Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis (original) (raw)

Nature Genetics volume 34, pages 455–459 (2003)Cite this article

Abstract

Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults1. NPHP may be associated with Leber congenital amaurosis, tapeto-retinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis2,3,4,5,6. Loci associated with an infantile type of NPHP on 9q22–q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12–q13 (NPHP1) and 1p36 (NPHP4) and an adolescent type of NPHP on 3q21–q22 (NPHP3) have been mapped7,8,9,10. NPHP1 and NPHP4 have been identified11,12,13, and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown13. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype14. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone15,16,17, suggesting therapeutic strategies for treating individuals with NPHP3.

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Acknowledgements

We thank the affected individuals and their families for their participation in this study, R. Melkaoui and M. Petry for technical assistance and B. Kränzlin for microscopic photographs. This work was supported by the Italian Association for Leber's Congenital Amaurosis and by grants from the German Research Foundation (H.O. and A.K.), Zentrum für klinische Forschung Freiburg (H.O.) and the F.G. L. Huetwell fund (F.H.).

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  1. Heike Olbrich and Manfred Fliegauf: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, 79106, Germany
    Heike Olbrich, Manfred Fliegauf, Andreas Volz, Gürsel Sasmaz & Heymut Omran
  2. Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
    Julia Hoefele, Edgar Otto, Matthias T Wolf & Friedhelm Hildebrandt
  3. Institut für Molekularbiologie, Medizinische Hochschule Hannover, Germany
    Andreas Kispert
  4. Max-Planck Institute for Molecular Genetics, Berlin, Germany
    Ute Trauer, Richard Reinhardt & Ralf Sudbrak
  5. Department of Genetics, INSERM U574, Necker Hospital, Paris 5 University, Paris, France
    Corinne Antignac
  6. Medical Research Center, Klinikum Mannheim, University of Heidelberg, Mannheim, D-68167, Germany
    Norbert Gretz
  7. Renal Division and Center for Clinical Research, University Hospital Freiburg, Freiburg, 79106, Germany
    Gerd Walz, Bernhard Schermer & Thomas Benzing

Authors

  1. Heike Olbrich
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  2. Manfred Fliegauf
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  3. Julia Hoefele
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  4. Andreas Kispert
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  5. Edgar Otto
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  6. Andreas Volz
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  7. Matthias T Wolf
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  8. Gürsel Sasmaz
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  9. Ute Trauer
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  10. Richard Reinhardt
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  11. Ralf Sudbrak
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  12. Corinne Antignac
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  13. Norbert Gretz
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  14. Gerd Walz
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  15. Bernhard Schermer
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  16. Thomas Benzing
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  17. Friedhelm Hildebrandt
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  18. Heymut Omran
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Correspondence toHeymut Omran.

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Olbrich, H., Fliegauf, M., Hoefele, J. et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis.Nat Genet 34, 455–459 (2003). https://doi.org/10.1038/ng1216

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