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:

Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy

Nature Genetics volume 25, pages 105–109 (2000)Cite this article

Abstract

Expansion of a CTG trinucleotide repeat in the 3′ UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy1,2,3, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy4,5 and cardiac conduction abnormalities6, but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7,8), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a β-galactosidase reporter. Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Six5 targeting.
Figure 2: Developmental expression of Six5, as reflected by expression of the integrated β-galactosidase reporter driven from the endogenous Six5 promoter.
Figure 3: Analysis of gene expression in adult Six5-mutant mice.
Figure 4: Cataract development in Six5-deficient mice.

Similar content being viewed by others

References

  1. Brook, J.D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68, 799–808 (1992).

    Article  CAS  Google Scholar 

  2. Fu, Y.H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1258 (1992).

    Article  CAS  Google Scholar 

  3. Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

    Article  CAS  Google Scholar 

  4. Jansen, G. et al. Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nature Genet. 13, 316–324 (1996).

    Article  CAS  Google Scholar 

  5. Reddy, S. et al. Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy. Nature Genet. 13, 325–335 (1996).

    Article  CAS  Google Scholar 

  6. Berul, C.I. et al. DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. J. Clin. Invest. 103, R1–7 (1999).

    Article  CAS  Google Scholar 

  7. Klesert, T.R., Otten, A.D., Bird, T.D. & Tapscott, S.J. Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. Nature Genet. 16, 402–406 (1997).

    Article  CAS  Google Scholar 

  8. Thornton, C.A., Wymer, J.P., Simmons, Z., McClain, C. & Moxley, R.T. III Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nature Genet. 16, 407–409 (1997).

    Article  CAS  Google Scholar 

  9. Boucher, C.A. et al. A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. Hum. Mol. Genet. 4, 1919–1925 (1995).

    Article  CAS  Google Scholar 

  10. Heath, S.K., Carne, S., Hoyle, C., Johnson, K.J. & Wells, D.J. Characterisation of expression of mDMAHP, a homeodomain-encoding gene at the murine DM locus. Hum. Mol. Genet. 6, 651–657 (1997).

    Article  CAS  Google Scholar 

  11. Behrens, M.I., Jalil, P., Serani, A., Vergara, F. & Alvarez, O. Possible role of apamin-sensitive K+ channels in myotonic dystrophy. Muscle Nerve 17, 1264–1270 (1994).

    Article  CAS  Google Scholar 

  12. Ramirez, B.U., Behrens, M.I. & Vergara, C. Neural control of the expression of a Ca(2+)-activated K+ channel involved in the induction of myotonic-like characteristics. Cell. Mol. Neurobiol. 16, 39–49 (1996).

    Article  CAS  Google Scholar 

  13. Kawakami, K., Ohto, H., Ikeda, K. & Roeder, R.G. Structure, function and expression of a murine homeobox protein AREC3, a homologue of Drosophila sine oculis gene product, and implication in development. Nucleic Acids Res. 24, 303–310 (1996).

    Article  CAS  Google Scholar 

  14. Kawakami, K., Ohto, H., Takizawa, T. & Saito, T. Identification and expression of six family genes in mouse retina. FEBS Lett. 393, 259–263 (1996).

    Article  CAS  Google Scholar 

  15. Damiani, E. et al. Skeletal muscle sarcoplasmic reticulum phenotype in myotonic dystrophy. Neuromuscul. Disord. 6, 33–47 (1996).

    Article  CAS  Google Scholar 

  16. Cheyette, B.N. et al. The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12, 977–996 (1994).

    Article  CAS  Google Scholar 

  17. Loosli, F., Winkler, S. & Wittbrodt, J. Six3 overexpression initiates the formation of ectopic retina. Genes Dev. 13, 649–654 (1999).

    Article  CAS  Google Scholar 

  18. Pignoni, F. et al. The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91, 881–891 (1997).

    Article  CAS  Google Scholar 

  19. Ohto, H. et al. Cooperation of Six and Eya in activation of their target genes through nuclear translocation of Eya. Mol. Cell. Biol. 19, 6815–6824 (1999).

