Messenger RNA Stability in Myotonic Dystrophy

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DESCRIPTION (provided by applicant): Myotonic dystrophy (DM) is an inherited disease primarily affecting skeletal muscle. There are two forms of the disease: DM1 is caused by a CUG repeat expansion in the 3' untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene while DM2 results from a CCUG repeat expansion in an intron of the Zinc Finger Protein 9 (ZNF9) gene. Pathogenesis in both cases is caused principally by accumulation of toxic RNA species containing the expanded repeat. The mutant RNA sequesters Muscleblind, an RNA-binding protein important for processing of clinically relevant mRNAs. In addition, the mutant RNA induces aberrant expression of another RNA-binding protein, CUGBP1 through an unknown mechanism. This in turn impacts processing and decay of additional mRNAs. We will first examine how the toxic RNA species is metabolized by the cell with a view to eventually enhancing its removal. We will then move on to investigate the effects of CUGBP1 on two sets of mRNAs encoding proteins involved in myogenesis and in protein secretion. Finally, we will generate novel cell culture models from patient muscle cells and utilize them to discover changes in mRNA stability that occur in DM1. Overall, we hope to elucidate the fundamental molecular changes that occur in myotonic dystrophy and identify novel targets for future therapeutics. PUBLIC HEALTH RELEVANCE: Myotonic dystrophy is a debilitating inherited disease primarily affecting skeletal muscle. The mutant gene produces a toxic RNA that impacts expression of other genes. Our research will determine the molecular mechanisms behind the toxicity of the mutant RNA and characterize the effects on expression of other clinically relevant genes. We hope to identify new avenues for therapeutic intervention.