Nature Genetics
34, 413 - 420 (2003)
Published online: 20 July 2003; | doi:10.1038/ng1217
Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determinationEdgar A Otto1, 12, Bernhard Schermer2, 12, Tomoko Obara3, John F O'Toole1, Karl S Hiller1, Adelheid M Mueller1, Rainer G Ruf1, Julia Hoefele1, Frank Beekmann1, Daniel Landau4, John W Foreman5, Judith A Goodship6, Tom Strachan6, Andreas Kispert7, Matthias T Wolf1, Marie F Gagnadoux8, Hubert Nivet9, Corinne Antignac10, Gerd Walz2, Iain A Drummond3, Thomas Benzing2, 13
& Friedhelm Hildebrandt1, 11, 131
Department of Pediatrics, 8220C MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109, USA. 2
Renal Division and Center for Clinical Research, University Hospital Freiburg, Freiburg, Germany. 3
Renal Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA. 4
Department of Pediatrics, Soroka Medical Center, Beer Sheva, Israel. 5
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. 6
Institute of Human Genetics, University of Newcastle, International Center for Life, Newcastle upon Tyne, UK. 7
Institute for Molecular Biology, Medizinische Hochschule Hannover, Germany. 8
Department of Pediatric Nephrology and INSERM U574, Necker Hospital, René Descartes University, Paris, France. 9
CHU Tours et Institut Régional pour la Santé, Chambray les Tours, France. 10
Department of Genetics and INSERM U574, Necker Hospital, René Descartes University, Paris, France. 11
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. 12
These authors contributed equally to this work. 13
These authors contributed equally to this work.
Correspondence should be addressed to Friedhelm Hildebrandt fhilde@umich.eduNephronophthisis (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  -tubulin, a main component of primary cilia. We show that nephrocystin, inversin and -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 -tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.
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