Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9

Bettina Mucha, Fatih Ozaltin, Bernward G. Hinkes, Katrin Hasselbacher, Rainer G. Ruf, Michael Schultheiss, Daniela Hangan, Bethan E. Hoskins, Anne Schulze Everding, Radovan Bogdanovic, Thomas Seeman, Bernd Hoppe, Friedhelm Hildebrandt, J. Thaarup, A. Noyan, A. Bakkaloglu, S. Kalman, J. Hopcian, K. Van Hoeck, G. GormanF. Burkhalter, B. Descoendres, M. Mayr, A. Peco-Antic, J. Putnik, N. Stajic, S. Briese, J. Gellermann, U. Querfeld, H. Bachmann, J. Springate, G. Reusz, A. Goldberg, C. Licht, D. Michalk, L. Stapenhorst, M. Gahr, G. Kvaldova, M. Laaß, W. Rascher, P. Hoyer, U. Neyer, M. Brandis, A. Fuchshuber, C. Von Schnakenburg, C. Mache, L. Patzer, M. Kemper, D. E. Müller-Wiefel, J. H H Ehrich, D. Hohmann, G. Offner, S. Skalova, F. Schäfer, T. Knüppel, O. Mehls, B. Tönshoff, D. Wenning, H. Patzer, G. Rönnefarth, R. Cohen-Becker, J. Scheinman, S. Hashmi, P. Eggert, R. Ettenger, L. Rangel, S. Wygoda, R. Beetz, F. Anacleto, H. Fehrenbach, K. Timmermann, M. Griebel, G. Filler, S. Pavicevic, J. Muscheites, G. Warnecke, N. Benador, J. Monterrode Pina Neto, M. Lilova, M. Bald, M. Holder, H. Leichter, Anna Y. Zolotnitskaya, R. Weiss, A. Pollak, G. Laube, T. Neuhaus

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.

Original languageEnglish (US)
Pages (from-to)325-331
Number of pages7
JournalPediatric Research
Volume59
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Fingerprint

Wilms' Tumor Genes
Wilms Tumor
Nephrotic Syndrome
Exons
Steroids
Mutation
Heteroduplex Analysis
Genes
Proteinuria
Introns
Chronic Kidney Failure
Kidney

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Mucha, B., Ozaltin, F., Hinkes, B. G., Hasselbacher, K., Ruf, R. G., Schultheiss, M., ... Neuhaus, T. (2006). Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. Pediatric Research, 59(2), 325-331. https://doi.org/10.1203/01.pdr.0000196717.94518.f0

Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. / Mucha, Bettina; Ozaltin, Fatih; Hinkes, Bernward G.; Hasselbacher, Katrin; Ruf, Rainer G.; Schultheiss, Michael; Hangan, Daniela; Hoskins, Bethan E.; Everding, Anne Schulze; Bogdanovic, Radovan; Seeman, Thomas; Hoppe, Bernd; Hildebrandt, Friedhelm; Thaarup, J.; Noyan, A.; Bakkaloglu, A.; Kalman, S.; Hopcian, J.; Van Hoeck, K.; Gorman, G.; Burkhalter, F.; Descoendres, B.; Mayr, M.; Peco-Antic, A.; Putnik, J.; Stajic, N.; Briese, S.; Gellermann, J.; Querfeld, U.; Bachmann, H.; Springate, J.; Reusz, G.; Goldberg, A.; Licht, C.; Michalk, D.; Stapenhorst, L.; Gahr, M.; Kvaldova, G.; Laaß, M.; Rascher, W.; Hoyer, P.; Neyer, U.; Brandis, M.; Fuchshuber, A.; Von Schnakenburg, C.; Mache, C.; Patzer, L.; Kemper, M.; Müller-Wiefel, D. E.; Ehrich, J. H H; Hohmann, D.; Offner, G.; Skalova, S.; Schäfer, F.; Knüppel, T.; Mehls, O.; Tönshoff, B.; Wenning, D.; Patzer, H.; Rönnefarth, G.; Cohen-Becker, R.; Scheinman, J.; Hashmi, S.; Eggert, P.; Ettenger, R.; Rangel, L.; Wygoda, S.; Beetz, R.; Anacleto, F.; Fehrenbach, H.; Timmermann, K.; Griebel, M.; Filler, G.; Pavicevic, S.; Muscheites, J.; Warnecke, G.; Benador, N.; Monterrode Pina Neto, J.; Lilova, M.; Bald, M.; Holder, M.; Leichter, H.; Zolotnitskaya, Anna Y.; Weiss, R.; Pollak, A.; Laube, G.; Neuhaus, T.

In: Pediatric Research, Vol. 59, No. 2, 02.2006, p. 325-331.

