Article abstract

Nature Genetics 40, 61 - 68 (2008)
Published online: 16 December 2007 | doi:10.1038/ng.2007.28

RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression

Ramesh S Yadava1,6, Carla D Frenzel-McCardell1, Qing Yu1, Varadamurthy Srinivasan1, Amy L Tucker2, Jack Puymirat3, Charles A Thornton4, Owen W Prall5, Richard P Harvey5 & Mani S Mahadevan1,6

Myotonic muscular dystrophy (DM1) is the most common inherited neuromuscular disorder in adults and is considered the first example of a disease caused by RNA toxicity. Using a reversible transgenic mouse model of RNA toxicity in DM1, we provide evidence that DM1 is associated with induced NKX2-5 expression. Transgene expression resulted in cardiac conduction defects, increased expression of the cardiac-specific transcription factor NKX2-5 and profound disturbances in connexin 40 and connexin 43. Notably, overexpression of the DMPK 3' UTR mRNA in mouse skeletal muscle also induced transcriptional activation of Nkx2-5 and its targets. In human muscles, these changes were specific to DM1 and were not present in other muscular dystrophies. The effects on NKX2-5 and its downstream targets were reversed by silencing toxic RNA expression. Furthermore, using Nkx2-5+/- mice, we show that NKX2-5 is the first genetic modifier of DM1-associated RNA toxicity in the heart.

  1. Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA.
  2. Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
  3. Human Genetics Research Unit, Laval University, Quebec City, Quebec G1V 4G2, Canada.
  4. Department of Neurology, University of Rochester, Rochester, New York 14642, USA.
  5. The Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
  6. These authors contributed equally to this work.

Correspondence to: Mani S Mahadevan1,6 e-mail:


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