title: A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1.
abstract: Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of-function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. Interestingly, expression of two isoforms of MBNL1, MBNL135 and MBNL140, leads to cleavage and concurrent upregulation of the levels of the RNA-repeat transcripts, with MBNL140 having more significant effects than MBNL135. This property is shared with a fly CUG-repeat expansion model. Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1.
authors.affiliation: Department of Biology and.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Neurosciences Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Goodman
authors.affiliation: Department of Biology and.
authors.forename: Shin-Yi
authors.initials: SY
authors.lastname: Shieh
authors.affiliation: Department of Biology and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Min
authors.affiliation: Department of Biology and.
authors.forename: Xiuyin
authors.initials: X
authors.lastname: Teng
authors.affiliation: Department of Biology and.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biology and Neurosciences Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA nbonini@sas.upenn.edu.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D030801:Animals, Genetically Modified; D002467:Cell Nucleus / Q000235:genetics; D042622:DNA Repeat Expansion; D004195:Disease Models, Animal; D004330:Drosophila; D015870:Gene Expression; D005804:Genes, Lethal; D056726:Genetic Association Studies; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D020871:RNA Stability; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D022661:RNA, Untranslated; D016601:RNA-Binding Proteins