Tissue-type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease.
Tissue-type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease.
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DOI：
10.1002/mco2.392
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发表时间：
2023-10
期刊：
影响因子：
9.9
通讯作者：
Tang, Liang V.
中科院分区：
文献类型：
--
作者：
Tao, Yanyi;Ma, Jiewen;Feng, Yuanzheng;Gao, Chenggang;Wu, Tingting;Xia, Yunqing;Cheng, Zhipeng;Zhang, Yi;Liu, Tingting;Hu, Yu;Tang, Liang V.
关键词：
组织型纤溶酶原激活剂（tPA）由PLAT基因编码，是促进纤维蛋白溶解和预防血栓形成的主要介质。与静脉血栓栓塞相关的PLAT基因致病性突变鲜有报道。在此，我们报告首例PLAT基因纯合点突变c.1411T>C（p.Y471H）导致血栓栓塞事件，并开展相关功能研究。在体外合成了相应的tPA突变蛋白（tPA - Y471H）和野生型tPA（tPA - WT），并构建了突变小鼠（PLAT H/H小鼠）。分子对接和表面等离子共振结果表明，该突变阻碍了tPA蛋白酶结构域与纤溶酶原kringle 4结构域之间的氢键相互作用，tPA与纤溶酶原的结合亲和力显著降低，相差一个数量级。mRNA半衰期测定显示，tPA - Y471H的半衰期缩短。下腔静脉血栓形成模型显示，PLAT H/H小鼠的静脉血栓形成率为80%，而野生型小鼠为53%。我们的数据表明tPA的蛋白酶结构域在纤溶酶原的有效激活中具有新的作用，并证明这种tPA突变会降低机体的纤维蛋白溶解功能，导致血栓形成倾向增加。
1. 我们已鉴定出首例与血栓栓塞性疾病相关的PLAT纯合突变（p. Y471H），该突变位于tPA的蛋白酶结构域，影响纤溶酶原的有效激活。
2. 我们的研究可能为控制纤溶酶生成提供一个独特靶点，也为临床血栓患者的诊断和治疗提供新的见解与思路。
Tissue‐type plasminogen activator (tPA) encoded by PLAT is a major mediator that promotes fibrinolysis and prevents thrombosis. Pathogenetic mutations in PLAT associated with venous thromboembolism have rarely been reported. Here, we report the first case of a homozygous point mutation c.1411T>C (p.Y471H) in PLAT leading to thromboembolic events and conduct related functional studies. The corresponding tPA mutant protein (tPA‐Y471H) and wild‐type tPA (tPA‐WT) were synthesized in vitro, and mutant mice (PLATH/H mice) were constructed. The molecular docking and surface plasmon resonance results indicated that the mutation impeded the hydrogen‐bonding interactions between the protease domain of tPA and the kringle 4 domain of plasminogen, and the binding affinity of tPA and plasminogen was significantly reduced with a difference of one order of magnitude. mRNA half‐life assay showed that the half‐life of tPA‐Y471H was shortened. The inferior vena cava thrombosis model showed that the rate of venous thrombosis in PLATH/H mice was 80% compared with 53% in wild‐type mice. Our data suggested a novel role for the protease domain of tPA in efficient plasminogen activation, and demonstrated that this tPA mutation could reduce the fibrinolysis function of the body and lead to an increased propensity for thrombosis. 1. We have identified the first PLAT homozygous mutation (p. Y471H) associated with thromboembolic disease, which is located in the protease domain of tPA and affects the effective activation of plasminogen. 2. Our study might provide a unique target for controlling plasmin generation, and also provides new insights and ideas for the diagnosis and treatment of patients with thrombosis in clinic.
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