title: Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy.
abstract: Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3' UTR of the gene encoding myotonic dystrophy protein kinase (DMPK), which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3' UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.
authors.affiliation: Department of Pathology, University of Virginia, PO Box 800904, Charlottesville, Virginia 22908-0904, USA. mahadevan@virginia.edu
authors.forename: Mani S
authors.initials: MS
authors.lastname: Mahadevan
authors.forename: Ramesh S
authors.initials: RS
authors.lastname: Yadava
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Sadguna
authors.initials: S
authors.lastname: Balijepalli
authors.forename: Carla D
authors.initials: CD
authors.lastname: Frenzel-McCardell
authors.forename: T David
authors.initials: TD
authors.lastname: Bourne
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Phillips
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D004576:Electromyography; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D009222:Myotonia / Q000503:physiopathology*; D009223:Myotonic Dystrophy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D065636:Myotonin-Protein Kinase; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D019076:Transgenes; D019680:Trinucleotide Repeat Expansion
chemical_list: D020413:3' Untranslated Regions; C585516:DMPK protein, mouse; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D012313:RNA; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases