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

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Acknowledgements

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.).

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Author notes

1. Bernward Hinkes and Roger C Wiggins: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Pediatrics, University of Michigan, Ann Arbor, 48109, Michigan, USA
   Bernward Hinkes, Rasheed Gbadegesin, Christopher N Vlangos, Hassan Chaib, Bethan E Hoskins, Shazia Ashraf, Jinhong Liu, Massimo Attanasio, John F O'Toole, Katrin Hasselbacher, Bettina Mucha, Edgar A Otto & Friedhelm Hildebrandt
2. Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, Michigan, USA
   Roger C Wiggins, Puneet Garg, Rakesh Verma, Meera Goyal, Bryan L Wharram & Lawrence B Holzman
3. Cologne Center for Genomics, University of Cologne, Cologne, Germany
   Dominik Seelow, Gudrun Nürnberg, Christian Becker, Hans Christian Hennies & Peter Nürnberg
4. RZPD Deutsches Ressourcenzentrum für Genomforschung GmbH, Berlin, Germany
   Dominik Seelow, Gudrun Nürnberg & Christian Becker
5. Institute for Genetics, University of Cologne, Cologne, Germany
   Hans Christian Hennies & Peter Nürnberg
6. Children's Hospital Boston and Renal Unit, Harvard Medical School, Massachusetts General Hospital, Charlestown, 02129, Massachusetts, USA
   Asher D Schachter, Sudha Mudumana & Iain Drummond
7. Clinical Institute of Pathology, Medical University of Vienna, Vienna, A-1090, Austria
   Dontscho Kerjaschki
8. Gemeinschaftspraxis Pathologie, Heidelberg, D-69115, Germany
   Rüdiger Waldherr
9. Department of Pharmacology and Toxicology, Philipps-University, Marburg, Germany
   Alexander Dietrich & Thomas Gudermann
10. Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey
    Fatih Ozaltin & Aysin Bakkaloglu
11. Department of Medical Genetics, Schneider Children's Medical Center of Israel and Rabin Medical Center, Petah Tiqva, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    Roxana Cleper & Lina Basel-Vanagaite
12. Department of Pediatrics, Freiburg University, Freiburg, D-79106, Germany
    Martin Pohl
13. Children's Hospital, Technical University, München-Schwabing, Germany
    Martin Griebel
14. The Scientific Center of Children's Health, Moscow, Russia
    Alexey N Tsygin
15. Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey
    Alper Soylu
16. Department of Pediatric Nephrology, Charite Children's Hospital, Berlin, Germany
    Dominik Müller
17. Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK
    Caroline S Sorli, Tom D Bunney & Matilda Katan
18. Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, D-30625, Germany
    Rannar Airik & Andreas Kispert
19. Department of Medicine, State University of New York Upstate Medical University, Syracuse, 13210, New York, USA
    Grant G Kelley
20. Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, 14642, New York, USA
    Alan V Smrcka
21. Department of Human Genetics, University of Michigan, Ann Arbor, 48109, Michigan, USA
    Friedhelm Hildebrandt

Authors

1. Bernward Hinkes
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2. Roger C Wiggins
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3. Rasheed Gbadegesin
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4. Christopher N Vlangos
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5. Dominik Seelow
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6. Gudrun Nürnberg
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7. Puneet Garg
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8. Rakesh Verma
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9. Hassan Chaib
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10. Bethan E Hoskins
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11. Shazia Ashraf
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12. Christian Becker
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13. Hans Christian Hennies
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14. Meera Goyal
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15. Bryan L Wharram
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16. Asher D Schachter
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17. Sudha Mudumana
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18. Iain Drummond
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19. Dontscho Kerjaschki
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20. Rüdiger Waldherr
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21. Alexander Dietrich
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22. Fatih Ozaltin
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23. Aysin Bakkaloglu
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24. Roxana Cleper
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25. Lina Basel-Vanagaite
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26. Martin Pohl
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27. Martin Griebel
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28. Alexey N Tsygin
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29. Alper Soylu
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30. Dominik Müller
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31. Caroline S Sorli
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32. Tom D Bunney
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33. Matilda Katan
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34. Jinhong Liu
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35. Massimo Attanasio
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36. John F O'Toole
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37. Katrin Hasselbacher
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38. Bettina Mucha
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39. Edgar A Otto
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40. Rannar Airik
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41. Andreas Kispert
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42. Grant G Kelley
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43. Alan V Smrcka
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44. Thomas Gudermann
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45. Lawrence B Holzman
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46. Peter Nürnberg
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47. Friedhelm Hildebrandt
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Corresponding author

Correspondence toFriedhelm Hildebrandt.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Protein domains of human SRN3 (AB040949) as predicted by PFAM. (PDF 33 kb)

Supplementary Fig. 2

Characterization of two different anti-PLCε1 polyclonal antibodies. (PDF 74 kb)

Supplementary Fig. 3

PLCE1 mutation leads to renal histology of diffuse mesangial sclerosis (DMS) and is associated in with interrupted glomerular development. (PDF 691 kb)

Supplementary Fig. 4

CLUSTAL_W amino acid multiple sequence alignment of PLCε1 throughout evolution. (PDF 80 kb)

Supplementary Table 1

Exon-flanking and morpholino oligonucleotide primers used in human and zebrafish PLCE1 studies. (PDF 54 kb)

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Hinkes, B., Wiggins, R., Gbadegesin, R. et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.Nat Genet 38, 1397–1405 (2006). https://doi.org/10.1038/ng1918

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• Received: 23 June 2006
• Accepted: 06 October 2006
• Published: 05 November 2006
• Issue Date: 01 December 2006
• DOI: https://doi.org/10.1038/ng1918