Myotonic dystrophy protein kinase pre-mRNA (DMPK pre-mRNA or CUGexp DMPK RNA)

DMPK pre-mRNA is the direct molecular target in myotonic dystrophy type 1 (DM1), a multisystemic autosomal dominant neuromuscular disorder affecting approximately 1 in 8,000 people worldwide. The disease is caused by pathogenic expansion of CTG trinucleotide repeats (from 50 to >3,500 copies) in the 3′ untranslated region of the DMPK gene, resulting in accumulation of mutant DMPK pre-mRNA molecules that form toxic nuclear foci. These expanded DMPK transcripts sequester essential RNA-binding proteins (particularly MBNL and CUG-BP1), disrupting the alternative splicing of numerous downstream genes and preventing normal muscle, cardiac, and neurological function. The DMPK protein itself is a serine/threonine kinase localized to the nuclear envelope that plays critical roles in muscle structure, function, and myogenic gene expression, though in DM1 the toxic RNA dominates over any loss of DMPK protein function. Antisense oligonucleotide therapeutics targeting DMPK pre-mRNA represent a direct molecular approach to reduce the pathogenic mutant transcript levels and counteract the RNA dominance mechanism underlying DM1 pathology, offering potential treatment for the progressive muscle weakness, myotonia, cardiac complications, and cognitive symptoms characteristic of this disease.

Other names

Dystrophia myotonica-protein kinase pre-mRNACUGexp DMPK RNA (mutant DMPK RNA containing expanded CUG repeat)DMPK1 mRNAMyotonic dystrophy type 1 transcript

Reduction of target DMPK pre-mRNA and protein levels through antisense compound complementarity to the target nucleic acid. Antisense oligonucleotides direct cleavage of pathogenic CUGexp DMPK transcripts. Selective reduction of expanded CUG repeat-containing DMPK RNA while potentially sparing normal DMPK transcripts. Reducing the pathogenic effects of mutant DMPK RNA that sequesters protein factors and disrupts gene expression.