Myotonic Dystrophy in Transgenic Mice Expressing an Expanded CUG Repeat

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3′ untranslated region of the DMPK gene. The mutantDMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.

Through genetic engineering we have generated the most widely used mouse model of DM1, HSALR (http://science.sciencemag.org/content/289/5485/1769.full).  These mice serve as a valuable model for testing novel therapeutics.  We are currently testing methods to improve drug delivery to muscle including treadmill exercise.

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