Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.
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.
Otto
Edgar A
EA
Department of Pediatrics, 8220C MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109, USA.
Schermer
Bernhard
B
Obara
Tomoko
T
O'Toole
John F
JF
Hiller
Karl S
KS
Mueller
Adelheid M
AM
Ruf
Rainer G
RG
Hoefele
Julia
J
Beekmann
Frank
F
Landau
Daniel
D
Foreman
John W
JW
Goodship
Judith A
JA
Strachan
Tom
T
Kispert
Andreas
A
Wolf
Matthias T
MT
Gagnadoux
Marie F
MF
Nivet
Hubert
H
Antignac
Corinne
C
Walz
Gerd
G
Drummond
Iain A
IA
Benzing
Thomas
T
Hildebrandt
Friedhelm
F
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
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