title: Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy.
abstract: RNA-mediated pathogenesis is a recently developed disease model that proposes that certain types of mutant genes produce toxic transcripts that inhibit the activities of specific proteins. This pathogenesis model was proposed first for the neuromuscular disease myotonic dystrophy (DM), which is associated with the expansion of structurally related (CTG)(n) and (CCTG)(n) microsatellites in two unrelated genes. At the RNA level, these expansions form stable hairpins that alter the pre-mRNA splicing activities of two antagonistic factor families, the MBNL and CELF proteins. It is unclear which altered activity is primarily responsible for disease pathogenesis and whether other factors and biochemical pathways are involved. Here, we show that overexpression of Mbnl1 in vivo mediated by transduction of skeletal muscle with a recombinant adeno-associated viral vector rescues disease-associated muscle hyperexcitability, or myotonia, in the HSA(LR) poly(CUG) mouse model for DM. Myotonia reversal occurs concurrently with restoration of the normal adult-splicing patterns of four pre-mRNAs that are misspliced during postnatal development in DM muscle. Our results support the hypothesis that the loss of MBNL1 activity is a primary pathogenic event in the development of RNA missplicing and myotonia in DM and provide a rationale for therapeutic strategies designed either to overexpress MBNL1 or inhibit MBNL1 interactions with CUG and CCUG repeat expansions.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Rahul N
authors.initials: RN
authors.lastname: Kanadia
authors.forename: Jihae
authors.initials: J
authors.lastname: Shin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Beattie
authors.forename: Thurman M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004576:Electromyography; D005091:Exons; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology / Q000503:physiopathology; D009222:Myotonia / Q000235:genetics / Q000628:therapy; D009223:Myotonic Dystrophy / Q000235:genetics / Q000628:therapy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D020033:Protein Isoforms; D012322:RNA Precursors; D016601:RNA-Binding Proteins