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Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy

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Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3′ UTR of the gene encoding myotonic dystrophy protein kinase (DMPK)1, which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions2. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3′ UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3′ UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.

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Figure 1: Transgene expression.
Figure 2: Myotonic dystrophy phenotypes in transgenic mice.
Figure 3: Reversal of RNA toxicity.
Figure 4: CUG-BP1 levels elevated by toxic RNA.

Change history

  • 18 August 2006

    In the version of this article initially published online, the sentence at the bottom of page 2 misrepresented one of the authors' results. It should read, “Furthermore, we performed RT-PCR for Clcn-1 and Tnnt3 in our mice and uncovered splicing abnormalities (Fig. 2c) similar to those in transgenic mice overexpressing CUG repeats15, in the Mbnl1ΔE3 knockout mouse16 and in individuals with myotonic dystrophy14–16.” The error has been corrected for all versions of the article.


  1. 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 

  2. Day, J.W. & Ranum, L.P. RNA pathogenesis of the myotonic dystrophies. Neuromuscul. Disord. 15, 5–16 (2005).

    Article  Google Scholar 

  3. Taneja, K.L., McCurrach, M., Schalling, M., Housman, D. & Singer, R.H. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol. 128, 995–1002 (1995).

    Article  CAS  Google Scholar 

  4. Davis, B.M., McCurrach, M.E., Taneja, K.L., Singer, R.H. & Housman, D.E. Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc. Natl. Acad. Sci. USA 94, 7388–7393 (1997).

    Article  CAS  Google Scholar 

  5. 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 

  6. Furling, D., Lemieux, D., Taneja, K. & Puymirat, J. Decreased levels of myotonic dystrophy protein kinase (DMPK) and delayed differentiation in human myotonic dystrophy myoblasts. Neuromuscul. Disord. 11, 728–735 (2001).

    Article  CAS  Google Scholar 

  7. Mankodi, A. et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289, 1769–1773 (2000).

    Article  CAS  Google Scholar 

  8. Berul, C.I., Maguire, C.T., Gehrmann, J. & Reddy, S. Progressive atrioventricular conduction block in a mouse myotonic dystrophy model. J. Interv. Card. Electrophysiol. 4, 351–358 (2000).

    Article  CAS  Google Scholar 

  9. O'Cochlain, D.F. et al. Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy. Hum. Mol. Genet. 13, 2505–2518 (2004).

    Article  CAS  Google Scholar 

  10. Storbeck, C.J., Sabourin, L.A., Waring, J.D. & Korneluk, R.G. Definition of regulatory sequence elements in the promoter region and the first intron of the myotonic dystrophy protein kinase gene. J. Biol. Chem. 273, 9139–9147 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Mankodi, A. et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum. Mol. Genet. 10, 2165–2170 (2001).

    Article  CAS  Google Scholar 

  13. Melacini, P. et al. Correlation between cardiac involvement and CTG trinucleotide repeat length in myotonic dystrophy. J. Am. Coll. Cardiol. 25, 239–245 (1995).

    Article  CAS  Google Scholar 

  14. Charlet, B.N. et al. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol. Cell 10, 45–53 (2002).

    Article  Google Scholar 

  15. Mankodi, A. et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol. Cell 10, 35–44 (2002).

    Article  CAS  Google Scholar 

  16. Kanadia, R.N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003).

    Article  CAS  Google Scholar 

  17. Timchenko, N.A. et al. Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis. J. Biol. Chem. 279, 13129–13139 (2004).

    Article  CAS  Google Scholar 

  18. Savkur, R.S., Philips, A.V. & Cooper, T.A. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat. Genet. 29, 40–47 (2001).

    Article  CAS  Google Scholar 

  19. Mankodi, A., Lin, X., Blaxall, B.C., Swanson, M.S. & Thornton, C.A. Nuclear RNA foci in the heart in myotonic dystrophy. Circ. Res. 97, 1152–1155 (2005).

    Article  CAS  Google Scholar 

  20. Storbeck, C.J. et al. Inhibition of myogenesis in transgenic mice expressing the human DMPK 3′-UTR. Hum. Mol. Genet. 13, 589–600 (2004).

    Article  CAS  Google Scholar 

  21. Seznec, H. et al. Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum. Mol. Genet. 10, 2717–2726 (2001).

    Article  CAS  Google Scholar 

  22. Lin, X. et al. Failure of MBNL1-dependent postnatal splicing transitions in myotonic dystrophy. Hum. Mol. Genet. 15, 2087–2097 (2006).

    Article  CAS  Google Scholar 

  23. Margolis, J.M., Schoser, B.G., Moseley, M.L., Day, J.W. & Ranum, L.P. DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. Hum. Mol. Genet. 15, 1808–1815 (2006).

    Article  CAS  Google Scholar 

  24. Amack, J.D. & Mahadevan, M.S. The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Hum. Mol. Genet. 10, 1879–1887 (2001).

    Article  CAS  Google Scholar 

  25. Houseley, J.M. et al. Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila. Hum. Mol. Genet. 14, 873–883 (2005).

    Article  CAS  Google Scholar 

  26. Ho, T.H. et al. Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. J. Cell Sci. 118, 2923–2933 (2005).

    Article  CAS  Google Scholar 

  27. Ho, T.H. et al. Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103–3112 (2004).

    Article  CAS  Google Scholar 

  28. Ho, T.H., Bundman, D., Armstrong, D.L. & Cooper, T.A. Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. Hum. Mol. Genet. 14, 1539–1547 (2005).

    Article  CAS  Google Scholar 

  29. Mahadevan, M.S. et al. Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene. Hum. Mol. Genet. 2, 299–304 (1993).

    Article  CAS  Google Scholar 

  30. Langlois, M.A., Lee, N.S., Rossi, J.J. & Puymirat, J. Hammerhead ribozyme-mediated destruction of nuclear foci in myotonic dystrophy myoblasts. Mol. Ther. 7, 670–680 (2003).

    Article  CAS  Google Scholar 

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We wish to thank P. Mahadevan and A. Tucker for their insights and continued support. MBNL antibodies were provided by M. Swanson and C. Thornton. Human tissues were provided by J. Puymirat and C. Thornton and purchased from the University of Miami Brain and Tissue Bank. Mouse tissues from other myotonic dystrophy models were provided by J. Puymirat, B. Wieringa and G. Gourdon. Transgenic mice were generated by the University of Wisconsin-Madison Transgenic Core Facility. All studies were done under the auspices of the University of Virginia Animal Care and Use Committee and Institutional Review Board. This work was supported by the Muscular Dystrophy Association and the US National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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Authors and Affiliations



M.S.M., R.S.Y., Q.Y., C.D.F.-M., T.D.B. and L.H.P. performed experimental work and data analysis. S.B. generated the transgene constructs. M.S.M. was responsible for conceptual design and execution.

Corresponding author

Correspondence to Mani S Mahadevan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Transgene expression. (PDF 477 kb)

Supplementary Fig. 2

RNA foci in all three muscle lineages in (CTG)200 mice. (PDF 202 kb)

Supplementary Fig. 3

CUG-BP1 levels elevated in DM1 muscle. (PDF 208 kb)

Supplementary Fig. 4

CUG-BP1 levels increased by toxic RNA. (PDF 288 kb)

Supplementary Fig. 5

Comparison of transgene expression in different mouse models of myotonic dystrophy. (PDF 496 kb)

Supplementary Fig. 6

Model for the splicing balance created by the mutual antagonism between MBNL1 and CUG-BP1 for splicing events. (PDF 429 kb)

Supplementary Methods (PDF 78 kb)

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Mahadevan, M., Yadava, R., Yu, Q. et al. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet 38, 1066–1070 (2006).

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