Dystrophia myotonica protein kinase mRNA CUG repeat expansion (DMPK mRNA CUG expansion)

The Dystrophia myotonica protein kinase (DMPK) mRNA CUG repeat expansion is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1), a multisystemic genetic disorder. In affected individuals, the 3' untranslated region of the DMPK gene contains an abnormally high number of CTG repeats, which are transcribed into toxic mRNA containing expanded CUG tracts (Thornton, 2014). These expanded repeats form stable hairpin structures that sequester essential RNA-binding proteins, most notably Muscleblind-like 1 (MBNL1), into insoluble nuclear foci (Wheeler et al., 2012). The resulting depletion of functional MBNL1 leads to widespread alternative splicing defects, or 'spliceopathy,' which causes the clinical hallmarks of the disease, including myotonia, progressive muscle wasting, and cardiac conduction abnormalities. Therapeutic strategies focus on reducing the levels of this toxic mRNA using antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) to trigger transcript degradation. Recent clinical developments have introduced antibody-oligonucleotide conjugates (AOCs) designed to enhance the delivery of these payloads specifically to muscle and heart tissues (Avidity Biosciences, 2024; Dyne Therapeutics, 2024).

Other names

DM1 CUG repeatsToxic DMPK mRNACUGexp mRNACTG repeat expansion in DMPK geneDMPK 3' UTR expansion

RNase H-mediated degradation of mutant mRNA, RNA interference (RNAi)-mediated knockdown, and steric hindrance to prevent protein sequestration.