Myotonic dystrophy protein kinase (DMPK) expanded trinucleotide repeat (DMPK-CUGexp)

The expanded CTG trinucleotide repeat located in the 3' untranslated region (UTR) of the Myotonic Dystrophy Protein Kinase (DMPK) gene is the primary genetic cause of Myotonic Dystrophy Type 1 (DM1) (https://www.ncbi.nlm.nih.gov/books/NBK1165/). In healthy individuals, this region typically contains 5 to 34 repeats, whereas affected individuals may harbor hundreds to thousands of repeats (https://medlineplus.gov/genetics/gene/dmpk/). When transcribed, the mutant mRNA contains expanded CUG repeats that form stable, toxic hairpin structures which accumulate in the nucleus as foci. These foci sequester essential RNA-binding proteins, most notably the Muscleblind-like (MBNL) family, which are critical for regulating the alternative splicing of numerous other pre-mRNAs (https://www.nature.com/articles/s41573-018-0002-x). This sequestration leads to a widespread 'spliceopathy' that results in the multi-systemic symptoms of DM1, including progressive muscle wasting, myotonia, and cardiac conduction defects (https://pubmed.ncbi.nlm.nih.gov/29114334/). Modern therapeutic approaches target this molecule using antisense oligonucleotides (ASOs) or antibody-oligonucleotide conjugates (AOCs) designed to selectively degrade the mutant transcript or prevent the sequestration of splicing factors (https://www.aviditybiosciences.com/pipeline/aoc-1001/).

Other names

CUG repeat RNADMPK 3' UTR expansionDM1 expansionExpanded CTG repeatDMPK-ASO target

Therapeutic strategies primarily utilize antisense oligonucleotides (ASOs) or antibody-oligonucleotide conjugates (AOCs) to induce RNase H-mediated degradation of the expanded CUG-containing DMPK mRNA, thereby reducing the formation of toxic nuclear foci and releasing sequestered splicing factors like MBNL1 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705543/).