Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair
Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair
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DOI：
10.1053/j.ajkd.2008.02.359
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发表时间：
2008-08-01
影响因子：
13.2
通讯作者：
Fremeaux-Bacchi, Veronique
中科院分区：
文献类型：
--
作者：
Couzi, Lionel;Contin-Bordes, Cecile;Fremeaux-Bacchi, Veronique
非典型溶血性尿毒综合征（阿胡斯）是一种罕见的血栓性微血管病，可能是家族性或散发性的。补体因子H（CFH）、因子I和膜辅因子蛋白（MCP; CD 46），补体系统激活的旁路途径的3种调节剂，已经涉及这种病理状态。迄今为止，已经报道了29种不同的CD 46突变，与CFH突变相比，其不完全突变和更好的临床结果。在这些突变中，只有6个被发现是纯合的（占8例患者），5个导致细胞表面CD 46表达缺乏或显著降低。我们在这里报告的第七例无效突变与复发性阿胡斯。这种突变，即内含子2的第一个核苷酸中鸟嘌呤被胞嘧啶取代，破坏了剪接供体位点。有趣的是，患者的无病姐妹也显示出相同的纯合突变。对其他补体调节蛋白和多态性相关风险因素的广泛分析并未发现患者与其姐姐之间的差异。总之，我们第一次描述了一个完全CD 46缺乏的无病个体，证实了阿胡斯的极端可变性和遗传复杂性。
Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathic disorder that may be familial or sporadic. Complement factor H (CFH), factor I, and membrane cofactor protein (MCP; CD46), 3 regulators of the alternative pathway of the complement system activation, have been implicated in this pathological state. To date, 29 different mutations of CD46 have been reported, with incomplete penetrance and better clinical outcome compared with CFH mutations. Of those mutations, only 6 were found to be homozygous (accounting for 8 patients), and 5 resulted in a lack of or dramatically decreased cell-surface CD46 expression. We report here the seventh patient with a null mutation associated with recurrent aHUS. This mutation, a guanine to cytosine substitution in the first nucleotide of intron 2, disrupts a splice donor site. Interestingly, the patient's disease-free sister showed the same homozygous mutation. Extensive analysis of other complement regulatory protein- and polymorphism-associated risk factors did not uncover a difference between the patient and his sister. In conclusion, we describe for the first time a disease-free individual with complete CD46 deficiency, confirming the extremely variable penetrance and genetic complexity of aHUS.