A Missense Mutation in Lectin Domain of Thrombomodulin Causing Functional Deficiency.
A Missense Mutation in Lectin Domain of Thrombomodulin Causing Functional Deficiency.
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血栓调节蛋白凝集素结构域的错义突变导致功能缺陷。
DOI：
10.1016/j.trsl.2022.07.006
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
T. Liang
中科院分区：
文献类型：
--
作者：
Ma Jiewen;Tao yanyi;Feng Yuanzheng;Cheng Zhipeng;Lin Wenyi;Hu Bei;Hu Yu;T. Liang
血栓调节蛋白（TM）通过其对蛋白C的辅因子活性、凝血酶激活的纤维蛋白溶解抑制物（TAFI）的激活和凝血酶诱导的高迁移率族蛋白1（HMGB1）降解而在凝血、纤维蛋白溶解和炎症中起作用。TM基因突变与血栓栓塞性疾病的发生有广泛的报道，但在凝集素结构域几乎没有报道。在这里，我们报告我们的研究结果，在TM的功能缺陷所造成的取代天冬氨酸与酪氨酸在残基126。三名患有复发性血栓栓塞性疾病的患者被鉴定为具有这种突变，并且他们的血浆可溶性TM水平降低。表达野生型TM或其变体和相应蛋白的转染细胞用于体外检查TM功能。突变体对蛋白C、TAFI活化的辅因子活性分别降低至约50%和60%。还观察到由于HMGB1降解减弱而导致的抗炎损失。小鼠血栓形成模型的研究表明，突变体对血栓形成的抑制作用减弱。总之，结果显示该突变引起的TM功能的有害变化，这可能解释了患者的血栓形成倾向。本研究为TM凝集素结构域的突变与血栓性疾病的发生有关提供了支持性证据，并有助于我们更好地理解TM的生理作用。
Thrombomodulin (TM) functions in coagulation, fibrinolysis and inflammation by its cofactor activity for protein C, thrombin-activatable fibrinolysis inhibitor (TAFI) activation and high mobility group box 1 (HMGB1) degradation induced by thrombin. It has been widely reported that mutations in TM are related to thromboembolic diseases but hardly in lectin domain. Here we report our findings about the functional deficiencies in TM caused by substitution of aspartate with tyrosine at residue 126. Three patients suffering from recurrent thromboembolic diseases were identified with this mutation and their plasma soluble TM levels were decreased. Transfected cells expressing wild-type TM or the variant and corresponding proteins were used to examine TM functions in vitro. The cofactor activity of the mutant for protein C, TAFI activation was reduced to approximately 50% and 60% respectively. Loss in anti-inflammation due to weakened HMGB1 degradation was also observed. And the study with thrombosis models of mice suggested the decreased inhibition of thrombus development of the mutant. Together the results showed deleterious changes on TM function caused by this mutation, which may explain the thrombophilia tendency of the patients. This work provided supportive evidence that mutation in lectin domain of TM might be related to thrombotic diseases and may help us better understand the physiological roles of TM.
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影响因子：
4.1
作者：
Rezaie AR
通讯作者：
Rezaie AR
DOI：
10.1016/s0021-9258(18)42676-2
发表时间：
1992-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Tsiang;S. Lentz;J. Sadler
通讯作者：
M. Tsiang;S. Lentz;J. Sadler
影响因子：
20.3
作者：
Bae, Jong-Sup;Rezaie, Alireza R.
通讯作者：
Rezaie, Alireza R.
DOI：
10.1073/pnas.78.4.2249
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
ESMON, CT;OWEN, WG
通讯作者：
OWEN, WG