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Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
Simone Rost1, Andreas Fregin, Vytautas Ivaskevicius
1Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
Nature
|February 7, 2004
Summary
Researchers identified the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, crucial for blood coagulation and warfarin drug function. Mutations in VKORC1 are linked to bleeding disorders and warfarin resistance.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Coumarin derivatives like warfarin are essential for preventing thromboembolic events.
- These drugs inhibit the vitamin K epoxide reductase (VKOR) complex, vital for blood coagulation factor synthesis.
- The precise components of the VKOR complex remained elusive, despite its known role in VKCFD2 and warfarin resistance.
Purpose of the Study:
- To identify the molecular components of the vitamin K epoxide reductase (VKOR) complex.
- To investigate the genetic basis of combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2) and warfarin resistance (WR).
Main Methods:
- Utilized linkage analysis across three species to identify candidate genes.
- Performed gene sequencing to detect mutations in affected individuals and animal models.
- Conducted functional assays involving gene overexpression to assess enzyme activity.
Main Results:
- Identified the gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), a small transmembrane protein.
- Found missense mutations in VKORC1 associated with both human VKCFD2 and warfarin-resistant rats.
- Overexpression of wild-type VKORC1 significantly increased VKOR activity, which was inhibited by warfarin.
Conclusions:
- VKORC1 is a key component of the vitamin K epoxide reductase complex.
- Mutations in VKORC1 underlie VKCFD2 and contribute to warfarin resistance.
- This discovery provides a molecular target for understanding and potentially treating coagulation disorders and drug resistance.
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