NEW YORK (Reuters Health) - By identifying the gene that activates vitamin K, mutations of which cause warfarin resistance and inherited clotting factor deficiency, researchers hope to design safer, more effective anticoagulant drugs than those currently used, according to reports in the February 5th issue of Nature.
Vitamin K is essential for blood clotting, the study authors explain. Warfarin acts as an anticoagulant by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR), which recycles vitamin K after it has undergone carboxylation. Combined deficiencies in vitamin-K-dependent proteins and warfarin resistance map to the same region on human chromosome 16. Up until now, VKOR proteins have never been characterized.
Dr. Johannes Oldenburg, at the University of Wurzburg in Germany, and his associates analyzed DNA sequences in the short arm of chromosome 16 from two patients with combined deficiency of vitamin-K-dependent clotting factors type 2 and four with resistance to coumarin-type anticoagulant drugs. All six individuals had missense mutations in the same gene, which the scientists called VKOR complex subunit 1.
The European research team found that the affected gene encodes a small transmembrane protein founding the endoplasmic reticulum. They identified a homologous gene sequences in mice and rats.
According to a second report in Nature, Dr. Daniel W. Stafford, at the University of North Carolina at Chapel Hill, and his American colleagues used short interfering RNA (siRNA) to identify what appears to be the same VKOR gene.
After eliminating genes in the suspected region on chromosome 16 with known function, they identified 13 genes predicted to code for integral membrane domains. Using a lung carcinoma cell line that exhibited warfarin-sensitive VKOR activity, they found that targeting this gene with siRNA reduced VKOR activity.
Transfection experiments showed that this nonmutated gene produced active VKOR, which was inhibited by warfarin.
In a related editorial, Dr. J Evan Sadler, at Washington University School of Medicine in St. Louis, Missouri, notes that the VKOR gene identified by the European team and by the US team appear to be identical. He believes that characterization of this warfarin target may lead to the identification of better vitamin K antagonists for treating blood clots.
Source: Nature 2004;427:493-494,537-544. [ Google search on this article ]
MeSH Headings:Genetic Techniques: Investigative Techniques: Sequence Analysis: Sequence Analysis, DNA: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
