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

Edgar A. Otto, Bernhard Schermer, Tomoko Obara, John F. O'Toole, Karl S. Hiller, Adelheid M. Mueller, Rainer G. Ruf, Julia Hoefele, Frank Beekmann, Daniel Landau, John W. Foreman, Judith A. Goodship, Tom Strachan, Andreas Kispert, Matthias T. Wolf, Marie F. Gagnadoux, Hubert Nivet, Corinne Antignac, Gerd Walz, Iain A. DrummondThomas Benzing, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

460 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)413-420
Number of pages8
JournalNature genetics
Volume34
Issue number4
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Genetics

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    Otto, E. A., Schermer, B., Obara, T., O'Toole, J. F., Hiller, K. S., Mueller, A. M., Ruf, R. G., Hoefele, J., Beekmann, F., Landau, D., Foreman, J. W., Goodship, J. A., Strachan, T., Kispert, A., Wolf, M. T., Gagnadoux, M. F., Nivet, H., Antignac, C., Walz, G., ... Hildebrandt, F. (2003). 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, 34(4), 413-420. https://doi.org/10.1038/ng1217