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

The CUG repeat RNA hairpin in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) mRNA is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1) [PMID: 11719800]. In healthy individuals, the DMPK gene contains 5 to 35 CTG repeats; however, in DM1 patients, this sequence expands to hundreds or thousands of repeats [PMID: 1346552]. These expanded repeats are transcribed into mRNA that folds into stable, toxic hairpin structures which accumulate in the nucleus as foci [PMID: 10910351]. These RNA foci sequester key RNA-binding proteins, most notably the Muscleblind-like (MBNL) family, and lead to the upregulation of CUG-binding protein 1 (CUGBP1) [PMID: 17652133]. The resulting imbalance in these splicing factors causes widespread spliceopathy, where fetal isoforms of various proteins are incorrectly expressed in adult tissues, leading to the clinical manifestations of DM1 such as myotonia, muscle wasting, and cardiac conduction defects [PMID: 22958864]. Therapeutic strategies targeting this RNA include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and small molecules designed to either degrade the toxic mRNA or disrupt the interaction between the CUG repeats and sequestered proteins [PMID: 35115704].

Other names

CUGexp RNAToxic CUG repeatsDM1 RNA fociExpanded CUG repeat RNADMPK 3' UTR expansion

Therapeutic agents target the CUG repeat expansion to either induce RNase H-mediated degradation of the toxic mRNA, utilize the RNA interference (RNAi) pathway for silencing, or sterically block the repeats to release sequestered Muscleblind-like (MBNL) proteins [PMID: 35115704, PMID: 22958864].