title: Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA.
abstract: Genomic expansions of simple tandem repeats can give rise to toxic RNAs that contain expanded repeats. In myotonic dystrophy, the expression of expanded CUG repeats (CUGexp) causes abnormal regulation of alternative splicing and neuromuscular dysfunction. We used a transgenic mouse model to show that derangements of myotonic dystrophy are reversed by a morpholino antisense oligonucleotide, CAG25, that binds to CUGexp RNA and blocks its interaction with muscleblind-like 1 (MBNL1), a CUGexp-binding protein. CAG25 disperses nuclear foci of CUGexp RNA and reduces the overall burden of this toxic RNA. As MBNL1 is released from sequestration, the defect of alternative splicing regulation is corrected, thereby restoring ion channel function. These findings suggest an alternative use of antisense methods, to inhibit deleterious interactions of proteins with pathogenic RNAs.
authors.affiliation: Departments of Neurology, Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Thurman M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sobczak
authors.forename: John D
authors.initials: JD
authors.lastname: Lueck
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Osborne
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lin
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D065636:Myotonin-Protein Kinase; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion
chemical_list: D020413:3' Untranslated Regions; D000199:Actins; C086321:CLC-1 channel; D018118:Chloride Channels; C585517:DMPK protein, human; C585516:DMPK protein, mouse; D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases