKORC1 encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1.[5] This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to it's 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.

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. [5]

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 it's effect (antagonize the enzyme) has changed. These isoform mutations are rare except in Ethiopian and certain Jewish populations.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000167397 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000096145 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: VKORC1 vitamin K epoxide reductase complex, subunit 1".

Further reading

  • Oldenburg J, Bevans CG, Müller CR, Watzka M (2006). "Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle". Antioxidants & Redox Signaling. 8 (3–4): 347–53. doi:10.1089/ars.2006.8.347. PMID 16677080.
  • Oldenburg J, Bevans CG, Fregin A, Geisen C, Müller-Reible C, Watzka M (September 2007). "Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles". Thrombosis and Haemostasis. 98 (3): 570–8. doi:10.1160/th07-07-0454. PMID 17849045.
  • Oldenburg J, von Brederlow B, Fregin A, Rost S, Wolz W, Eberl W, Eber S, Lenz E, Schwaab R, Brackmann HH, Effenberger W, Harbrecht U, Schurgers LJ, Vermeer C, Müller CR (December 2000). "Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex". Thrombosis and Haemostasis. 84 (6): 937–41. PMID 11154138.
  • Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J (November 2002). "Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16". Blood. 100 (9): 3229–32. doi:10.1182/blood-2002-03-0698. PMID 12384421.
  • Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J (February 2004). "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2". Nature. 427 (6974): 537–41. doi:10.1038/nature02214. PMID 14765194.
  • Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (February 2004). "Identification of the gene for vitamin K epoxide reductase". Nature. 427 (6974): 541–4. doi:10.1038/nature02254. PMID 14765195.
  • Goodstadt L, Ponting CP (June 2004). "Vitamin K epoxide reductase: homology, active site and catalytic mechanism". Trends in Biochemical Sciences. 29 (6): 289–92. doi:10.1016/j.tibs.2004.04.004. PMID 15276181.
  • D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (January 2005). "A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin". Blood. 105 (2): 645–9. doi:10.1182/blood-2004-06-2111. PMID 15358623.
  • Harrington DJ, Underwood S, Morse C, Shearer MJ, Tuddenham EG, Mumford AD (January 2005). "Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1". Thrombosis and Haemostasis. 93 (1): 23–6. doi:10.1267/THRO05010023. PMID 15630486.
  • Tie JK, Nicchitta C, von Heijne G, Stafford DW (April 2005). "Membrane topology mapping of vitamin K epoxide reductase by in vitro translation/cotranslocation". The Journal of Biological Chemistry. 280 (16): 16410–6. doi:10.1074/jbc.M500765200. PMID 15716279.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA (July 2005). "Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity". Blood. 106 (1): 135–40. doi:10.1182/blood-2005-01-0341. PMID 15790782.
  • Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, Wallerman O, Melhus H, Wadelius C, Bentley D, Deloukas P (2005). "Common VKORC1 and GGCX polymorphisms associated with warfarin dose". The Pharmacogenomics Journal. 5 (4): 262–70. doi:10.1038/sj.tpj.6500313. PMID 15883587.
  • Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (June 2005). "Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose". The New England Journal of Medicine. 352 (22): 2285–93. doi:10.1056/NEJMoa044503. PMID 15930419.
  • Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (October 2005). "The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen". Blood. 106 (7): 2329–33. doi:10.1182/blood-2005-03-1108. PMID 15947090.
  • Wang Y, Zhen Y, Shi Y, Chen J, Zhang C, Wang X, Yang X, Zheng Y, Liu Y, Hui R (June 2005). "Vitamin k epoxide reductase: a protein involved in angiogenesis". Molecular Cancer Research. 3 (6): 317–23. doi:10.1158/1541-7786.MCR-04-0221. PMID 15972850.
  • Bodin L, Horellou MH, Flaujac C, Loriot MA, Samama MM (July 2005). "A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance". Journal of Thrombosis and Haemostasis. 3 (7): 1533–5. doi:10.1111/j.1538-7836.2005.01449.x. PMID 15978113.
  • Wajih N, Hutson SM, Owen J, Wallin R (September 2005). "Increased production of functional recombinant human clotting factor IX by baby hamster kidney cells engineered to overexpress VKORC1, the vitamin K 2,3-epoxide-reducing enzyme of the vitamin K cycle". The Journal of Biological Chemistry. 280 (36): 31603–7. doi:10.1074/jbc.M505373200. PMID 16030016.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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