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

Mutant DMPK mRNA containing expanded CUG repeats is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1), a multisystemic genetic disorder [1]. The disease is caused by a CTG trinucleotide repeat expansion in the 3' untranslated region (UTR) of the DMPK gene, which is transcribed into a toxic mRNA containing long CUG repeats [2]. These expanded repeats form stable hairpin structures that sequester essential RNA-binding proteins, particularly Muscleblind-like 1 (MBNL1), into insoluble nuclear foci [2]. The resulting depletion of functional MBNL1 leads to widespread alternative splicing defects (spliceopathy) in various downstream genes, causing symptoms such as myotonia, muscle wasting, and cardiac conduction abnormalities [1, 2]. Therapeutic strategies targeting this molecule aim to reduce the levels of the toxic transcript using antisense oligonucleotides (ASOs) or antibody-oligonucleotide conjugates (AOCs) to restore normal cellular function [3, 4]. By degrading the mutant mRNA, these therapies seek to release sequestered proteins and correct the underlying spliceopathy [5].

Other names

CUG-expanded DMPK mRNAToxic DMPK transcriptDM1 mRNAExpanded CUG repeat RNA

Therapeutic agents typically utilize antisense oligonucleotides (ASOs) or siRNA-based approaches to induce RNase H-mediated degradation or RNA interference (RNAi) of the mutant transcript, thereby reducing the toxic RNA load and releasing sequestered RNA-binding proteins like MBNL1 [5].