Research output: Contribution to journalArticle

Mucha, B, Ozaltin, F, Hinkes, BG, Hasselbacher, K, Ruf, RG, Schultheiss, M, Hangan, D, Hoskins, BE, Everding, AS, Bogdanovic, R, Seeman, T, Hoppe, B, Hildebrandt, F, Thaarup, J, Noyan, A, Bakkaloglu, A, Kalman, S, Hopcian, J, Van Hoeck, K, Gorman, G, Burkhalter, F, Descoendres, B, Mayr, M, Peco-Antic, A, Putnik, J, Stajic, N, Briese, S, Gellermann, J, Querfeld, U, Bachmann, H, Springate, J, Reusz, G, Goldberg, A, Licht, C, Michalk, D, Stapenhorst, L, Gahr, M, Kvaldova, G, Laaß, M, Rascher, W, Hoyer, P, Neyer, U, Brandis, M, Fuchshuber, A, Von Schnakenburg, C, Mache, C, Patzer, L, Kemper, M, Müller-Wiefel, DE, Ehrich, JHH, Hohmann, D, Offner, G, Skalova, S, Schäfer, F, Knüppel, T, Mehls, O, Tönshoff, B, Wenning, D, Patzer, H, Rönnefarth, G, Cohen-Becker, R, Scheinman, J, Hashmi, S, Eggert, P, Ettenger, R, Rangel, L, Wygoda, S, Beetz, R, Anacleto, F, Fehrenbach, H, Timmermann, K, Griebel, M, Filler, G, Pavicevic, S, Muscheites, J, Warnecke, G, Benador, N, Monterrode Pina Neto, J, Lilova, M, Bald, M, Holder, M, Leichter, H, Zolotnitskaya, AY, Weiss, R, Pollak, A, Laube, G & Neuhaus, T 2006, 'Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9', Pediatric Research, vol. 59, no. 2, pp. 325-331. https://doi.org/10.1203/01.pdr.0000196717.94518.f0
Mucha, Bettina ; Ozaltin, Fatih ; Hinkes, Bernward G. ; Hasselbacher, Katrin ; Ruf, Rainer G. ; Schultheiss, Michael ; Hangan, Daniela ; Hoskins, Bethan E. ; Everding, Anne Schulze ; Bogdanovic, Radovan ; Seeman, Thomas ; Hoppe, Bernd ; Hildebrandt, Friedhelm ; Thaarup, J. ; Noyan, A. ; Bakkaloglu, A. ; Kalman, S. ; Hopcian, J. ; Van Hoeck, K. ; Gorman, G. ; Burkhalter, F. ; Descoendres, B. ; Mayr, M. ; Peco-Antic, A. ; Putnik, J. ; Stajic, N. ; Briese, S. ; Gellermann, J. ; Querfeld, U. ; Bachmann, H. ; Springate, J. ; Reusz, G. ; Goldberg, A. ; Licht, C. ; Michalk, D. ; Stapenhorst, L. ; Gahr, M. ; Kvaldova, G. ; Laaß, M. ; Rascher, W. ; Hoyer, P. ; Neyer, U. ; Brandis, M. ; Fuchshuber, A. ; Von Schnakenburg, C. ; Mache, C. ; Patzer, L. ; Kemper, M. ; Müller-Wiefel, D. E. ; Ehrich, J. H H ; Hohmann, D. ; Offner, G. ; Skalova, S. ; Schäfer, F. ; Knüppel, T. ; Mehls, O. ; Tönshoff, B. ; Wenning, D. ; Patzer, H. ; Rönnefarth, G. ; Cohen-Becker, R. ; Scheinman, J. ; Hashmi, S. ; Eggert, P. ; Ettenger, R. ; Rangel, L. ; Wygoda, S. ; Beetz, R. ; Anacleto, F. ; Fehrenbach, H. ; Timmermann, K. ; Griebel, M. ; Filler, G. ; Pavicevic, S. ; Muscheites, J. ; Warnecke, G. ; Benador, N. ; Monterrode Pina Neto, J. ; Lilova, M. ; Bald, M. ; Holder, M. ; Leichter, H. ; Zolotnitskaya, Anna Y. ; Weiss, R. ; Pollak, A. ; Laube, G. ; Neuhaus, T. / Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. In: Pediatric Research. 2006 ; Vol. 59, No. 2. pp. 325-331.
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title = "Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9",
abstract = "Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25{\%} of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.",
author = "Bettina Mucha and Fatih Ozaltin and Hinkes, {Bernward G.} and Katrin Hasselbacher and Ruf, {Rainer G.} and Michael Schultheiss and Daniela Hangan and Hoskins, {Bethan E.} and Everding, {Anne Schulze} and Radovan Bogdanovic and Thomas Seeman and Bernd Hoppe and Friedhelm Hildebrandt and J. Thaarup and A. Noyan and A. Bakkaloglu and S. Kalman and J. Hopcian and {Van Hoeck}, K. and G. Gorman and F. Burkhalter and B. Descoendres and M. Mayr and A. Peco-Antic and J. Putnik and N. Stajic and S. Briese and J. Gellermann and U. Querfeld and H. Bachmann and J. Springate and G. Reusz and A. Goldberg and C. Licht and D. Michalk and L. Stapenhorst and M. Gahr and G. Kvaldova and M. Laa{\ss} and W. Rascher and P. Hoyer and U. Neyer and M. Brandis and A. Fuchshuber and {Von Schnakenburg}, C. and C. Mache and L. Patzer and M. Kemper and M{\"u}ller-Wiefel, {D. E.} and Ehrich, {J. H H} and D. Hohmann and G. Offner and S. Skalova and F. Sch{\"a}fer and T. Kn{\"u}ppel and O. Mehls and B. T{\"o}nshoff and D. Wenning and H. Patzer and G. R{\"o}nnefarth and R. Cohen-Becker and J. Scheinman and S. Hashmi and P. Eggert and R. Ettenger and L. Rangel and S. Wygoda and R. Beetz and F. Anacleto and H. Fehrenbach and K. Timmermann and M. Griebel and G. Filler and S. Pavicevic and J. Muscheites and G. Warnecke and N. Benador and {Monterrode Pina Neto}, J. and M. Lilova and M. Bald and M. Holder and H. Leichter and Zolotnitskaya, {Anna Y.} and R. Weiss and A. Pollak and G. Laube and T. Neuhaus",
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TY - JOUR

