Myotonic dystrophy protein kinase 3' untranslated region CUG-repeat RNA foci (DMPK CUG-repeat RNA foci) (DMPK CUG-repeat RNA foci)

Mutant DMPK 3'UTR CUG-repeat RNA foci are pathogenic nuclear aggregates formed by the transcription of the DMPK gene containing expanded CTG repeats (Thornton, 2014; PubMed: 25037086). In Myotonic Dystrophy Type 1 (DM1), these expanded CUG repeats in the mRNA's 3' untranslated region (UTR) fold into stable hairpin structures that accumulate in the nucleus (Miller et al., 2000; PubMed: 10944116). These foci act as a molecular sink, sequestering essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family, while causing the upregulation of CELF1 (Nature Reviews Disease Primers, 2021; DOI: 10.1038/s41572-020-00232-7). This protein imbalance leads to widespread spliceopathies, where fetal isoforms of various proteins are incorrectly expressed in adult tissues, resulting in the multi-systemic symptoms of DM1, such as myotonia, muscle wasting, and cardiac conduction defects (JCI, 2018; DOI: 10.1172/JCI123854). Therapeutic strategies targeting these foci include antibody-oligonucleotide conjugates (AOCs) like delpacibart zotadirsen and antisense oligonucleotides (ASOs) designed to either degrade the mutant RNA or displace sequestered proteins to restore normal cellular function (Avidity Biosciences, 2024; Dyne Therapeutics, 2024).

Other names

Mutant DMPK RNACUG-expanded RNADM1 RNA fociToxic CUG RNADMPK (CUG)n RNA

RNase H-mediated RNA degradation, RNA interference (RNAi), and steric hindrance to prevent protein sequestration (Nature Reviews Disease Primers, 2021; DOI: 10.1038/s41572-020-00232-7).