Thrombomodulin突变在非典型溶血性尿毒症。
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Delvaeye M, Noris M、德Vriese Esmon CT, Esmon NL法瑞尔G, Del-Favero J,普莱桑斯年代,克拉斯B, Lambrechts D, Zoja C, Remuzzi G,康威EM
Thrombomodulin突变在非典型溶血性尿毒症。
郑传经地中海J。2009年7月23日,361 (4):345 - 57。doi: 10.1056 / NEJMoa0810739。
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19625716 (在PubMed]
- 文摘
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背景:三位一体的溶血性尿毒症由microangiopathic溶血性贫血,血小板减少,肾功能衰竭。常见的综合症是由感染志贺产毒细菌和有一个良好的结果。不常见的综合征,称为非典型溶血性尿毒症,约占10%的情况下,这种形式的综合症患者预后不良。大约一半的非典型溶血性尿毒症患者的突变基因调节补充系统。遗传因素在剩余的情况下是未知的。我们研究thrombomodulin的作用,内皮糖蛋白与抗凝、抗炎,和cytoprotective属性,在典型的溶血性尿毒症。方法:我们整个thrombomodulin基因测序(THBD) 152年非典型溶血性尿毒症患者和380名对照。使用纯化蛋白质和cell-expression系统,我们调查是否thrombomodulin调节补充系统,我们描述的机制。我们评估的影响thrombomodulin错义突变与非典型溶血性尿毒症对补体的激活表达thrombomodulin培养细胞的变异。结果:152例非典型溶血性尿毒症,7无关的病人有六个不同的杂合的错义THBD突变。 In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. CONCLUSIONS: Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.