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Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

Nature Genetics volume 34, pages 413–420 (2003)Cite this article

Abstract

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with β-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and β-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and β-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.

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Figure 1: Mutations in INVS in individuals with NPHP2.
Figure 2: Nephrocystin associates with inversin in HEK293T cells and mouse tissue.
Figure 3: Molecular interaction of nephrocystin with β-tubulin.
Figure 4: Nephrocystin and inversin localize to primary cilia in renal tubular epithelial cells.
Figure 5: Disruption of zebrafish invs function results in renal cyst formation.

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Acknowledgements

We thank the affected individuals and their families for participation, J. Robillard for discussion, R.H. Lyons and A. Imm for large-scale sequencing and P. Cochat for contribution of clinical data on individuals A8 and A10. F.H., G.W. and T.B. are supported by Sonderforschungsbereich 592 of the German Research Foundation and by DFG grants to T.B. and G.W.; I.A.D. and T.O. are supported by grants from the US National Institutes of Health to I.A.D.

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Author notes

  1. Edgar A Otto and Bernhard Schermer: These authors contributed equally to this work.

  2. Thomas Benzing and Friedhelm Hildebrandt: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, 8220C MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Edgar A Otto, John F O'Toole, Karl S Hiller, Adelheid M Mueller, Rainer G Ruf, Julia Hoefele, Frank Beekmann, Matthias T Wolf & Friedhelm Hildebrandt

  2. Renal Division and Center for Clinical Research, University Hospital Freiburg, Freiburg, Germany

    Bernhard Schermer, Gerd Walz & Thomas Benzing

  3. Massachusetts General Hospital and Department of Medicine, Renal Unit, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Tomoko Obara & Iain A Drummond

  4. Department of Pediatrics, Soroka Medical Center, Beer Sheva, Israel

    Daniel Landau

  5. Department of Pediatrics, Duke University Medical Center, Durham, 27710, North Carolina, USA

    John W Foreman

  6. Institute of Human Genetics, University of Newcastle, International Center for Life, Newcastle upon Tyne, UK

    Judith A Goodship & Tom Strachan

  7. Institute for Molecular Biology, Medizinische Hochschule Hannover, Germany

    Andreas Kispert

  8. Department of Pediatric Nephrology and INSERM U574, Necker Hospital, René Descartes University, Paris, France

    Marie F Gagnadoux

  9. CHU Tours et Institut Régional pour la Santé, Chambray les Tours, France

    Hubert Nivet

  10. Department of Genetics and INSERM U574, Necker Hospital, René Descartes University, Paris, France

    Corinne Antignac

  11. Department of Human Genetics, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Friedhelm Hildebrandt

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Correspondence to Friedhelm Hildebrandt.

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Otto, E., Schermer, B., Obara, T. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 34, 413–420 (2003). https://doi.org/10.1038/ng1217

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