Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
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DOI：
10.1016/s0140-6736(10)60670-8
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发表时间：
2010-09-04
期刊：
影响因子：
168.9
通讯作者：
Pickering, Matthew C.
中科院分区：
文献类型：
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作者：
Gale, Daniel P.;de Jorge, Elena Goicoechea;Cook, H. Terence;Martinez-Barricarte, Ruben;Hadjisavvas, Andreas;McLean, Adam G.;Pusey, Charles D.;Pierides, Alkis;Kyriacou, Kyriacos;Athanasiou, Yiannis;Voskarides, Konstantinos;Deltas, Constantinos;Palmer, Andrew;Fremeaux-Bacchi, Veronique;Rodriguez de Cordoba, Santiago;Maxwell, Patrick H.;Pickering, Matthew C.
补体是先天免疫系统的关键组成部分，调节其激活的基因变异与肾脏疾病和其他疾病有关。我们的目的是建立与持续性镜下血尿、复发性肉眼血尿、肾小球肾炎和进行性肾衰竭相关的家族性补体调节疾病的遗传基础。我们从西伦敦肾脏和移植中心（英国伦敦）寻找患有异常肾脏疾病的患者和受影响的家庭成员，作为识别肾脏疾病新遗传原因的方法。确定了两个塞浦路斯血统的家族，其中肾脏疾病符合常染色体显性遗传，并且至少一名个体的肾活检显示 C3 肾小球肾炎。通过全基因组连锁研究和候选基因分析鉴定出突变。随后开发了一种基于 PCR 的诊断测试，并用于筛查基于人群的样本以及患有肾病的个人和家庭中的突变。家族性肾病的发生与补体因子 H 相关蛋白 5 基因 (CFHR5) 的相同突变共分离。在 84 名患有不明原因肾病的塞浦路斯人中，有 4 人出现 CFHR5 突变。总体而言，我们从 11 个表面上不相关的亲属（包括最初的两个家族）中确定了 26 名具有突变和肾脏疾病证据的个体。患者血清中存在的突变 CFHR5 蛋白对表面结合补体的亲和力降低。我们将这种肾脏疾病称为 CFHR5 肾病。 CFHR5 肾病是塞浦路斯血统患者肾脏疾病的重大负担，可以通过特定的分子检测进行诊断。 CFHR5突变携带者患进展性肾病的高风险意味着，孤立的镜下血尿或复发性肉眼血尿不应被视为塞浦路斯血统个体的良性发现。英国医学研究委员会和威康信托基金。
Complement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure. We sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease. Occurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy. CFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent. UK Medical Research Council and Wellcome Trust.