Myotonic Dystrophy in Transgenic Mice Expressing an Expanded CUG Repeat

TLDR

Myotonic dystrophy is caused by a CTG repeat expansion in the DMPK gene, producing mutant mRNA with expanded CUG repeats that accumulate in the nucleus. The authors introduced an untranslated CUG repeat into an unrelated mRNA in transgenic mice to test its effect. Mice expressing the expanded repeat developed myotonia and myopathy, whereas those with a nonexpanded repeat did not, proving that the RNA gain‑of‑function is sufficient to generate the disease phenotype.

Abstract

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 mutant DMPK 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.