RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression
Ramesh S Yadava, Carla D Frenzel-McCardell, Qing Yu, Varadamurthy Srinivasan, Amy L Tucker, Jack Puymirat, Charles A Thornton, Owen W Prall, Richard P Harvey, Mani S Mahadevan, Ramesh S Yadava, Carla D Frenzel-McCardell, Qing Yu, Varadamurthy Srinivasan, Amy L Tucker, Jack Puymirat, Charles A Thornton, Owen W Prall, Richard P Harvey, Mani S Mahadevan
Abstract
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.
Conflict of interest statement
COMPETING INTERESTS STATEMENT
The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/.
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Source: PubMed