Expanded CUG repeat RNA in Dystrophia Myotonica Protein Kinase mRNA (CUGexp RNA)

Expanded CUG repeat RNA in Dystrophia Myotonica Protein Kinase (DMPK) mRNA is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1), a multisystemic neuromuscular disorder [1, 19]. This toxic gain-of-function RNA arises from an unstable CTG trinucleotide expansion in the 3' untranslated region (UTR) of the DMPK gene [11, 20]. When transcribed, these expanded repeats (CUGexp) fold into stable, branched hairpin structures that aggregate into discrete nuclear ribonuclear foci [1, 11]. These foci sequester essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family of splicing regulators, leading to a widespread failure of alternative splicing known as 'splicopathy' [8, 13, 23]. The resulting molecular dysfunction causes the hallmark symptoms of DM1, including myotonia, progressive muscle wasting, and cardiac conduction defects [15, 21]. Therapeutic development focuses on reducing the levels of this toxic RNA or neutralizing its effects. Current strategies include antisense oligonucleotides (ASOs) and siRNAs designed to trigger the degradation of the mutant transcript, as well as small molecules and artificial RNA cleavers (ARCs) intended to disrupt the sequestration of MBNL proteins and restore normal cellular splicing patterns [2, 3, 15, 21].

Other names

Toxic CUG repeat RNAMutant DMPK transcriptCUGexpDMPK 3' UTR expansionPathogenic CUG repeats

Drugs targeting this molecule primarily act through RNase H-mediated degradation (antisense oligonucleotides), RNA interference (siRNAs), or by using small molecules to competitively bind the CUG repeats and displace sequestered RNA-binding proteins like MBNL1 [2, 3, 5, 21].