    Article  CAS  Google Scholar 

  20. Winchester, C.L., Ferrier, R.K., Sermoni, A., Clark, B.J. & Johnson, K.J. Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy. Hum. Mol. Genet. 8, 481–492 (1999).

    Article  CAS  Google Scholar 

  21. Philips, A.V., Timchenko, L.T. & Cooper, T.A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737–741 (1998).

    Article  CAS  Google Scholar 

  22. Amack, J.D., Paguio, A.P. & Mahadevan, M.S. Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model. Hum. Mol. Genet. 8, 1975–1984 (1999).

    Article  CAS  Google Scholar 

  23. Timchenko, L.T. Myotonic dystrophy: the role of RNA CUG triplet repeats. Am. J. Hum. Genet. 64, 360–364 (1999).

    Article  CAS  Google Scholar 

  24. Harris, S., Moncrieff, C. & Johnson, K. Myotonic dystrophy: will the real gene please step forward. Hum. Mol. Genet. 5, 1417–1423 (1996).

    Article  CAS  Google Scholar 

  25. Groenen, P. & Wieringa, B. Expanding the complexity in myotonic dystrophy. Bioessays 20, 901–912 (1998).

    Article  CAS  Google Scholar 

  26. Korade-Mirnics, Z., Babitzke, P. & Hoffman, E. Myotonic dystrophy: molecular windows on a complex etiology. Nucleic Acids Res. 26, 1363–1368 (1998).

    Article  CAS  Google Scholar 

  27. Ranum, L.P., Rasmussen, P.F., Benzow, K.A., Koob, M.D. & Day, J.W. Genetic mapping of a second myotonic dystrophy locus. Nature Genet. 19, 196–198 (1998).

    Article  CAS  Google Scholar 

  28. Day, J.W. et al. Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscul. Disord. 9, 19–27 (1999).

    Article  CAS  Google Scholar 

  29. Hiraoka, T. & Clark, J.I. Inhibition of lens opacification during the early stages of cataract formation. Invest. Opthalmol. Vis. Sci. 36, 2550–2555 (1995).

    CAS  Google Scholar 

  30. Clark, J.I., Livesey, J.C. & Steele, J.E. Delay or inhibition of rat lens opacification using pantethine and WR-77913. Exp. Eye Res. 62, 75–84 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Sarnat for review of the skeletal muscle histology; M. Tallquist for valued advice; and C. Ganders and J. Ilano for technical assistance. This work was supported by NIAMS AR45203 to S.J.T., NEI EY04542 to J.I.C, HD 24875 and HD 25326 to P.S., and a Poncin Scholarship to T.R.K.

Author information

Authors and Affiliations

  1. Program in Developmental Biology and Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Todd R. Klesert, Diane H. Cho, Lauren Snider & Stephen J. Tapscott

  2. Basic Science, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Philippe Soriano

  3. Department of Pathology, School of Medicine, University of Washington, Seattle, Washington, USA

    Todd R. Klesert & Stephen J. Tapscott

  4. Department of Biological Structure, School of Medicine, University of Washington, Seattle, Washington, USA

    John I. Clark

  5. Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA

    Eric C. Yuen & Stephen J. Tapscott

  6. Departments of Obstetrics and Gynecology and Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon, USA

    James Maylie

  7. Vollum Institute, Oregon Health Sciences University, Portland, Oregon, USA

    John Adelman

Authors
  1. Todd R. Klesert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diane H. Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John I. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James Maylie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Adelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lauren Snider
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eric C. Yuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philippe Soriano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen J. Tapscott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen J. Tapscott.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klesert, T., Cho, D., Clark, J. et al. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat Genet 25, 105–109 (2000). https://doi.org/10.1038/75490

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/75490

This article is cited by

Search

Advanced 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