title: Sodium Channel Inhibitors Reduce DMPK mRNA and Protein.
abstract: Myotonic dystrophy type 1 (DM1) is caused by an expanded trinucleotide (CTG)n tract in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. This results in the aggregation of an expanded mRNA forming toxic intranuclear foci which sequester splicing factors. We believe down-regulation of DMPK mRNA represents a potential, and as yet unexplored, DM1 therapeutic avenue. Consequently, a computational screen for agents which down-regulate DMPK mRNA was undertaken, unexpectedly identifying the sodium channel blockers mexiletine, prilocaine, procainamide, and sparteine as effective suppressors of DMPK mRNA. Analysis of DMPK mRNA in C2C12 myoblasts following treatment with these agents revealed a reduction in the mRNA levels. In vivo analysis of CD1 mice also showed DMPK mRNA and protein down-regulation. The role of DMPK mRNA suppression in the documented efficacy of this class of compounds in DM1 is worthy of further investigation.
authors.affiliation: University of Ottawa, Ottawa, Canada.|Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa, Canada.
authors.forename: Luke
authors.initials: L
authors.lastname: Witherspoon
authors.affiliation: University of Ottawa, Ottawa, Canada.|Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: O'Reilly
authors.affiliation: University of Ottawa, Ottawa, Canada.|Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa, Canada.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Hadwen
authors.affiliation: University of Ottawa, Ottawa, Canada.|Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa, Canada.
authors.forename: Nafisa
authors.initials: N
authors.lastname: Tasnim
authors.affiliation: University of Ottawa, Ottawa, Canada.|Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: MacKenzie
authors.affiliation: Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa, Canada.|Emirates College for Advance Education, Abu Dhabi, UAE.
authors.forename: Faraz
authors.initials: F
authors.lastname: Farooq
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D065636:Myotonin-Protein Kinase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D011318:Prilocaine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis*; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D011318:Prilocaine; D065636:Myotonin-Protein Kinase
keywords: drug therapy; drugs; molecular biology; molecular genetics; muscle