ArticleBlood2014
The Arg98Trp mutation in human VKORC1 causing VKCFD2 disrupts a di-arginine-based ER retention motif.
Article in Blood, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- Structural disruption of VKORC1 by resistance mutations reveals a conserved hydrophobic pattern essential for warfarin binding: insights from molecular dynamics analyses.Molecular diversity · 2026Article
- Missense VKOR mutants exhibit severe warfarin resistance but lack VKCFD via shifting to an aberrantly reduced state.Blood advances · 2023Article
- Article
- Blocking transmembrane219 protein signaling inhibits autophagy and restores normal cell death.PloS one · 2019Article
- VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues.Nutrients · 2018Review
- Vitamin K epoxide reductase and its paralogous enzyme have different structures and functions.Scientific reports · 2017Article
- Review
- Membrane Cholesterol Modulates Superwarfarin Toxicity.Biophysical journal · 2016Article
- Structural and functional insights into enzymes of the vitamin K cycle.Journal of thrombosis and haemostasis : JTH · 2016Review
- Structural Modeling Insights into Human VKORC1 Phenotypes.Nutrients · 2015Review
- Review
- GGCX and VKORC1 inhibit osteocalcin endocrine functions.The Journal of cell biology · 2015Article
- VKORC1 ER mislocalization causes rare disease.Blood · 2014Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is an enzyme localized to the endoplasmic reticulum (ER) membrane. VKORC1 catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K and to vitamin K hydroquinone, the latter required by the enzyme γ-carboxylase for γ-carboxylation of all vitamin K-dependent (VKD) proteins. Until now, only 1 human VKORC1 mutation, p.Arg98Trp, is known to cause combined deficiency of VKD clotting factors type 2 (VKCFD2), a disease phenotype reported in 3 unrelated families. VKCFD2 patients suffer from spontaneous bleeding episodes because of decreased levels of γ-carboxylated VKD clotting factors. Daily supraphysiological vitamin K supplementation restores clotting for VKCFD2 patients and results in high serum levels of vitamin K 2,3-epoxide, suggesting that supplemented vitamin K is reduced in vivo. Although the p.Arg98Trp mutation results in reduced vitamin K 2,3-epoxide reductase activity, the molecular mechanism underlying this pathophysiology is unknown. Using a combination of in silico analysis and confocal microscopy, we demonstrate for the first time that VKORC1:p.Arg98Trp disrupts a di-arginine ER retention motif resulting in 20% ER colocalization only. As a consequence, VKORC1 exits the ER membrane by cellular quality control systems and results in the observed VKCFD2 phenotype.
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