Fremeaux-Bacchi Véronique, Moulton Elizabeth A, Kavanagh David, Dragon-Durey Marie-Agnès, Blouin Jacques, Caudy Amy, Arzouk Nadia, Cleper Roxanna, Francois Maud, Guest Genevieve, Pourrat Jacques, Seligman Roland, Fridman Wolf Herman, Loirat Chantal, Atkinson John P
Assitance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris cedex 15, France.
J Am Soc Nephrol. 2006 Jul;17(7):2017-25. doi: 10.1681/ASN.2005101051. Epub 2006 Jun 8.
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; CD46) 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.
溶血尿毒综合征（HUS）的特征为血小板减少、微血管病性溶血性贫血和急性肾衰竭三联征。非志贺毒素相关性HUS（非典型HUS [aHUS]）已被证明是一种补体调节异常的疾病。血浆补体调节因子H和因子I以及广泛表达的膜辅助蛋白（MCP；CD46）的突变最近已有报道。本研究在一组120例aHUS患者中寻找MCP突变。在该队列中，约10%的aHUS患者（11例患者；9个家系）存在MCP突变。发病通常在儿童早期。与因子I或因子H突变的患者不同，大多数患者在aHUS后不会发展为终末期肾衰竭。大多数患者存在导致MCP表面表达降低的突变。一小部分患者表达功能异常但水平正常的蛋白。与其他研究一样，显示出不完全外显率，提示MCP是一个易感因素而非直接致病因素。证实了MCP突变患者移植时aHUS的低复发率，并描述了首例MCP缺失个体。本研究证实了MCP缺乏与aHUS之间的关联，并进一步确定补体调节缺陷，特别是辅因子活性缺陷，易导致肾血管严重血栓性微血管病。
