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

Item Type:	Article
Title:	Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
Creators Name:	Hinkes, B. and Wiggins, R.C. and Gbadegesin, R. and Vlangos, C.N. and Seelow, D. and Nuernberg, G. and Garg, P. and Verma, R. and Chaib, H. and Hoskins, B.E. and Ashraf, S. and Becker, C. and Hennies, H.C. and Goyal, M. and Wharram, B.L. and Schachter, A.D. and Mudumana, S. and Drummond, I. and Kerjaschki, D. and Waldherr, R. and Dietrich, A. and Ozaltin, F. and Bakkaloglu, A. and Cleper, R. and Basel-Vanagaite, L. and Pohl, M. and Griebel, M. and Tsygin, A.N. and Soylu, A. and Mueller, D. and Sorli, C.S. and Bunney, T.D. and Katan, M. and Liu, J. and Attanasio, M. and O'Toole, J.F. and Hasselbacher, K. and Mucha, B. and Otto, E.A. and Airik, R. and Kispert, A. and Kelley, G.G. and Smrcka, A.V. and Gudermann, T. and Holzman, L.B. and Nuernberg, P. and Hildebrandt, F.
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.
Keywords:	Animal Disease Models, Genes, Recessive, Genetic Models, Gene Targeting, Homozygote, Kidney, Missense Mutation, Molecular Cloning, Mutation, Nephrotic Syndrome, Phosphoinositide Phospholipase C, Sequence Deletion, Type C Phospholipases, Animals, Rats, Zebrafish
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	38
Number:	12
Page Range:	1397-1405
Date:	December 2006
Official Publication:	https://doi.org/10.1038/ng1918
PubMed:	View item in PubMed

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