Dystrophia myotonica protein kinase (DMPK) mRNA expanded CUG repeat (DMPK (CUG)n RNA)

The mutant DMPK pre-mRNA expanded CUG repeat hairpin is the primary molecular driver of Myotonic Dystrophy Type 1 (DM1), a multi-systemic genetic disorder (Source: Thornton, 2014, Neurologic Clinics). This target is formed when an abnormally expanded CTG trinucleotide repeat in the 3' untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene is transcribed into mRNA (Source: NIH GARD). These expanded CUG repeats fold into stable, double-stranded hairpin structures that accumulate within the cell nucleus as toxic RNA foci (Source: Wheeler et al., 2012, Nature). The primary mechanism of pathogenesis is a toxic gain-of-function, where the hairpin structures sequester Muscleblind-like (MBNL) proteins, which are critical for regulating alternative splicing (Source: Miller et al., 2000, EMBO J). This sequestration leads to the depletion of functional MBNL, causing the mis-splicing of numerous downstream transcripts such as CLCN1 and INSR, which results in myotonia and insulin resistance (Source: PubMed). Therapeutic strategies targeting this RNA hairpin include antisense oligonucleotides (ASOs) and siRNA designed to promote the degradation of the mutant transcript (Source: Avidity Biosciences). Additionally, small molecule inhibitors are being explored to disrupt the binding between the CUG repeats and MBNL proteins, thereby restoring normal splicing patterns (Source: Dyne Therapeutics). Modern clinical approaches often utilize specialized delivery systems, such as antibody-oligonucleotide conjugates, to ensure the therapeutic reaches skeletal and cardiac muscle tissues effectively (Source: Entrada Therapeutics).

Other names

CUGexp RNAMutant DMPK transcriptDM1 toxic RNAExpanded CUG repeat hairpinDMPK 3' UTR expanded repeat

Antisense-mediated degradation of mutant mRNA via RNase H or RNA interference (RNAi), and steric inhibition of protein-RNA interactions to release sequestered splicing factors.