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¹ Wolfson Centre for Inherited Neuromuscular Disease, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, SY10 7AG, UK
² Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK
³ UMRS 787, Institute of Myology, INSERM-Universite Paris 6, 75013 Paris, France
⁴ Institute for Science and Technology in Medicine, Keele University, Keele, ST5 5BG, UK

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.

^* Correspondence: E-mail: glenn.morris{at}rjah.nhs.uk

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