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

doi:10.1038/ng2072

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 language	English (US)
Pages (from-to)	1018-1024
Number of pages	7
Journal	Nature genetics
Volume	39
Issue number	8
DOIs	https://doi.org/10.1038/ng2072
State	Published - Aug 2007

ASJC Scopus subject areas

Genetics

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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

Attanasio, M, Uhlenhaut, NH, Sousa, VH, O'Toole, JF, Otto, E, Anlag, K, Klugmann, C, Treier, AC, Helou, J, Sayer, JA, Seelow, D, Nürnberg, G, Becker, C, Chudley, AE, Nürnberg, P, Hildebrandt, F & Treier, M 2007, 'Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis', Nature genetics, vol. 39, no. 8, pp. 1018-1024. https://doi.org/10.1038/ng2072

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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.",

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

note = "Funding Information: 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).",

year = "2007",

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AU - Attanasio, Massimo

AU - Uhlenhaut, N. Henriette

AU - Sousa, Vitor H.

AU - O'Toole, John F.

AU - Otto, Edgar

AU - Anlag, Katrin

AU - Klugmann, Claudia

AU - Treier, Anna Corina

AU - Helou, Juliana

AU - Sayer, John A.

AU - Seelow, Dominik

AU - Nürnberg, Gudrun

AU - Becker, Christian

AU - Chudley, Albert E.

AU - Nürnberg, Peter

AU - Hildebrandt, Friedhelm

AU - Treier, Mathias

N1 - Funding Information: 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).

PY - 2007/8

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N2 - 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.

AB - 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.

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

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