Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome
Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome
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DOI：
10.1681/asn.2005101051
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发表时间：
2006-07-01
影响因子：
13.6
通讯作者：
Atkinson, John P.
中科院分区：
文献类型：
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作者：
Fremeaux-Bacchi, Veronique;Moulton, Elizabeth A.;Atkinson, John P.
溶血性尿毒综合征（HUS）的特征是血小板减少、微血管病性溶血性贫血和急性肾衰竭三联征。非志贺毒素相关的HUS（非典型HUS [阿胡斯]）已被证明是一种补体失调疾病。血浆补体调节因子H和因子I以及广泛表达的膜辅因子蛋白（MCP; C1346）的突变最近已被描述。这项研究在一组120名阿胡斯患者中寻找MCP突变。在该队列中，大约10%的阿胡斯患者（11例患者; 9个家系）具有MCP突变。发病通常发生在儿童早期。与具有因子I或因子H突变的患者不同，大多数患者在阿胡斯后不会发展为终末期肾衰竭。大多数患者具有导致MCP表面表达降低的突变。一小部分表达正常水平的功能失调蛋白质。在其他研究中，显示不完全的过敏反应，表明MCP是一个诱发因素，而不是一个直接的因果因素。证实了在具有MCP突变的患者中移植中阿胡斯的低水平复发，并且描述了第一个MCP无效个体。本研究证实了MCP缺乏和阿胡斯之间的关联，并进一步确定了补体调节的缺乏，特别是辅因子活性，易导致肾血管系统中严重的血栓性微血管病。
Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; C1346) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.