Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis

Massimo Attanasio, N. Henriette Uhlenhaut, Vitor H. Sousa, John F. O'Toole, Edgar Otto, Katrin Anlag, Claudia Klugmann, Anna Corina Treier, Juliana Helou, John A. Sayer, Dominik Seelow, Gudrun Nürnberg, Christian Becker, Albert E. Chudley, Peter Nürnberg, Friedhelm Hildebrandt, Mathias Treier

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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.

Original languageEnglish (US)
Pages (from-to)1018-1024
Number of pages7
JournalNature genetics
Volume39
Issue number8
DOIs
StatePublished - Aug 1 2007

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ASJC Scopus subject areas

  • Genetics

Cite this

Attanasio, M., Uhlenhaut, N. H., Sousa, V. H., O'Toole, J. F., Otto, E., Anlag, K., Klugmann, C., Treier, A. C., Helou, J., Sayer, J. A., Seelow, D., Nürnberg, G., Becker, C., Chudley, A. E., Nürnberg, P., Hildebrandt, F., & Treier, M. (2007). Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nature genetics, 39(8), 1018-1024. https://doi.org/10.1038/ng2072