The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation.
The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation.
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DOI：
10.1016/j.molimm.2007.01.036
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发表时间：
2007-05
影响因子：
3.6
通讯作者：
D. Kavanagh;R. Burgess;D. Spitzer;A. Richards;M. Diaz-Torres;J. Goodship;D. Hourcade;J. Atkinson;T. Goodship
中科院分区：
文献类型：
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作者：
D. Kavanagh;R. Burgess;D. Spitzer;A. Richards;M. Diaz-Torres;J. Goodship;D. Hourcade;J. Atkinson;T. Goodship
溶血性尿毒症综合征是血小板减少症、微血管病性溶血性贫血和急性肾功能衰竭的临床三联征。与先前产生志贺样毒素的大肠杆菌无关的病例被描述为非典型 HUS (aHUS)。大约 50% 的 aHUS 患者的三种补体调节蛋白之一存在突变，即 H 因子 (CFH)、膜辅因子蛋白 (MCP;CD46) 或 I 因子 (IF)。这三种蛋白质的一个共同特征是它们通过辅因子活性调节补体。衰变加速因子（DAF；CD55）通过解离替代途径和经典途径转化酶来调节补体系统。与 CFH 和 MCP 一样，DAF 基因位于 1q32 的补体激活调节因子 (RCA) 基因簇内。 1998 年，我们描述了 aHUS 家族与该区域的联系，从而发现了 CFH 和 MCP 中的突变。因此，我们对 46 名 aHUS 患者（其中包括与 RCA 簇有关联的家族）进行了 DAF 基因分型。在一名家族性 HUS 患者中发现了一种突变 I197V，而在 100 名健康对照者中未发现这种突变。该突变的分子模型表明，I197V 突变并不存在于预计对衰变加速活动起重要作用的区域。 EBV 转化的 B 淋巴细胞上 I197V 的表达与野生型对照相当。通过补体介导的裂解测定测量，与野生型相比，重组产生的 I197V 突变体的衰变加速活性没有显着降低。总之，本研究在 46 名 aHUS 患者中仅发现了一种 DAF 突变。这种突变 I197V 不会损害补体调节，并且与该患者的 aHUS 发病机制无关。这表明 aHUS 中的补体调节异常主要是辅因子活性缺陷而不是衰变加速活性之一。
Hemolytic uremic syndrome is the clinical triad of thrombocytopenia, microangiopathic hemolytic anaemia and acute renal failure. Cases not associated with a preceding Shiga-like toxin producing Escherichia coli are described as atypical HUS (aHUS). Approximately 50% of patients with aHUS have mutations in one of three complement regulatory proteins, Factor H (CFH), membrane cofactor protein (MCP;CD46) or factor I (IF). A common feature of these three proteins is that they regulate complement by cofactor activity. Decay accelerating factor (DAF; CD55) regulates the complement system by disassociating the alternative and classical pathway convertases. Like CFH and MCP, the gene for DAF lies within the regulators of complement activation (RCA) gene cluster at 1q32. In 1998, we described linkage to this region in families with aHUS which led to the discovery of mutations in CFH and MCP. We therefore genotyped DAF in a panel of 46 aHUS patients including families with linkage to the RCA cluster. A mutation, I197V, was identified in one patient with familial HUS which was not found in 100 healthy controls. Molecular modelling of this mutation shows that the I197V mutation does not reside in an area which would be predicted to be important in decay accelerating activity. The expression of I197V on EBV-transformed B lymphocytes was equivalent to that of wild type controls. There was no significant decrease in decay acceleration activity of the recombinantly produced I197V mutant compared with wild type, as measured by a complement-mediated lytic assay. In conclusion, this study, identifies only one mutation in DAF in 46 patients with aHUS. This mutation, I197V, does not impair complement regulation and cannot be implicated in the pathogenesis of aHUS in this patient. This suggests that the complement regulatory abnormality in aHUS is principally one of deficient cofactor activity rather than of decay acceleration activity.