Dystrophia myotonica protein kinase (DMPK) gene CTG repeat expansion (DMPK CTG expansion)

The CTG repeat expansion in the 3' untranslated region (UTR) of the Dystrophia myotonica protein kinase (DMPK) gene is the primary genetic cause of Myotonic Dystrophy Type 1 (DM1). In healthy individuals, this region contains 5 to 34 CTG repeats, whereas affected individuals possess 50 to several thousand repeats (NIH GeneReviews, 2021). These expanded repeats are transcribed into toxic CUG-expanded mRNA, which forms stable hairpin structures that sequester key RNA-binding proteins, most notably the Muscleblind-like (MBNL) family (Thornton, 2014). This sequestration leads to widespread alternative splicing defects (spliceopathy) in various tissues, resulting in the clinical manifestations of DM1, such as myotonia, muscle wasting, and cardiac conduction abnormalities (Nature Reviews Disease Primers, 2017). Therapeutic strategies targeting this expansion include antisense oligonucleotides (ASOs) and small interference RNAs (siRNAs) designed to degrade the mutant mRNA or block the repeats to release sequestered proteins (Avidity Biosciences, 2024). Additionally, gene-editing approaches like CRISPR/Cas9 are being explored to excise the expansion from the genomic DNA (Dyne Therapeutics, 2024).

Other names

DM1 expansionCUG repeat expansionDMPK 3' UTR expansionMyotonic dystrophy type 1 locus

Degradation of CUG-expanded mRNA via RNase H or RNA interference (RNAi), or steric blocking of CUG repeats to prevent sequestration of RNA-binding proteins like MBNL1.