CUG-repeat-containing RNA (CUG-RNA)

CUG-repeat-containing RNAs are transcripts characterized by expanded cytosine-uracil-guanine (CUG) motifs, which are central to the pathogenesis of Myotonic Dystrophy Type 1 (DM1) and several other microsatellite expansion disorders. These RNAs form stable, pathogenic hairpin secondary structures that act through a toxic gain-of-function mechanism by sequestering essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family (Miller et al., 2000; PMID: 10612410). The resulting depletion of functional MBNL proteins leads to widespread alternative splicing defects, known as spliceopathy, which affects the maturation of transcripts critical for muscle, heart, and brain function (Kanadia et al., 2003; PMID: 14578915). Beyond DM1, similar CUG-rich motifs are found in the transcripts associated with Huntington Disease-Like 2 (HDL2) and Spinocerebellar Ataxia Type 8 (SCA8). Therapeutic development focuses on reducing the burden of these toxic RNAs using antisense oligonucleotides (ASOs), antibody-oligonucleotide conjugates (AOCs), or small molecules designed to disrupt the RNA-protein interactions and restore cellular homeostasis (Avidity Biosciences, 2023; Dyne Therapeutics, 2023).

Other names

CUG expansion RNAToxic CUG RNACUG-rich RNA motifsPoly-CUG RNAExpanded CUG repeat transcript

Therapeutic strategies primarily utilize antisense oligonucleotides (ASOs) or small molecules to induce RNase H-mediated degradation of the expanded CUG RNA, sterically block the repeats to prevent the sequestration of RNA-binding proteins, or displace sequestered splicing factors like MBNL1 to restore normal alternative splicing patterns (Thornton, 2014; PMID: 24607024).