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 & 27 others 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

Research output: Contribution to journalArticle

370 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.

LanguageEnglish
Pages1397-1405
Number of pages9
JournalNature Genetics
Volume38
Issue number12
DOIs
Publication statusPublished - 5 Dec 2006
Externally publishedYes

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Nephrotic Syndrome
Organism Cloning
Mutation
Chronic Kidney Failure
Histology
Kidney
Focal Segmental Glomerulosclerosis
Podocytes
Zebrafish
Missense Mutation
Proteinuria
Fluorescent Antibody Technique
Exons
Edema
Catalytic Domain
Therapeutics
Steroids
Genes

Cite this

Hinkes, B., Wiggins, R. C., Gbadegesin, R., Vlangos, C. N., Seelow, D., Nürnberg, G., ... 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
Hinkes, Bernward ; Wiggins, Roger C. ; Gbadegesin, Rasheed ; Vlangos, Christopher N. ; Seelow, Dominik ; Nürnberg, Gudrun ; Garg, Puneet ; Verma, Rakesh ; Chaib, Hassan ; Hoskins, Bethan E. ; Ashraf, Shazia ; Becker, Christian ; Hennies, Hans Christian ; Goyal, Meera ; Wharram, Bryan L. ; Schachter, Asher D. ; Mudumana, Sudha ; Drummond, Iain ; Kerjaschki, Dontscho ; Waldherr, Rüdiger ; Dietrich, Alexander ; Ozaltin, Fatih ; Bakkaloglu, Aysin ; Cleper, Roxana ; Basel-Vanagaite, Lina ; Pohl, Martin ; Griebel, Martin ; Tsygin, Alexey N. ; Soylu, Alper ; Müller, Dominik ; Sorli, Caroline S. ; Bunney, Tom D. ; Katan, Matilda ; Liu, Jinhong ; Attanasio, Massimo ; O'Toole, John F. ; Hasselbacher, Katrin ; Mucha, Bettina ; Otto, Edgar A. ; Airik, Rannar ; Kispert, Andreas ; Kelley, Grant G. ; Smrcka, Alan V. ; Gudermann, Thomas ; Holzman, Lawrence B. ; Nürnberg, Peter ; Hildebrandt, Friedhelm. / Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. In: Nature Genetics. 2006 ; Vol. 38, No. 12. pp. 1397-1405.
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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.",
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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

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. / Hinkes, Bernward; Wiggins, Roger C.; Gbadegesin, Rasheed; Vlangos, Christopher N.; Seelow, Dominik; Nürnberg, Gudrun; Garg, Puneet; Verma, Rakesh; Chaib, Hassan; Hoskins, Bethan E.; Ashraf, Shazia; Becker, Christian; Hennies, Hans Christian; Goyal, Meera; Wharram, Bryan L.; Schachter, Asher D.; Mudumana, Sudha; Drummond, Iain; Kerjaschki, Dontscho; Waldherr, Rüdiger; Dietrich, Alexander; Ozaltin, Fatih; Bakkaloglu, Aysin; Cleper, Roxana; Basel-Vanagaite, Lina; Pohl, Martin; Griebel, Martin; Tsygin, Alexey N.; Soylu, Alper; Müller, Dominik; Sorli, Caroline S.; Bunney, Tom D.; Katan, Matilda; Liu, Jinhong; Attanasio, Massimo; O'Toole, John F.; Hasselbacher, Katrin; Mucha, Bettina; Otto, Edgar A.; Airik, Rannar; Kispert, Andreas; Kelley, Grant G.; Smrcka, Alan V.; Gudermann, Thomas; Holzman, Lawrence B.; Nürnberg, Peter; Hildebrandt, Friedhelm.

In: Nature Genetics, Vol. 38, No. 12, 05.12.2006, p. 1397-1405.

Research output: Contribution to journalArticle

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.

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Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nürnberg G et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nature Genetics. 2006 Dec 5;38(12):1397-1405. https://doi.org/10.1038/ng1918