title: Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.
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 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.
authors.affiliation: Department of Pediatrics, 8220C MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Tomoko
authors.initials: T
authors.lastname: Obara
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Karl S
authors.initials: KS
authors.lastname: Hiller
authors.forename: Adelheid M
authors.initials: AM
authors.lastname: Mueller
authors.forename: Rainer G
authors.initials: RG
authors.lastname: Ruf
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefele
authors.forename: Frank
authors.initials: F
authors.lastname: Beekmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Landau
authors.forename: John W
authors.initials: JW
authors.lastname: Foreman
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Tom
authors.initials: T
authors.lastname: Strachan
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wolf
authors.forename: Marie F
authors.initials: MF
authors.lastname: Gagnadoux
authors.forename: Hubert
authors.initials: H
authors.lastname: Nivet
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology; D002648:Child; D002923:Cilia / Q000502:physiology*; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012857:Situs Inversus / Q000196:embryology / Q000235:genetics; D014157:Transcription Factors; D014404:Tubulin / Q000502:physiology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C114503:INVS protein, human; D008565:Membrane Proteins; C108725:NPHP1 protein, human; C491578:NPHP4 protein, human; D011506:Proteins; D014157:Transcription Factors; D014404:Tubulin; D004247:DNA