Insights into hemolytic uremic syndrome:: Segregation of three independent predisposition factors in a large, multiple affected pedigree
Insights into hemolytic uremic syndrome:: Segregation of three independent predisposition factors in a large, multiple affected pedigree
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DOI：
10.1016/j.molimm.2005.11.008
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发表时间：
2006-04-01
影响因子：
3.6
通讯作者：
de Córdoba, SR
中科院分区：
文献类型：
--
作者：
Esparza-Gordillo, J;de Jorge, EG;de Córdoba, SR
补体调节因子 H、膜辅因子蛋白 (MCP) 和因子 I 的突变与非典型溶血性尿毒症综合征 (aHUS, MIM 235400) 相关，表明该疾病的发生是由于补体系统无法有效保护肾内皮免受损伤的结果。然而，携带这些突变的个体的疾病不完全外显率相对较高。在这里，我们报告了一个大的、多重受影响的 aHUS 谱系的鉴定，其中存在三种不同 aHUS 危险因素的独立分离：降低细胞表面 MCP 表达的 MCP 错义突变（c.-598C > T；Pro 165Ser）、因子 I 编码序列中的二核苷酸插入（c.- 1610insAT），在因子 I 蛋白中引入过早终止密码子，以及 MCPggaac SNP先前显示单倍型块可以降低 MCP 启动子的转录活性。有趣的是，家谱中受 aHUS 影响的个体只是那些继承了三个 aHUS 危险因素的人。这些数据显示了 MCP 和 I 因子突变的累加效应，并为以下结论提供了明确的支持：aHUS 是由于细胞表面免受补体激活的保护缺陷造成的。此外，它们有助于解释该疾病的不完全外显率，说明补体调节蛋白中的多次命中可能是显着损害宿主组织保护并赋予 aHUS 易感性所必需的。 (c) 2005 Elsevier Ltd. 保留所有权利。
Mutations in the complement regulators factor H, membrane cofactor protein (MCP), and factor I are associated with atypical hemolytic uremic syndrome (aHUS, MIM 235400), suggesting that the disease develops as a consequence of the inefficient protection of the renal endothelium from damage by the complement system. Incomplete penetrance of the disease in individuals carrying these mutations is, however, relatively frequent. Here, we report the identification of a large, multiple affected aHUS pedigree in which there is independent segregation of three different aHUS risk factors: a MCP missense mutation (c.-598C > T; Pro 165Ser) that decreases MCP expression on the cell surface, a dinucleotide insertion in the coding sequence of factor I (c.- 1610insAT) that introduces a premature stop codon in the factor I protein, and the MCPggaac SNP haplotype block that was previously shown to decrease the transcription activity from the MCP promoter. Interestingly, individuals affected by aHUS in the pedigree are only those who have inherited the three aHUS risk factors. These data show an additive effect for mutations in MCP and factor I and provide definitive support to the conclusion that aHUS results from a defective protection of cellular surfaces from complement activation. Furthermore, they help to explain the incomplete penetrance of the disease, illustrating that concurrence of multiple hits in complement regulatory proteins may be necessary to significantly impair host tissue protection and to confer susceptibility to aHUS. (c) 2005 Elsevier Ltd. All rights reserved.