Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
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DOI：
10.1038/nature02214
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发表时间：
2004-02-05
期刊：
影响因子：
64.8
通讯作者：
Oldenburg, J
中科院分区：
文献类型：
--
作者：
Rost, S;Fregin, A;Oldenburg, J
香豆素衍生物，例如华法林，是长期治疗和预防血栓栓塞事件的首选疗法。香豆素通过抑制维生素 K 环氧化物还原酶多蛋白复合物 (VKOR) 来实现凝血(1)。该复合物将维生素 K 2,3-环氧化物回收为维生素 K 对苯二酚，这是一种对于多种凝血因子翻译后 γ-羧化至关重要的辅助因子 (2,3)。尽管付出了巨大的努力，VKOR 复合体的组成部分仍未被确定(4-8)。该复合物被认为与两种人类遗传性疾病有关：维生素 K 依赖性凝血因子 2 型联合缺乏（VKCFD2；在线人类孟德尔遗传（OMIM）607473），以及对香豆素类抗凝药物的耐药性（华法林耐药性，WR；OMIM 122700）。在这里，我们通过使用来自三个物种的连锁信息，鉴定了维生素 K 环氧化物还原酶复合物亚基 1 (VKORC1) 基因，该基因编码内质网的一种小型跨膜蛋白。 VKORC1 在人类疾病和华法林耐药大鼠品系中均含有错义突变。野生型 VKORC1 的过表达（而非携带 VKCFD2 突变的 VKORC1）会导致 VKOR 活性显着增加，而 VKOR 活性对华法林抑制敏感。
Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR)(1). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors(2,3). Despite extensive efforts, the components of the VKOR complex have not been identified(4-8). The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wildtype VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition.