title: Gain of RNA function in pathological cases: Focus on myotonic dystrophy.
abstract: Expansion of repeated sequences in non-coding regions of different genes causes a number of inherited diseases including myotonic dystrophies, Huntington disease-like 2, Fragile X tremor/ataxia syndrome and spinocerebellar ataxia 8, 10, 12, 31. Involvement of an RNA gain-of-function mechanism in pathological case has been described and studied in-depth in myotonic dystrophy type 1 (DM1). This inherited neuromuscular disorder is caused by a (CTG)n >50 expansion in the 3' non-coding region of the dystrophia myotonica-protein kinase (DMPK) gene. Expanded CUG transcripts (CUGexp-RNAs) are sequestered in the nucleus within small aggregates and interfere with the regulatory splicing activities of MBNL1 and CELF1 RNA-binding proteins, leading to the misregulation of the alternative splicing of several transcripts. Despite the relevance of aberrant splicing events in this complex pathology, the CUGexp-RNAs trans-dominant effects alter other splicing-independent processes that may also contribute to DM1 pathogenesis. This review will focus on toxic RNA gain-of-function as a pathologic mechanism for DM1 and other repeat expansion disorders.
authors.affiliation: UPMC Univ Paris 06, UM 76, F-75013 Paris, France.
authors.forename: A F
authors.initials: AF
authors.lastname: Klein
authors.forename: E
authors.initials: E
authors.lastname: Gasnier
authors.forename: D
authors.initials: D
authors.lastname: Furling
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000067879:CELF1 Protein; D006801:Humans; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; C585517:DMPK protein, human; C493663:MBNL1 protein, human; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; D012313:RNA; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases