Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons

TLDR

Myotonic dystrophy type 1 is caused by a CTG repeat expansion in the DMPK gene, and in skeletal muscle it is thought to involve nuclear accumulation of mutant transcripts that disrupt alternative splicing. This study investigates whether a similar RNA‑dominant mechanism operates in the brain. Post‑mortem DM1 brain tissue shows widespread expression of mutant DMPK mRNA with expanded CUG repeats that form nuclear foci, recruit and deplete muscleblind proteins, and lead to abnormal splicing of neuronal pre‑mRNAs, indicating that CNS dysfunction may arise from a toxic gain‑of‑function of mutant mRNA.

Abstract

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene. In skeletal muscles, DM1 may involve a novel, RNA-dominant disease mechanism in which transcripts from the mutant DMPK allele accumulate in the nucleus and compromise the regulation of alternative splicing. Here we show evidence for a similar disease mechanism in brain. Examination of post-mortem DM1 tissue by fluorescence in situ hybridization indicates that the mutant DMPK mRNA, with its expanded CUG repeat in the 3′-untranslated region, is widely expressed in cortical and subcortical neurons. The mutant transcripts accumulate in discrete foci within neuronal nuclei. Proteins in the muscleblind family are recruited into the RNA foci and depleted elsewhere in the nucleoplasm. In parallel, a subset of neuronal pre-mRNAs show abnormal regulation of alternative splicing. These observations suggest that CNS impairment in DM1 may result from a deleterious gain-of-function by mutant DMPK mRNA.