title: RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.
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.
authors: Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors: Ramesh S
authors: RS
authors: Yadava
authors: Carla D
authors: CD
authors: Frenzel-McCardell
authors: Qing
authors: Q
authors: Yu
authors: Varadamurthy
authors: V
authors: Srinivasan
authors: Amy L
authors: AL
authors: Tucker
authors: Jack
authors: J
authors: Puymirat
authors: Charles A
authors: CA
authors: Thornton
authors: Owen W
authors: OW
authors: Prall
authors: Richard P
authors: RP
authors: Harvey
authors: Mani S
authors: MS
authors: Mahadevan
mesh_terms: 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
chemical_list: 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