title: Defective mRNA in myotonic dystrophy accumulates at the periphery of nuclear splicing speckles.
abstract: Nuclear speckles are storage sites for small nuclear RNPs (snRNPs) and other splicing factors. Current ideas about the role of speckles suggest that some pre-mRNAs are processed at the speckle periphery before being exported as mRNA. In myotonic dystrophy type 1 (DM1), the export of mutant DMPK mRNA is prevented by the presence of expanded CUG repeats that accumulate in nuclear foci. We now show that these foci accumulate at the periphery of nuclear speckles. In myotonic dystrophy type 2 (DM2), mRNA from the mutant ZNF9 gene is exported normally because the expanded CCUG repeats are removed during splicing. We now show that the nuclear foci formed by DM2 intronic repeats are widely dispersed in the nucleoplasm and not associated with either nuclear speckles or exosomes. We hypothesize that the expanded CUG repeats in DMPK mRNA are blocking a stage in its export pathway that would normally occur at the speckle periphery. Localization of the expanded repeats at the speckle periphery is not essential for their pathogenic effects because DM1 and DM2 are quite similar clinically.
authors.affiliation: Wolfson Centre for Inherited Neuromuscular Disease, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, SY10 7AG, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Holt
authors.forename: Saloni
authors.initials: S
authors.lastname: Mittal
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Butler-Browne
authors.forename: J David
authors.initials: JD
authors.lastname: Brook
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Morris
mesh_terms: D000906:Antibodies / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism; D022003:Cell Nucleus Structures / Q000378:metabolism*; D005333:Fetus / Q000378:metabolism; D006367:HeLa Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007438:Introns; D008954:Models, Biological; D009154:Mutation; D009223:Myotonic Dystrophy / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D065636:Myotonin-Protein Kinase; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000502:physiology*; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D018911:Trinucleotide Repeats