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

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

doi:10.1038/ng1918

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

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 WaldherrAlexander 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^*

^*Corresponding author for this work

Clinic of Otorhinolaryngology

496 Citations (Scopus)

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 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.

Original language	English
Journal	Nature Genetics
Volume	38
Issue number	12
Pages (from-to)	1397-1405
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng1918
Publication status	Published - 05.12.2006

Funding

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.).

Research Areas and Centers

Research Area: Center for Population Medicine and Public Health (ZBV)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hinkes, B., Wiggins, R. C., Gbadegesin, R., Vlangos, C. N., Seelow, D., Nürnberg, G., Garg, P., Verma, R., Chaib, H., Hoskins, B. E., Ashraf, S., Becker, C., Hennies, H. C., Goyal, M., Wharram, B. L., Schachter, A. D., Mudumana, S., Drummond, I., Kerjaschki, D., ... Hildebrandt, F. (2006). Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nature Genetics, 38(12), 1397-1405. https://doi.org/10.1038/ng1918

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

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 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.",

author = "Bernward Hinkes and Wiggins, \{Roger C.\} and Rasheed Gbadegesin and Vlangos, \{Christopher N.\} and Dominik Seelow and Gudrun N{\"u}rnberg and Puneet Garg and Rakesh Verma and Hassan Chaib and Hoskins, \{Bethan E.\} and Shazia Ashraf and Christian Becker and Hennies, \{Hans Christian\} and Meera Goyal and Wharram, \{Bryan L.\} and Schachter, \{Asher D.\} and Sudha Mudumana and Iain Drummond and Dontscho Kerjaschki and R{\"u}diger Waldherr and Alexander Dietrich and Fatih Ozaltin and Aysin Bakkaloglu and Roxana Cleper and Lina Basel-Vanagaite and Martin Pohl and Martin Griebel and Tsygin, \{Alexey N.\} and Alper Soylu and Dominik M{\"u}ller and Sorli, \{Caroline S.\} and Bunney, \{Tom D.\} and Matilda Katan and Jinhong Liu and Massimo Attanasio and O'Toole, \{John F.\} and Katrin Hasselbacher and Bettina Mucha and Otto, \{Edgar A.\} and Rannar Airik and Andreas Kispert and Kelley, \{Grant G.\} and Smrcka, \{Alan V.\} and Thomas Gudermann and Holzman, \{Lawrence B.\} and Peter N{\"u}rnberg and Friedhelm Hildebrandt",

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doi = "10.1038/ng1918",

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Hinkes, B, Wiggins, RC, Gbadegesin, R, Vlangos, CN, Seelow, D, Nürnberg, G, Garg, P, Verma, R, Chaib, H, Hoskins, BE, Ashraf, S, Becker, C, Hennies, HC, Goyal, M, Wharram, BL, Schachter, AD, Mudumana, S, Drummond, I, Kerjaschki, D, Waldherr, R, Dietrich, A, Ozaltin, F, Bakkaloglu, A, Cleper, R, Basel-Vanagaite, L, Pohl, M, Griebel, M, Tsygin, AN, Soylu, A, Müller, D, Sorli, CS, Bunney, TD, Katan, M, Liu, J, Attanasio, M, O'Toole, JF, Hasselbacher, K, Mucha, B, Otto, EA, Airik, R, Kispert, A, Kelley, GG, Smrcka, AV, Gudermann, T, Holzman, LB, Nürnberg, P & Hildebrandt, F 2006, 'Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible', Nature Genetics, vol. 38, no. 12, pp. 1397-1405. https://doi.org/10.1038/ng1918

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

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 - https://www.scopus.com/pages/publications/33751531864

U2 - 10.1038/ng1918

DO - 10.1038/ng1918

M3 - Journal articles

C2 - 17086182

AN - SCOPUS:33751531864

SN - 1061-4036

VL - 38

SP - 1397

EP - 1405

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

Abstract

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