Dystrophia myotonica protein kinase messenger RNA with expanded CUG repeats (Mutant DMPK RNA)

Mutant DMPK RNA is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1), a multisystemic disorder characterized by progressive muscle wasting and myotonia (Source: NIH, 2023). The condition arises from an unstable expansion of CTG repeats in the 3' untranslated region of the Dystrophia myotonica protein kinase (DMPK) gene (Source: Thornton, C. A., 2014, Lancet Neurology). When transcribed, these expanded repeats form stable CUG-hairpin structures that aggregate into toxic nuclear foci, which are a hallmark of the disease (Source: Miller et al., 2000, EMBO J). These RNA foci sequester crucial RNA-binding proteins, particularly the Muscleblind-like (MBNL) family, preventing them from performing their normal role in regulating alternative splicing (Source: Kanadia et al., 2003, Science). The resulting loss of MBNL function leads to the mis-splicing of various downstream transcripts, such as the chloride channel 1 (CLCN1) and insulin receptor (INSR), which directly causes clinical symptoms (Source: Wheeler et al., 2012, Nature). Therapeutic approaches focus on reducing the levels of this toxic RNA using antisense oligonucleotides (ASOs), siRNA, or antibody-oligonucleotide conjugates (AOCs) to trigger its degradation (Source: Avidity Biosciences, 2024). By targeting the mutant RNA directly, these therapies aim to address the root cause of DM1 and restore normal cellular splicing patterns.

Other names

CUG-expanded DMPK RNAToxic DMPK RNADM1 mRNAExpanded CUG repeat RNADMPK 3' UTR expanded RNA

RNase H-mediated degradation of mRNA, RNA interference (siRNA), and steric blocking of RNA-protein interactions to release sequestered MBNL proteins.