T1 - Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9

AU - Mucha, Bettina

AU - Ozaltin, Fatih

AU - Hinkes, Bernward G.

AU - Hasselbacher, Katrin

AU - Ruf, Rainer G.

AU - Schultheiss, Michael

AU - Hangan, Daniela

AU - Hoskins, Bethan E.

AU - Everding, Anne Schulze

AU - Bogdanovic, Radovan

AU - Seeman, Thomas

AU - Hoppe, Bernd

AU - Hildebrandt, Friedhelm

AU - Thaarup, J.

AU - Noyan, A.

AU - Bakkaloglu, A.

AU - Kalman, S.

AU - Hopcian, J.

AU - Van Hoeck, K.

AU - Gorman, G.

AU - Burkhalter, F.

AU - Descoendres, B.

AU - Mayr, M.

AU - Peco-Antic, A.

AU - Putnik, J.

AU - Stajic, N.

AU - Briese, S.

AU - Gellermann, J.

AU - Querfeld, U.

AU - Bachmann, H.

AU - Springate, J.

AU - Reusz, G.

AU - Goldberg, A.

AU - Licht, C.

AU - Michalk, D.

AU - Stapenhorst, L.

AU - Gahr, M.

AU - Kvaldova, G.

AU - Laaß, M.

AU - Rascher, W.

AU - Hoyer, P.

AU - Neyer, U.

AU - Brandis, M.

AU - Fuchshuber, A.

AU - Von Schnakenburg, C.

AU - Mache, C.

AU - Patzer, L.

AU - Kemper, M.

AU - Müller-Wiefel, D. E.

AU - Ehrich, J. H H

AU - Hohmann, D.

AU - Offner, G.

AU - Skalova, S.

AU - Schäfer, F.

AU - Knüppel, T.

AU - Mehls, O.

AU - Tönshoff, B.

AU - Wenning, D.

AU - Patzer, H.

AU - Rönnefarth, G.

AU - Cohen-Becker, R.

AU - Scheinman, J.

AU - Hashmi, S.

AU - Eggert, P.

AU - Ettenger, R.

AU - Rangel, L.

AU - Wygoda, S.

AU - Beetz, R.

AU - Anacleto, F.

AU - Fehrenbach, H.

AU - Timmermann, K.

AU - Griebel, M.

AU - Filler, G.

AU - Pavicevic, S.

AU - Muscheites, J.

AU - Warnecke, G.

AU - Benador, N.

AU - Monterrode Pina Neto, J.

AU - Lilova, M.

AU - Bald, M.

AU - Holder, M.

AU - Leichter, H.

AU - Zolotnitskaya, Anna Y.

AU - Weiss, R.

AU - Pollak, A.

AU - Laube, G.

AU - Neuhaus, T.

PY - 2006/2

Y1 - 2006/2

N2 - Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.

AB - Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.

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