Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
| Autor: | Tom D. Bunney, Grant G. Kelley, Puneet Garg, Christian Becker, Alper Soylu, Dontscho Kerjaschki, Thomas Gudermann, Alexander Dietrich, Roxana Cleper, Jinhong Liu, Alexey N. Tsygin, Lina Basel-Vanagaite, Andreas Kispert, Caroline S. Sorli, Rannar Airik, Martin Pohl, Friedhelm Hildebrandt, Bettina E. Mucha, Matilda Katan, Martin Griebel, Alan V. Smrcka, Meera Goyal, Aysin Bakkaloglu, Katrin Hasselbacher, Bernward Hinkes, Rasheed Gbadegesin, John F. O'Toole, Rüdiger Waldherr, Massimo Attanasio, Roger C. Wiggins, Sudha Mudumana, Bryan L. Wharram, Christopher N. Vlangos, Edgar A. Otto, Asher D. Schachter, Lawrence B. Holzman, Fatih Ozaltin, Bethan E. Hoskins, Gudrun Nürnberg, Iain A. Drummond, Hassan Chaib, Dominik Seelow, Peter Nürnberg, Rakesh Verma, Shazia Ashraf, Dominik N. Müller, Hans Christian Hennies |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty Pathology Nephrotic Syndrome Positional cloning Mutation Missense Genes Recessive Biology Kidney Phosphoinositide Phospholipase C Focal segmental glomerulosclerosis Internal medicine Edema Genetics medicine Animals Humans Missense mutation Cloning Molecular Child Zebrafish Sequence Deletion Models Genetic Homozygote Infant Glomerulonephritis medicine.disease Rats Disease Models Animal Endocrinology medicine.anatomical_structure Child Preschool Type C Phospholipases Gene Targeting Mutation Female medicine.symptom Nephrotic syndrome Kidney disease |
| Zdroj: | Nature Genetics. 38:1397-1405 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng1918 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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