Title |
Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
|
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Published in |
Nature Genetics, November 2006
|
DOI | 10.1038/ng1918 |
Pubmed ID | |
Authors |
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 Waldherr, Alexander 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 |
Abstract |
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 PLCepsilon1 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 PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 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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Geographical breakdown
Country | Count | As % |
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United States | 2 | 1% |
Germany | 1 | <1% |
Czechia | 1 | <1% |
Italy | 1 | <1% |
Sri Lanka | 1 | <1% |
Belarus | 1 | <1% |
Unknown | 132 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 28 | 20% |
Researcher | 28 | 20% |
Student > Master | 13 | 9% |
Student > Bachelor | 8 | 6% |
Student > Doctoral Student | 7 | 5% |
Other | 30 | 22% |
Unknown | 25 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 46 | 33% |
Agricultural and Biological Sciences | 32 | 23% |
Biochemistry, Genetics and Molecular Biology | 22 | 16% |
Nursing and Health Professions | 3 | 2% |
Neuroscience | 2 | 1% |
Other | 8 | 6% |
Unknown | 26 | 19% |