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Human Molecular Genetics Advance Access published online on February 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi080
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila

Jonathan M. Houseley 1, Zongsheng Wang 2, Graham J.R. Brock 3, Judith Soloway 2, Ruben Artero 4, Manuel Perez-Alonso 4, Kevin M.C. O'Dell 2, and Darren G. Monckton 2*

1 Institute of Biomedical and Life Sciences, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, UK; The Wellcome Trust Centre for Cell Biology, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK
2 Institute of Biomedical and Life Sciences, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, UK
3 Institute of Biomedical and Life Sciences, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, UK; Target and Drug Discovery, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA
4 Department of Genetics, University of Valencia, Dr. Moliner 50, 46100 Burjasot, Spain

* To whom correspondence should be addressed.
Darren G. Monckton, E-mail: d.monckton{at}bio.gla.ac.uk


  Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder associated with the expansion of a CTG repeat in the 3' untranslated region (UTR) of the DMPK gene. Recent data suggest that pathogenesis is predominantly mediated by a gain of function of the mutant transcript. In patients these expanded CUG repeat containing transcripts are sequestered into ribonuclear foci that also contain the muscleblind-like (MBNL) proteins. To provide further insights into muscleblind function and the pathogenesis of myotonic dystrophy, we generated Drosophila incorporating CTG repeats in the 3' UTR of a reporter gene. As in patients, expanded CUG repeats form discrete ribonuclear foci in Drosophila muscle cells that co-localise with muscleblind. Unexpectedly however, foci are not observed in all cell types and muscleblind is neither necessary nor sufficient for their formation. The foci are dynamic transient structures with short half-lifes that do not co-localise with the proteasome, suggesting they are unlikely to contain mis-folded proteins. However, they do co-localise with nonA, the human orthologues of which are implicated in both RNA splicing and attachment of dsRNA to the nuclear matrix. Muscleblind is also revealed as having a previously unrecognised role in stabilising CUG transcripts. Most interestingly, Drosophila expressing (CUG)162 repeats have no detectable pathological phenotype suggesting that, in contrast to expanded polyglutamine containing proteins, neither the expanded CUG repeat RNA nor the ribonuclear foci are directly toxic.


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