Expanded CUG repeats in DMPK mRNA (CUGexp)

Pathogenic expanded CUG repeats in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) mRNA are the primary molecular drivers of Myotonic Dystrophy Type 1 (DM1). These expansions, typically exceeding 50 repeats and often reaching thousands, adopt stable hairpin secondary structures that aggregate into ribonuclear foci within the cell nucleus. These foci sequester essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family, which are critical for regulating alternative splicing across hundreds of genes. The resulting loss of functional MBNL leads to a global spliceopathy, causing the multisystemic symptoms of DM1, such as myotonia, muscle wasting, and cardiac conduction defects. Therapeutic strategies focus on reducing the levels of this toxic RNA using antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) to trigger its degradation, or small molecules to displace sequestered proteins. Successful intervention aims to restore normal splicing patterns and alleviate the clinical manifestations of the disease.

Other names

Toxic CUG repeatsr(CUG)expExpanded DMPK mRNACUG repeat expansionMutant DMPK mRNA

RNase H-mediated RNA degradation; RNA interference (RNAi); Steric blocking of RNA-binding proteins; Inhibition of transcription