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

• Published in: Nature genetics Vol. 34; no. 4; pp. 413 - 420
• Main Authors: Obara, Tomoko, Hoefele, Julia, Nivet, Hubert, Otto, Edgar A, O'Toole, John F, Gagnadoux, Marie F, Kispert, Andreas, Hildebrandt, Friedhelm, Ruf, Rainer G, Beekmann, Frank, Strachan, Tom, Walz, Gerd, Schermer, Bernhard, Mueller, Adelheid M, Drummond, Iain A, Landau, Daniel, Foreman, John W, Wolf, Matthias T, Antignac, Corinne, Benzing, Thomas, Hiller, Karl S, Goodship, Judith A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-08-2003
• Subjects: Adaptor Proteins, Signal Transducing; Ageing, cell death; Animals; Base Sequence; Biological and medical sciences; Body Patterning - genetics; Body Patterning - physiology; Cell physiology; Child; Chromosome mapping; Cilia - physiology; Complications and side effects; Diagnosis; DNA - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene loci; Gene mutations; Gene Targeting; Genetic aspects; Genetics; Genotype & phenotype; Hospitals; Humans; Kidney diseases; Kidney Diseases, Cystic - genetics; Kidney Diseases, Cystic - physiopathology; Kidneys; Kinases; Male; Membrane Proteins; Molecular and cellular biology; Molecular Sequence Data; Mutation; Pathogenesis; Pediatrics; Physiological aspects; Polycystic Kidney, Autosomal Recessive - genetics; Proteins - genetics; Proteins - physiology; Risk factors; Situs Inversus - embryology; Situs Inversus - genetics; Transcription Factors; Tubulin - physiology; Zebrafish - embryology; Zebrafish - genetics; United States; United States > US; Massachusetts; Paris France; Israel; France; Ann Arbor Michigan; Germany; Michigan; Kidney disease; Urinary system disease; Renal function; Nephropathy; Mutation; Cilia
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1217

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 beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-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 beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.