Premature termination codons in the DMD gene cause reduced local mRNA synthesis

Significance Duchenne muscular dystrophy is a rare disease caused by lack of dystrophin due to mutations in theDMD gene. The presence of mutations leads to a reduction of the transcript levels. In this study, we show that the transcript reduction is not caused by the cytoplasmic nonsense-mediated decay mechanism as previously thought. We demonstrate that dystrophin mRNA is primarily localized in the nuclear compartment of skeletal muscle fibers. Analysis of nascent RNA and histone marks shows that transcription is less efficient in the presence of premature termination codons. Treatment of dystrophic mice with an epigenetic drug, currently in clinical development, partially restores transcription of the locus. This work will help the development of RNA targeting therapies for Duchenne patients.