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Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs

Nature Structural & Molecular Biology volume 18, pages 85–87 (2011)Cite this article

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Abstract

We describe a function for modified human U7 small nuclear RNAs (hU7-snRNAs) distinct from modification of pre-mRNA splicing events. Engineered hU7-snRNAs containing a poly-CAG antisense sequence targeting the expanded CUG repeats of mutant DMPK transcripts in myotonic dystrophy caused specific degradation of pathogenic DMPK mRNAs without affecting the products of wild-type DMPK alleles. Abolition of the RNA gain-of-function toxicity that is responsible for pathogenesis supports the use of hU7-snRNAs for gene silencing in RNA-dominant disorders in which expanded repeats are expressed.

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Figure 1: Silencing of CUGexp RNAs by hU7-(CAG)15.
Figure 2: Consequences of hU7-(CAG)n expression in DM1 muscle cells.

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Acknowledgements

This work was supported by the Association Française contre les Myopathies. We thank D. Brook (Institute of Genetics, University of Nottingham) for the DM1 Bpm1-fibroblasts; I. Holt and G. Morris (Centre for Inherited Neuromuscular Disease; Robert Jones and Agnes Hunt Orthopaedic Hospital) and The Muscular Dystrophy Association Monoclonal Antibody Resource for the MBNL1 (MB1a) and DMPK (MANDM1) monoclonal antibodies; MyoBank-AFM for the muscle biopsies; O. Danos for viral production facility; S. Chaouch and V. Mouly for cell culture facility; and the French DM1 network, J. Puymirat, Myocastor Study Group, G. Butler-Browne and T. Voit for discussions.

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Author notes

  1. Virginie François and Arnaud F Klein: These authors contributed equally to this work.

  2. Luis Garcia and Denis Furling: These authors jointly directed this work.

Authors and Affiliations

  1. Université Pierre et Marie Curie-Paris6, Um76, Paris, France

    Virginie François, Arnaud F Klein, Cyriaque Beley, Arnaud Jollet, Camille Lemercier, Luis Garcia & Denis Furling

  2. Centre Nationale de la Recherche Scientifique, Unité Mixte de Recherche, Paris, 7215, France

    Virginie François, Arnaud F Klein, Cyriaque Beley, Arnaud Jollet, Camille Lemercier, Luis Garcia & Denis Furling

  3. INSERM, U974, Paris, France

    Virginie François, Arnaud F Klein, Cyriaque Beley, Arnaud Jollet, Camille Lemercier, Luis Garcia & Denis Furling

  4. Institut de Myologie, Paris, France

    Virginie François, Arnaud F Klein, Cyriaque Beley, Arnaud Jollet, Camille Lemercier, Luis Garcia & Denis Furling

Authors
  1. Virginie François
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  3. Cyriaque Beley
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Contributions

V.F. and A.F.K. conducted most of the experiments. C.B. made the constructs. A.J. produced the lentiviral vectors. C.L. supported some experiments. L.G. engineered the modified hU7-snRNA. D.F. supervised the entire project. L.G. and D.F. wrote the manuscript.

Corresponding author

Correspondence to Denis Furling.

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Competing interests

L.G., D.F., C.B. and T.V. are named as inventors on a patent application to the US Patent Office covering the method described in this paper.

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Supplementary Figures 1–9 and Supplementary Methods (PDF 1047 kb)

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François, V., Klein, A., Beley, C. et al. Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs. Nat Struct Mol Biol 18, 85–87 (2011). https://doi.org/10.1038/nsmb.1958

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