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

The pathogenic expanded CUG repeat hairpin structure in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) mRNA is the primary molecular driver of Myotonic Dystrophy Type 1 (DM1) [1]. In affected individuals, the CTG repeat sequence in the DMPK gene expands significantly, often reaching hundreds or thousands of repeats, which are then transcribed into RNA that forms stable, double-stranded hairpin structures [2]. These expanded CUG repeats aggregate into nuclear foci and exert a toxic gain-of-function effect by sequestering essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family [3]. This sequestration leads to the stabilization of CELF1 and subsequent widespread mis-splicing of various pre-mRNAs, resulting in the multisystemic symptoms of DM1 such as myotonia and muscle wasting [1,2]. Therapeutic strategies targeting this structure primarily involve the use of antisense oligonucleotides (ASOs) or siRNAs to induce the degradation of the toxic transcript [4]. Additionally, research is ongoing into small molecules and steric-blocking oligonucleotides designed to displace sequestered MBNL proteins and restore normal cellular splicing patterns [5].

Other names

Toxic CUG repeatsDMPK 3' UTR CUG expansionCUGexp RNAMyotonic dystrophy type 1 RNA

RNase H-mediated degradation of expanded CUG repeat mRNA, RNA interference (RNAi) mediated cleavage of DMPK transcripts, and steric blocking of CUG repeats to prevent sequestration of RNA-binding proteins like MBNL1.