Dystrophia myotonica protein kinase mRNA CUG repeats (DMPK (CUG)n mRNA)

Pathogenic CUG repeat hairpin loops 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) (Thornton, 2014, PubMed: 25072437). In affected individuals, the CTG repeat section of the DMPK gene expands to hundreds or thousands of copies, which are then transcribed into mRNA containing long CUG repeats that fold into stable, double-stranded hairpin structures (Miller et al., 2000, PubMed: 10655056). These toxic RNA structures accumulate in the nucleus as discrete foci and sequester essential RNA-binding proteins, most notably Muscleblind-like 1 (MBNL1), while simultaneously causing the stabilization of CELF1 (Wheeler, 2008, PubMed: 18835341). The resulting depletion of functional MBNL1 leads to a widespread failure of alternative splicing regulation, known as spliceopathy, which affects various downstream genes responsible for muscle contraction, insulin signaling, and cardiac conduction (Mankodi et al., 2002, PubMed: 12114629). Current drug development efforts focus on reducing the burden of these toxic transcripts through antisense oligonucleotides (ASOs), siRNA-conjugates, or small molecules designed to liberate sequestered proteins and restore normal RNA processing.

Other names

CUG repeat RNAExpanded CUG repeatsDMPK 3' UTR CUG repeatsToxic CUG RNADMPK mRNA hairpin loops

Therapeutic strategies primarily utilize antisense oligonucleotides (ASOs) or siRNA to trigger RNase H-mediated or RISC-mediated degradation of the expanded DMPK mRNA, or employ steric-blocking oligonucleotides and small molecules to disrupt the hairpin structure and prevent the sequestration of RNA-binding proteins (Thornton et al., 2017, PubMed: 29033130; Pandey et al., 2017, PubMed: 28115223).