Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible

Bernward Hinkes, Roger C. Wiggins, Rasheed Gbadegesin, Christopher N. Vlangos, Dominik Seelow, Gudrun Nürnberg, Puneet Garg, Rakesh Verma, Hassan Chaib, Bethan E. Hoskins, Shazia Ashraf, Christian Becker, Hans Christian Hennies, Meera Goyal, Bryan L. Wharram, Asher D. Schachter, Sudha Mudumana, Iain Drummond, Dontscho Kerjaschki, Rüdiger WaldherrAlexander Dietrich, Fatih Ozaltin, Aysin Bakkaloglu, Roxana Cleper, Lina Basel-Vanagaite, Martin Pohl, Martin Griebel, Alexey N. Tsygin, Alper Soylu, Dominik Müller, Caroline S. Sorli, Tom D. Bunney, Matilda Katan, Jinhong Liu, Massimo Attanasio, John F. O'Toole, Katrin Hasselbacher, Bettina Mucha, Edgar A. Otto, Rannar Airik, Andreas Kispert, Grant G. Kelley, Alan V. Smrcka, Thomas Gudermann, Lawrence B. Holzman, Peter Nürnberg, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

474 Citations (Scopus)


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 PLCε1 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 PLCε1. Two siblings with a missense mutation in an exon encoding the PLCε1 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.

Original languageEnglish
Pages (from-to)1397-1405
Number of pages9
JournalNature Genetics
Issue number12
Publication statusPublished - 5 Dec 2006
Externally publishedYes


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