title: Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: N Henriette
authors.initials: NH
authors.lastname: Uhlenhaut
authors.forename: Vitor H
authors.initials: VH
authors.lastname: Sousa
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Edgar
authors.initials: E
authors.lastname: Otto
authors.forename: Katrin
authors.initials: K
authors.lastname: Anlag
authors.forename: Claudia
authors.initials: C
authors.lastname: Klugmann
authors.forename: Anna-Corina
authors.initials: AC
authors.lastname: Treier
authors.forename: Juliana
authors.initials: J
authors.lastname: Helou
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Mathias
authors.initials: M
authors.lastname: Treier
mesh_terms: 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
chemical_list: C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors