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

The Dystrophia myotonica protein kinase (DMPK) mRNA containing expanded CUG repeats is the central pathogenic agent in Myotonic Dystrophy Type 1 (DM1) [PMID: 11073455]. In healthy individuals, the 3' untranslated region (UTR) of the DMPK gene contains 5 to 34 CUG repeats, but in DM1 patients, this sequence expands to hundreds or thousands of repeats [PMID: 12191481]. These expanded transcripts adopt a stable hairpin secondary structure that resists degradation and accumulates within the cell nucleus as toxic ribonucleoprotein complexes called foci [PMID: 10612430]. These foci sequester essential RNA-binding proteins, particularly Muscleblind-like 1 (MBNL1), preventing them from regulating the alternative splicing of numerous other pre-mRNAs [PMID: 15317802]. This "spliceopathy" leads to the diverse clinical symptoms of DM1, including myotonia, progressive muscle wasting, and cardiac arrhythmias [PMID: 19782031]. Therapeutic interventions focus on reducing the levels of the toxic mRNA using antisense oligonucleotides (ASOs) or siRNA, or using small molecules to disrupt the interaction between the CUG repeats and sequestered proteins [PMID: 31515474]. Current clinical candidates like Delpacibart zotadirsen utilize antibody-oligonucleotide conjugation to deliver these payloads specifically to muscle tissue [Avidity Biosciences, 2024]. Monitoring efficacy often involves measuring the restoration of normal splicing patterns in muscle biopsies [PMID: 23857330].

Other names

Toxic DMPK mRNACUG expansion RNADM1 mRNADMPK 3' UTR expansionExpanded CUG repeat RNA

RNase H-mediated degradation of expanded mRNA, RNA interference (siRNA), and steric inhibition of protein sequestration.