Identification of the gene for vitamin K epoxide reductase

Tao Li, Chun-Yun Chang, Da-Yun Jin, Pen-Jen Lin, Anastasia Khvorova and Darrel W. Stafford ()
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Tao Li: University of North Carolina at Chapel Hill
Chun-Yun Chang: University of North Carolina at Chapel Hill
Da-Yun Jin: University of North Carolina at Chapel Hill
Pen-Jen Lin: University of North Carolina at Chapel Hill
Anastasia Khvorova: Dharmacon, Inc.
Darrel W. Stafford: University of North Carolina at Chapel Hill

Nature, 2004, vol. 427, issue 6974, 541-544

Abstract: Abstract Vitamin K epoxide reductase (VKOR) is the target of warfarin, the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode1, warfarin is under-used because of the difficulty of controlling dosage and the fear of inducing bleeding. Although identified in 1974 (ref. 2), the enzyme has yet to be purified or its gene identified. A positional cloning approach has become possible after the mapping of warfarin resistance to rat chromosome 1 (ref. 3) and of vitamin K-dependent protein deficiencies to the syntenic region of human chromosome 16 (ref. 4). Localization of VKOR to 190 genes within human chromosome 16p12-q21 narrowed the search to 13 genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes to test their ability to inhibit VKOR activity in human cells. Here, we report the identification of the gene for VKOR based on specific inhibition of VKOR activity by a single siRNA pool. We confirmed that MGC11276 messenger RNA encodes VKOR through its expression in insect cells and sensitivity to warfarin. The expressed enzyme is 163 amino acids long, with at least one transmembrane domain. Identification of the VKOR gene extends our understanding of blood clotting, and should facilitate development of new anticoagulant drugs.

Date: 2004
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DOI: 10.1038/nature02254

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