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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References

  1. Hildebrandt, F. & Omran, H. New insights: nephronophthisis/medullary cystic kidney disease. Ped. Nephrol. 16, 168–176 (2001).
    Article CAS Google Scholar
  2. Mainzer, F., Saldino, R.M., Ozonoff, M.B. & Minagi, H. Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am. J. Med. 49, 556–562 (1970).
    Article CAS Google Scholar
  3. Boichis, H., Passwell, J., David, R. & Miller, H. Congenital hepatic fibrosis and nephronophthisis: a family study. Q. J. Med. 42, 221–233 (1973).
    CAS PubMed Google Scholar
  4. Løken, A.C., Hanssen, O., Halvorsen, S. & Jølster, N.J. Hereditary renal dysplasia and blindness. Acta Paediatr. 50, 177–184 (1961).
    Article Google Scholar
  5. Senior, B., Friedmann, A.I. & Braudo, J.L. Juvenile familial nephropathy with tapetoretinal degeneration: a new oculo-renal dystrophy. Am. J. Opthalmol. 52, 625–633 (1961).
    Article CAS Google Scholar
  6. Betz, R. et al. Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J. Pediatr. 136, 828–831 (2000).
    CAS PubMed Google Scholar
  7. Haider, N.B. et al. A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. Am. J. Hum. Genet. 63, 1404–1410 (1998).
    Article CAS Google Scholar
  8. Antignac, C. et al. A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p. Nat. Genet. 3, 342–345 (1993).
    Article CAS Google Scholar
  9. Schuermann, M.J. et al. Mapping of gene loci for nephronophthisis type 4 and Senior-Løken syndrome to chromosome 1p36. Am. J. Hum. Genet. 70, 1240–1246 (2002).
    Article CAS Google Scholar
  10. Omran, H. et al. Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am. J. Hum. Genet. 66, 118–127 (2000).
    Article CAS Google Scholar
  11. Hildebrandt, F. et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat. Genet. 17, 149–153 (1997).
    Article CAS Google Scholar
  12. Otto, E. et al. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am. J. Hum. Genet. 71, 1240–1246 (2002).
    Article Google Scholar
  13. Mollet, G. et al. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat. Genet. 32, 300–305 (2002).
    Article CAS Google Scholar
  14. Takahashi, H. et al. A new mouse model of genetically transmitted polycystic kidney disease. J. Urol. 135, 1280–1283 (1986).
    Article CAS Google Scholar
  15. Aukema, H.M. et al. Effects of dietary protein restriction and oil type on the early progression of murine polycystic kidney disease. Kidney Int. 42, 837–842 (1992).
    Article CAS Google Scholar
  16. Tomobe, K. Effect of dietary soy protein and genistein on disease progression in mice with polycystic kidney disease. Am. J. Kidney Dis. 31, 55–61 (1998).
    Article CAS Google Scholar
  17. Gattone, V.H. et al. Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents. Am. J. Kidney Dis. 25, 302–313 (1995).
    Article CAS Google Scholar
  18. Omran, H. et al. Identification of a gene locus for Senior-Løken Syndrome in the region of the nephronophthisis type 3 Gene. J. Am. Soc. Nephrol. 13, 75–79 (2002).
    CAS PubMed Google Scholar
  19. Volz, A., Melkaoui, R., Hildebrandt, F. & Omran, H. Candidate gene analysis of KIAA0678 encoding a DnaJ-like protein for adolescent nephronophthisis and Senior-Løken syndrome type 3. Cytogenet. Genome Res. 97, 163–166 (2002).
    Article CAS Google Scholar
  20. Omran, H. et al. Evidence for further genetic heterogeneity in nephronophthisis. Nephrol. Dial. Transplant. 16, 755–758 (2001).
    Article CAS Google Scholar
  21. Omran, H. et al. Human adolescent nephronophthisis: gene locus synteny with polycystic kidney disease in pcy mice. J. Am. Soc. Nephrol. 12, 107–113 (2001).
    CAS PubMed Google Scholar
  22. Pazour, G.J. et al. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J. Cell Biol. 151, 709–718 (2000).
    Article CAS Google Scholar
  23. Murcia, N.S. et al. The Oak Ridge polycystic kidney (orpk) disease gene is required for left-right axis determination. Development 127, 2347–2355 (2000).
    CAS PubMed Google Scholar
  24. Moyer, J.H. et al. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science 264, 1329–1333 (1994).
    Article CAS Google Scholar
  25. Pennekamp, P. et al. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr. Biol. 12, 938–943 (2002).
    Article CAS Google Scholar
  26. Pazour, G.J. et al. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr. Biol. 12, R378–R380 (2002).
    Article CAS Google Scholar
  27. Erck, C., Frank, R. & Wehland, J. Tubulin-tyrosine ligase, a long lasting enigma. Neurochem. Res. 25, 5–10 (2000).
    Article CAS Google Scholar
  28. Benzing, T. et al. Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2. Proc. Natl. Acad. Sci. USA 98, 9784–9789 (2001).
    Article CAS Google Scholar
  29. Donaldson, J.C. et al. Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. Exp. Cell Res. 256, 168–178 (2000).
    Article CAS Google Scholar
  30. Nauli, S.M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).
    Article CAS Google Scholar

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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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