Gene analysis of a novel thrombotic risk factor; antithrombin-resistance.

静脉血栓栓塞症是一种由环境因素和遗传因素复杂相互作用引起的多因素疾病。在这项研究中，我们调查了一个遗传性血栓形成症日本大家族可能的致病基因缺陷，发现了一个新的凝血酶原基因的错义突变，导致了一个变异的凝血酶原基因。该突变位于凝血酶分子的抗凝血酶(AT)结合位点之一。我们制备了野生型和突变型重组凝血酶原酶，并通过凝血酶原激活、AT结合和凝血酶生成实验进行了比较。在凝血酶-抗凝血酶复合体(TAT)的形成中，突变的凝血酶被嵌入形成TAT。在重组凝血酶原缺陷型血浆的凝血酶生成实验中，突变体的凝血酶峰值降低，内源性凝血酶电位升高。我们发现了一个新的F2突变导致抗凝血酶突变，这可能是该家族遗传性血栓形成的原因之一。

Venous thromboembolism is a multifactorial disease resulting from a complex interaction between circumstantial and genetic factors. In this study, we investigated possible causative gene defects in a large Japanese family with inherited thrombophilia, and found a novel missense mutation in the prothrombin gene resulting in a variant prothrombin. The mutation located at one of the antithrombin (AT) binding sites of thrombin molecule. We prepared wild-type and mutant recombinant prothrombins, and compared by prothrombin activation, AT-binding, and thrombin generation assays. In thrombin-antithrombin complex (TAT) formation, the mutant thrombin was impareded to form TAT. In thrombin generation assay of reconstituted prothrombin-deficient plasma with recombinant prothrombins, the mutant showed a decreased peak thrombin and an increased endogenous thrombin potential. We identified a novel F2 mutation leading to the mutant AT-resistant thrombin, which could be a cause of the inherited thrombophilia in this family.