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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 genes1,2,3,4 has linked its pathogenesis to primary cilia function3,5. 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.

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Figure 1: Haplotype analysis at the GLIS2 locus on chromosome 16p in the consanguineous kindred F761.
Figure 2: GLIS2 localizes to both nuclei and primary cilia in renal epithelial cell cultures.
Figure 3: Generation of a Glis2lacZ allele by homologous recombination.
Figure 4: Time course of renal degeneration in of Glis2lacZ/lacZ mutant mice.
Figure 5: Increased apoptosis and α-smooth muscle actin expression in Glis2lacZ/lacZ mutant kidneys.
Figure 6: Molecular and histochemical analysis of Glis2lacZ/lacZ mutant kidneys.

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We thank the EMBL/Heidelberg Transgenic Facility for generation of chimeric animals and the staff of the EMBL Laboratory Animal Resources for expert animal husbandry. The US National Institutes of Health supported F.H. (DK064614, DK068306, DK069274) and J.O.T. (DK071108); F.H. is the Frederick G.L. Huetwell Professor and Doris Duke Distinguished Clinical Scientist. This research was further supported by the German Federal Ministry of Science and Education through the National Genome Research Network (D.S., G.N., C.B. and P.N.) and the Fritz-Thyssen Stiftung (Germany) (M.T).

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Authors and Affiliations



M.A. carried out positional cloning, mutation analysis, immunofluorescence studies, minigene expression studies and clinical evaluation. N.H.U. performed gene expression analysis, transient transfections and overall characterization of Glis2 mutant mice. V.H.S. and K.A. generated Glis2 mutant mice. J.F.O'T. carried out positional cloning and fine mapping. E.O. carried out the genome-wide search for linkage. C.K. and A.-C.T. performed histological analysis. J.H. carried out exon sequencing of a large number of NPHP patients and healthy control individuals. J.A.S. was involved in the genome-wide search for linkage and positional cloning. D.S. and G.N. carried out statistical evaluation of the genome-wide search for linkage. C.B. and P.N. performed SNP chip analysis for the genome-wide search for linkage. A.E.C. was involved in clinical characterization of subjects. F.H. designed the study on gene identification in individuals with NPHP and directed all studies on the genome-wide search for linkage, positional cloning, mutation analysis, immunofluorescence, minigene expression studies and clinical evaluation. M.T. initiated the project and designed, directed and analyzed all animal studies. F.H and M.T. wrote the paper, with feedback from the other authors.

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Correspondence to Friedhelm Hildebrandt or Mathias Treier.

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The authors declare no competing financial interests.

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Attanasio, M., Uhlenhaut, N., Sousa, V. et al. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet 39, 1018–1024 (2007).

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