Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Hildebrandt, F. et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat. Genet. 17, 149–153 (1997).

    Article  CAS  Google Scholar 

  2. Otto, E.A. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat. Genet. 34, 413–420 (2003).

    Article  CAS  Google Scholar 

  3. Hildebrandt, F. & Otto, E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat. Rev. Genet. 6, 928–940 (2005).

    Article  CAS  Google Scholar 

  4. Sayer, J.A. et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat. Genet. 38, 674–681 (2006).

    Article  CAS  Google Scholar 

  5. Watnick, T. & Germino, G. From cilia to cyst. Nat. Genet. 34, 355–356 (2003).

    Article  CAS  Google Scholar 

  6. Zollinger, H.U. et al. Nephronophthisis (medullary cystic disease of the kidney). A study using electron microscopy, immunofluorescence, and a review of the morphological findings. Helv. Paediatr. Acta 35, 509–530 (1980).

    CAS  Google Scholar 

  7. Igarashi, P. & Somlo, S. Genetics and pathogenesis of polycystic kidney disease. J. Am. Soc. Nephrol. 13, 2384–2398 (2002).

    Article  CAS  Google Scholar 

  8. Zhang, F. & Jetten, A.M. Genomic structure of the gene encoding the human GLI-related, Kruppel-like zinc finger protein GLIS2. Gene 280, 49–57 (2001).

    Article  CAS  Google Scholar 

  9. Zhang, F. et al. Characterization of Glis2, a novel gene encoding a Gli-related, Kruppel-like transcription factor with transactivation and repressor functions. Roles in kidney development and neurogenesis. J. Biol. Chem. 277, 10139–10149 (2002).

    Article  CAS  Google Scholar 

  10. Mollet, G. et al. Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum. Mol. Genet. 14, 645–656 (2005).

    Article  CAS  Google Scholar 

  11. Haycraft, C.J. et al. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1, e53 (2005).

    Article  Google Scholar 

  12. Okada, H. et al. Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int. 58, 587–597 (2000).

    Article  CAS  Google Scholar 

  13. Lin, F., Moran, A. & Igarashi, P. Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J. Clin. Invest. 115, 1756–1764 (2005).

    Article  CAS  Google Scholar 

  14. Dai, P. et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143–8152 (1999).

    Article  CAS  Google Scholar 

  15. Louro, I.D. et al. Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res. 62, 5867–5873 (2002).

    CAS  Google Scholar 

  16. Hu, M.C. et al. GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development 133, 569–578 (2006).

    Article  CAS  Google Scholar 

  17. Mangan, S. & Alon, U. Structure and function of the feed-forward loop network motif. Proc. Natl. Acad. Sci. USA 100, 11980–11985 (2003).

    Article  CAS  Google Scholar 

  18. Strutz, F. & Muller, G.A. Renal fibrosis and the origin of the renal fibroblast. Nephrol. Dial. Transplant. 21, 3368–3370 (2006).

    Article  Google Scholar 

  19. Moreno-Bueno, G. et al. Genetic profiling of epithelial cells expressing e-cadherin repressors reveals a distinct role for snail, slug, and e47 factors in epithelial-mesenchymal transition. Cancer Res. 66, 9543–9556 (2006).

    Article  CAS  Google Scholar 

  20. Harris, R.C. & Neilson, E.G. Toward a unified theory of renal progression. Annu. Rev. Med. 57, 365–380 (2006).

    Article  CAS  Google Scholar 

  21. Shi, Y. & Massague, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    Article  CAS  Google Scholar 

  22. Anders, H.J., Vielhauer, V. & Schlondorff, D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int. 63, 401–415 (2003).

    Article  CAS  Google Scholar 

  23. Abreu, J.G., Ketpura, N.I., Reversade, B. & De Robertis, E.M. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat. Cell Biol. 4, 599–604 (2002).

    Article  CAS  Google Scholar 

  24. Bonner, J.C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 15, 255–273 (2004).

    Article  CAS  Google Scholar 

  25. Qi, W. et al. Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis. Am. J. Physiol. Renal Physiol. 288, F800–F809 (2005).

    Article  CAS  Google Scholar 

  26. Zhang, M., Tang, J. & Li, X. Interleukin-1beta-induced transdifferentiation of renal proximal tubular cells is mediated by activation of JNK and p38 MAPK. Nephron Exp. Nephrol. 99, e68–e76 (2005).

    Article  CAS  Google Scholar 

  27. Yu, J., Carroll, T.J. & McMahon, A.P. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development 129, 5301–5312 (2002).

    CAS  Google Scholar 

  28. Huber, M.A., Kraut, N. & Beug, H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol. 17, 548–558 (2005).

    Article  CAS  Google Scholar 

  29. Senee, V. et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat. Genet. 38, 682–687 (2006).

    Article  CAS  Google Scholar 

  30. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Friedhelm Hildebrandt or Mathias Treier.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–2, Supplementary Figs 1–4, Supplementary Methods (PDF 2874 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/ng2072

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng2072

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing