Dystrophia myotonica protein kinase (DMPK) mutant CUG-repeat mRNA (CUGexp-DMPK)

The DMPK mutant CUG-repeat mRNA is the primary pathogenic driver of Myotonic Dystrophy type 1 (DM1), a multisystemic neuromuscular disorder. It arises from an unstable expansion of CTG trinucleotide repeats in the 3' untranslated region (UTR) of the DMPK gene, which, when transcribed, results in a toxic gain-of-function mRNA containing hundreds to thousands of CUG repeats. These expanded repeats fold into stable hairpin structures that aggregate into ribonuclear foci within the cell nucleus. These foci sequester essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family, leading to their functional loss and subsequent widespread defects in alternative splicing of downstream target genes. Therapeutic strategies targeting this molecule include antisense oligonucleotides (ASOs), siRNAs, and small molecules designed to either induce the degradation of the mutant transcript or disrupt the sequestration of MBNL proteins to restore normal cellular function.

Other names

CUG-expanded DMPK mRNAToxic CUG-repeat RNAr(CUG)expDMPK-CUGexpMutant DMPK transcriptDMPK 3' UTR CUG expansion

Drugs targeting this molecule primarily act through RNase H-mediated degradation of the mutant mRNA (antisense oligonucleotides), RNA interference (siRNAs), or by competitively binding to the CUG repeats to displace sequestered MBNL1 proteins and disrupt toxic ribonuclear foci.