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

一种新型血栓危险因素的基因分析；

• 批准号: 22590524
• 负责人: KOJIMA Tetsuhito
• 金额: $ 2.83万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590524/
• 关键词: 臨床血液学; 静脈血栓塞栓症; 先天性血栓性素因; 遺伝子変異; アンチトロンビン抵抗性; 原因遺伝子変異; ｱﾝﾁﾄﾛﾝﾋﾞﾝ欠損症; ﾌﾟﾛﾃｲﾝC欠損症; ﾌﾟﾛﾃｲﾝS欠損症; ｱﾝﾁﾄﾛﾝﾋﾞﾝ抵抗性; ｽｸﾘ―ﾆﾝｸﾞ検査法; アンチトロンビン欠損症; プロテインC欠損症; プロテインS欠損症; スクリーニング検査法

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.

静脉血栓栓塞是一种多因素疾病，由环境因素和遗传因素之间复杂的相互作用引起。在这项研究中，我们调查了一个患有遗传性血栓形成倾向的日本大家族中可能存在的致病基因缺陷，发现凝血酶原基因中存在一种新的错义突变，导致凝血酶原变异。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，并通过凝血酶原激活、AT 结合和凝血酶生成测定进行比较。在凝血酶-抗凝血酶复合物 (TAT) 形成过程中，突变型凝血酶无法形成 TAT。在用重组凝血酶重构缺乏凝血酶原的血浆的凝血酶生成测定中，突变体表现出凝血酶峰值降低和内源凝血酶潜力增加。我们发现了一种新的 F2 突变，导致 AT 抗性凝血酶突变，这可能是该家族遗传性血栓形成倾向的原因。

项目成果

A possible mechanism for Inv22-related F8 large deletions in severe hemophilia a patients with high responding factor VIII inhibitors

严重血友病患者中 Inv22 相关 F8 大缺失的可能机制

• 发表时间: 2012
• 影响因子: 10.4
• 作者: Fujita J; Miyawaki Y; Suzuki A; Maki A; Okuyama E; Murata M; Takagi A; Murate T; Suzuki N; Matsushita T; Saito H; Kojima T
• 通讯作者: Kojima T

A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiestasia

一种新的 ENG 突变导致与遗传性出血性毛细血管扩张症相关的内皮糖蛋白共翻译加工受损

• DOI: 10.1016/j.thromres.2011.12.030
• 发表时间: 2012
• 影响因子: 7.5
• 作者: Atsuo Suzuki

Historical perspective and future direction of coagulation research

凝血研究的历史回顾和未来方向

• 发表时间: 2011
• 作者: H Saito; T Matsushita; T Kojima
• 通讯作者: T Kojima

A novel endoglin gene mutation associated with hereditary hemorrhagic telangiectasia in a Japanese

一种与日本遗传性出血性毛细血管扩张相关的新型内皮糖蛋白基因突变

• 发表时间: 2010
• 作者: A Suzuki; Y Miyawaki; J Fujita; A Maki; Y Fujimori; A Takagi; T Murate; M Teranishi; H Saito; T Kojima
• 通讯作者: T Kojima

「あなたも名医！新しい経口抗凝固薬、どう使う」

“你也是一位伟大的医生！新型口服抗凝剂的使用方法”

• 发表时间: 2012
• 作者: 小嶋哲人