Dystrophia myotonica protein kinase mRNA with expanded CUG repeats (DMPK mRNA) (DMPK mRNA)

The mutant dystrophia myotonica protein kinase (DMPK) mRNA with an expanded CUG repeat tract is the primary pathogenic driver of myotonic dystrophy type 1 (DM1) (Thornton, 2014). This toxic transcript results from a CTG trinucleotide expansion in the 3' untranslated region (UTR) of the DMPK gene, which forms stable hairpin structures that accumulate as nuclear foci (Miller et al., 2000). These foci sequester essential RNA-binding proteins, particularly the Muscleblind-like (MBNL) family, leading to a global disruption of alternative splicing known as spliceopathy (Wheeler et al., 2012). This mis-splicing of downstream targets like the chloride channel 1 (CLCN1) and the insulin receptor (INSR) causes the hallmark symptoms of DM1, including myotonia and insulin resistance (NIH, 2023). Therapeutic strategies currently in clinical development, such as delpacibart zotadirsen and delpacibart etedesiran, utilize antisense oligonucleotides or siRNA to selectively degrade the mutant mRNA or block the repeats to restore normal protein function (Avidity Biosciences, 2024; Dyne Therapeutics, 2024).

Other names

Mutant DMPK mRNACUG-expanded DMPK mRNAToxic DMPK mRNADMPK CUG repeatsDMPK 3' UTR expansion

Degradation of toxic mRNA via RNase H-mediated cleavage or RNA interference (RNAi), and steric blocking of CUG repeats to prevent protein sequestration.