TY - JOUR
T1 - Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible
AU - Hinkes, Bernward
AU - Wiggins, Roger C.
AU - Gbadegesin, Rasheed
AU - Vlangos, Christopher N.
AU - Seelow, Dominik
AU - Nürnberg, Gudrun
AU - Garg, Puneet
AU - Verma, Rakesh
AU - Chaib, Hassan
AU - Hoskins, Bethan E.
AU - Ashraf, Shazia
AU - Becker, Christian
AU - Hennies, Hans Christian
AU - Goyal, Meera
AU - Wharram, Bryan L.
AU - Schachter, Asher D.
AU - Mudumana, Sudha
AU - Drummond, Iain
AU - Kerjaschki, Dontscho
AU - Waldherr, Rüdiger
AU - Dietrich, Alexander
AU - Ozaltin, Fatih
AU - Bakkaloglu, Aysin
AU - Cleper, Roxana
AU - Basel-Vanagaite, Lina
AU - Pohl, Martin
AU - Griebel, Martin
AU - Tsygin, Alexey N.
AU - Soylu, Alper
AU - Müller, Dominik
AU - Sorli, Caroline S.
AU - Bunney, Tom D.
AU - Katan, Matilda
AU - Liu, Jinhong
AU - Attanasio, Massimo
AU - O'Toole, John F.
AU - Hasselbacher, Katrin
AU - Mucha, Bettina
AU - Otto, Edgar A.
AU - Airik, Rannar
AU - Kispert, Andreas
AU - Kelley, Grant G.
AU - Smrcka, Alan V.
AU - Gudermann, Thomas
AU - Holzman, Lawrence B.
AU - Nürnberg, Peter
AU - Hildebrandt, Friedhelm
N1 - Funding Information:
We thank the affected individuals and their families for participation. We acknowledge R.H. Lyons for large-scale sequencing. We thank S.J. Allen and M. Petry for technical assistance and M. McKee for electron microscopy in zebrafish. GFP-tagged IQGAP1 constructs were provided by G. Bloom (University of Virginia). This research was supported by grants from the US National Institutes of Health to F.H., R.C.W. and L.B.H. (P50-DK039255), to R.C.W. (DK46073), to A.V.S. (R01-GM053536) to I.D. (R01-DK53093) and to G.G.K. (R01-DK56294) and by a grant from the KMD Foundation and the Thrasher Research Fund to F.H.; F.H. is the Frederick G.L. Huetwell Professor and a Doris Duke Distinguished Clinical Scientist. The work was further supported by the German Federal Ministry of Science and Education through the National Genome Research Network (C.B., H.C.H., G.N., P.N. and D.S.), by a EuReGene grant to D.M. (E.U., FP6005085) and by grants from the German Research Foundation (A.K., A.D. and T.G.).
PY - 2006/12/5
Y1 - 2006/12/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33751531864&partnerID=8YFLogxK
U2 - 10.1038/ng1918
DO - 10.1038/ng1918
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C2 - 17086182
AN - SCOPUS:33751531864
SN - 1061-4036
VL - 38
SP - 1397
EP - 1405
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -