Nature Genetics
- 38, 1066 - 1070 (2006)
Published online: 30 July 2006; Corrected online: 18 August 2006 | doi:10.1038/ng1857
Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophyMani S Mahadevan1, 4, Ramesh S Yadava1, 4, Qing Yu1, Sadguna Balijepalli2, Carla D Frenzel-McCardell1, T David Bourne1 & Lawrence H Phillips31
Department of Pathology, University of Virginia, PO Box 800904, Charlottesville, Virginia 22908-0904, USA. 2
Department of Medicine, University of Wisconsin-Madison, C4132 Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705, USA. 3
Department of Neurology, University of Virginia, PO Box 800394, Charlottesville, Virginia, USA, 22908-0394. 4
These authors contributed equally to this work.
Correspondence should be addressed to Mani S Mahadevan mahadevan@virginia.edu DMPKMBNL1DMPKGFPCUG-BP1Myotonic 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)1, which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions2. 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.
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