Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
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DOI：
10.1038/ng1918
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发表时间：
2006-12-01
期刊：
影响因子：
30.8
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Hinkes, Bernward;Wiggins, Roger C.;Hildebrandt, Friedhelm
肾病综合征是肾小球滤过功能异常，导致蛋白尿、水肿，在激素抵抗型肾病综合征中还会导致终末期肾病。通过定位克隆，我们确定磷脂酶C ε基因（PLCE1）的突变会导致早发性肾病综合征及终末期肾病。受影响个体的肾脏组织学显示为弥漫性系膜硬化（DMS）。通过免疫荧光，我们发现PLC ε1在发育中和成熟的肾小球足细胞中表达，并表明DMS代表正常肾小球发育的停滞。我们确定含IQ模体的GTP酶激活蛋白1是PLC ε1的一种新的相互作用蛋白。两个在外显子（编码PLCe1催化结构域）存在错义突变的兄弟姐妹显示出局灶节段性肾小球硬化的组织学特征。值得注意的是，另外两名受影响个体对治疗有反应，这是首次报道肾病综合征的一种分子病因在治疗后可能消除。这些发现，连同通过plce1敲低产生的人类肾病综合征斑马鱼模型，为肾病综合征的病理生理学和治疗机制开辟了新的途径。
Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLC epsilon 1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLC epsilon 1. Two siblings with a missense mutation in an exon encoding the PLCe1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.