RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression

Yadava RS, Frenzel-McCardell CD, Yu Q, Srinivasan V, Tucker AL, Puymirat J, Thornton CA, Prall OW, Harvey RP, Mahadevan MS
Source: Nat Genet
Publication Date: (2008)
Issue: 40(1): 61-8
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Species: mouse
Tissue Origin: skeletal muscle
Nucleofector™ I/II/2b
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.