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

Bernward Hinkes^1, 22, Roger C Wiggins^2, 22, Rasheed Gbadegesin¹, Christopher N Vlangos¹, Dominik Seelow^3, 4, Gudrun Nürnberg^3, 4, Puneet Garg², Rakesh Verma², Hassan Chaib¹, Bethan E Hoskins¹, Shazia Ashraf¹, Christian Becker^3, 4, Hans Christian Hennies^3, 5, Meera Goyal², Bryan L Wharram², Asher D Schachter⁶, Sudha Mudumana⁶, Iain Drummond⁶, Dontscho Kerjaschki⁷, Rüdiger Waldherr⁸, Alexander Dietrich⁹, Fatih Ozaltin¹⁰, Aysin Bakkaloglu¹⁰, Roxana Cleper¹¹, Lina Basel-Vanagaite¹¹, Martin Pohl¹², Martin Griebel¹³, Alexey N Tsygin¹⁴, Alper Soylu¹⁵, Dominik Müller¹⁶, Caroline S Sorli¹⁷, Tom D Bunney¹⁷, Matilda Katan¹⁷, Jinhong Liu¹, Massimo Attanasio¹, John F O'Toole¹, Katrin Hasselbacher¹, Bettina Mucha¹, Edgar A Otto¹, Rannar Airik¹⁸, Andreas Kispert¹⁸, Grant G Kelley¹⁹, Alan V Smrcka²⁰, Thomas Gudermann⁹, Lawrence B Holzman², Peter Nürnberg^3, 5 & Friedhelm Hildebrandt^1, 21

¹  Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.

²  Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

³  Cologne Center for Genomics, University of Cologne, Cologne, Germany.

⁴  RZPD Deutsches Ressourcenzentrum für Genomforschung GmbH, Berlin, Germany.

⁵  Institute for Genetics, University of Cologne, Cologne, Germany.

⁶  Children's Hospital Boston and Renal Unit, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.

⁷  Clinical Institute of Pathology, Medical University of Vienna, Vienna, A-1090, Austria.

⁸  Gemeinschaftspraxis Pathologie, D-69115 Heidelberg, Germany.

⁹  Department of Pharmacology and Toxicology, Philipps-University, Marburg, Germany.

¹⁰  Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

¹¹  Department of Medical Genetics, Schneider Children's Medical Center of Israel and Rabin Medical Center, Petah Tiqva, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

¹²  Department of Pediatrics, Freiburg University, D-79106 Freiburg, Germany.

¹³  Children's Hospital, Technical University, München-Schwabing, Germany.

¹⁴  The Scientific Center of Children's Health, Moscow, Russia.

¹⁵  Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey.

¹⁶  Department of Pediatric Nephrology, Charite Children's Hospital, Berlin, Germany.

¹⁷  Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.

¹⁸  Institute for Molecular Biology, Medizinische Hochschule Hannover, D-30625 Hannover, Germany.

¹⁹  Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.

²⁰  Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, New York 14642, USA.

²¹  Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

²²  These authors contributed equally to this work.

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 PLC1 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 PLC1. Two siblings with a missense mutation in an exon encoding the PLC1 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.

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