Dystrophia myotonica protein kinase mRNA expanded CUG trinucleotide repeat hairpins (DMPK (CUG)exp mRNA) (DMPK (CUG)exp mRNA)

The Dystrophia myotonica protein kinase (DMPK) mRNA expanded CUG trinucleotide repeat hairpins are the primary pathogenic drivers of Myotonic Dystrophy Type 1 (DM1), a multisystemic neuromuscular disorder (Thornton, 2014, PubMed: 24183552). In affected individuals, the 3' untranslated region of the DMPK gene contains an abnormally high number of CTG repeats, which are transcribed into toxic CUG repeat expansions in the mRNA. These expanded repeats fold into stable hairpin structures that accumulate in the nucleus as discrete foci (Miller et al., 2000, PubMed: 10944115). These foci sequester essential RNA-binding proteins, most notably Muscleblind-like 1 (MBNL1), preventing them from performing their normal roles in regulating alternative splicing of various pre-mRNAs (Kanadia et al., 2003, PubMed: 14585967). This "RNA gain-of-function" mechanism leads to widespread splicing defects that cause the clinical symptoms of DM1, such as myotonia, muscle wasting, and cardiac conduction abnormalities. Therapeutic strategies targeting these hairpins include antisense oligonucleotides and small molecules designed to either degrade the toxic mRNA or displace sequestered proteins to restore cellular homeostasis (Avidity Biosciences, 2024; Dyne Therapeutics, 2024).

Other names

CUG repeat RNAToxic DMPK mRNAExpanded CUG repeatsDM1 RNA hairpinsDMPK 3' UTR CUG expansion

Therapeutic agents target the expanded CUG repeats to either trigger the degradation of the toxic mRNA via RNase H or RNA interference pathways, or to sterically block the repeats to displace sequestered Muscleblind-like (MBNL) proteins and restore normal splicing.