RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.
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.
Yadava
Ramesh S
RS
Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA.
Frenzel-McCardell
Carla D
CD
Yu
Qing
Q
Srinivasan
Varadamurthy
V
Tucker
Amy L
AL
Puymirat
Jack
J
Thornton
Charles A
CA
Prall
Owen W
OW
Harvey
Richard P
RP
Mahadevan
Mani S
MS
D000818:Animals; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000633:toxicity*; D012333:RNA, Messenger / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics*; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D014157:Transcription Factors; D000097003:Gap Junction alpha-5 Protein; C585517:DMPK protein, human; C585516:DMPK protein, mouse; C484469:Nkx2-5 protein, mouse