Myotonic dystrophy type 1 (DM1) is a multi-system disease (with skeletal muscle, cardiac, neuroendocrine involvement) that is caused by expansion of a CTG repeat in the 5’ untranslated region of the DM protein kinase (DMPK) gene. In collaboration with Dr. C. Thornton, we have investigated the molecular mechanisms by which the repeat expansion causes myotonia in myotonic dystrophy type I (DM1). Using a mouse model that express expanded CUG repeats specifically in skeletal muscle, we found that the expanded CUG repeat transcripts are retained in the nucleus and sequester splicing factors in the muscleblind-like family that are required for proper alternative splicing of developmentally-controlled mRNAs. The transcript for the skeletal muscle chloride channel (CLC1) is one such transcript that is not properly processed in DM1 and this mouse model. The CLC1 missplicing leads to a premature truncation, loss of cholide channel function, and an increase in muscle excitability and myotonia. Correction of this single splicing defect with morpholinos or reduction in the level of the nuclear retained expanded CUG repeat transcripts rescues myotonia in these mice, thus providing proof-of-principle for novel RNA-based therapeutic interventions in DM1. Current studies are investigating the cellular and molecular mechanisms by which repeat expansions result in cardiac conduction defects that lead to life-threatening arrythmias.
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