非典型溶血性尿毒症综合征中的血栓调节蛋白突变
Thrombomodulin mutations in atypical hemolytic-uremic syndrome.
作者信息
Delvaeye Mieke, Noris Marina, De Vriese Astrid, Esmon Charles T, Esmon Naomi L, Ferrell Gary, Del-Favero Jurgen, Plaisance Stephane, Claes Bart, Lambrechts Diether, Zoja Carla, Remuzzi Giuseppe, Conway Edward M
机构信息
VIB-K.U.Leuven Vesalius Research Center, Leuven, Belgium.
出版信息
N Engl J Med. 2009 Jul 23;361(4):345-57. doi: 10.1056/NEJMoa0810739.
BACKGROUND
The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.
METHODS
We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.
RESULTS
Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. 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.
背景
溶血尿毒综合征由微血管病性溶血性贫血、血小板减少和肾衰竭三联征组成。该综合征的常见形式由产志贺毒素细菌感染引发，预后良好。该综合征较不常见的形式称为非典型溶血尿毒综合征，约占病例的10%，此型综合征患者预后较差。约一半的非典型溶血尿毒综合征患者存在调节补体系统的基因突变。其余病例的遗传因素尚不清楚。我们研究了具有抗凝、抗炎和细胞保护特性的内皮糖蛋白血栓调节蛋白在非典型溶血尿毒综合征中的作用。
方法
我们对152例非典型溶血尿毒综合征患者和380名对照者的整个血栓调节蛋白基因（THBD）进行了测序。使用纯化蛋白和细胞表达系统，我们研究了血栓调节蛋白是否调节补体系统，并对其机制进行了表征。我们通过在培养细胞中表达血栓调节蛋白变体，评估了与非典型溶血尿毒综合征相关的血栓调节蛋白错义突变对补体激活的影响。
结果
在152例非典型溶血尿毒综合征患者中，7名无亲缘关系的患者有6种不同的杂合错义THBD突变。在体外，血栓调节蛋白与C3b和因子H（CFH）结合，并在辅因子CFH或C4b结合蛋白存在的情况下，通过加速因子I介导的C3b失活来负调节补体。通过促进血浆前羧肽酶B的激活，血栓调节蛋白还加速过敏毒素C3a和C5a的失活。表达与非典型溶血尿毒综合征相关的血栓调节蛋白变体的培养细胞灭活C3b和激活前羧肽酶B的能力减弱，因此对激活的补体的保护作用较小。
结论
约5%的非典型溶血尿毒综合征患者存在损害血栓调节蛋白功能的突变。
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