Expanded CUG repeat tract in mutant Dystrophia Myotonica Protein Kinase (DMPK) mRNA (DMPK (CUG)n mRNA)

The expanded CUG repeat tract in the 3' untranslated region (UTR) of the mutant Dystrophia Myotonica Protein Kinase (DMPK) mRNA is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1) [1.1.1, 1.2.3]. In healthy individuals, the DMPK gene contains 5 to 35 CUG repeats, but in DM1 patients, this tract expands to hundreds or thousands of repeats [1.4.3]. These expanded repeats form stable hairpin structures that accumulate in the nucleus as ribonuclear foci, where they sequester key RNA-binding proteins, most notably the Muscleblind-like (MBNL) family [1.1.2, 1.4.1]. The sequestration of MBNL proteins, combined with the stabilization of CELF1 proteins, leads to widespread alternative splicing defects (spliceopathy) across numerous genes essential for muscle and cardiac function, such as CLCN1 and INSR [1.3.2, 1.4.2]. Therapeutic interventions targeting this RNA tract aim to either degrade the mutant mRNA using antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs), or to use small molecules that disrupt the interaction between the toxic RNA and sequestered proteins [1.2.1, 1.3.5]. Successfully targeting this tract restores normal splicing patterns and alleviates the multisystemic symptoms of DM1, including myotonia, muscle wasting, and cardiac conduction defects [1.2.2, 1.2.5]. Current clinical candidates like DYNE-101 and Delpacibart etedesiran (AOC 1001) utilize advanced delivery technologies to reach muscle tissues and reduce the burden of toxic DMPK transcripts [1.2.1, 1.3.5].

Other names

CUGexpToxic CUG repeatsMutant DMPK mRNADM1 repeat expansionDMPK 3' UTR CUG expansion

Therapeutic strategies involve the use of antisense oligonucleotides (ASOs) or siRNAs to induce RNase H-mediated or RISC-mediated degradation of the mutant DMPK mRNA, or small molecules to displace sequestered RNA-binding proteins from the CUG repeats [1.2.1, 1.3.5].