Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis.
Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of end-stage renal failure in the first three decades of life. Positional cloning of the six known NPHP genes has linked its pathogenesis to primary cilia function. Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively. Kidneys of Glis2 mutant mice show severe renal atrophy and fibrosis starting at 8 weeks of age. Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2. Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.
Attanasio
Massimo
M
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Uhlenhaut
N Henriette
NH
Sousa
Vitor H
VH
O'Toole
John F
JF
Otto
Edgar
E
Anlag
Katrin
K
Klugmann
Claudia
C
Treier
Anna-Corina
AC
Helou
Juliana
J
Sayer
John A
JA
Seelow
Dominik
D
Nürnberg
Gudrun
G
Becker
Christian
C
Chudley
Albert E
AE
Nürnberg
Peter
P
Hildebrandt
Friedhelm
F
Treier
Mathias
M
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004285:Dogs; D005260:Female; D005355:Fibrosis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000502:physiology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D010375:Pedigree
C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors