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Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy

Nature Structural & Molecular Biology volume 17, pages 187193 (2010) | Download Citation

Abstract

The common form of myotonic dystrophy (DM1) is associated with the expression of expanded CTG DNA repeats as RNA (CUGexp RNA). To test whether CUGexp RNA creates a global splicing defect, we compared the skeletal muscle of two mouse models of DM1, one expressing a CTGexp transgene and another homozygous for a defective muscleblind 1 (Mbnl1) gene. Strong correlation in splicing changes for 100 new Mbnl1-regulated exons indicates that loss of Mbnl1 explains >80% of the splicing pathology due to CUGexp RNA. In contrast, only about half of mRNA-level changes can be attributed to loss of Mbnl1, indicating that CUGexp RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix proteins. We propose that CUGexp RNA causes two separate effects: loss of Mbnl1 function (disrupting splicing) and loss of another function that disrupts extracellular matrix mRNA regulation, possibly mediated by Mbnl2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies.

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Acknowledgements

We thank D. Black (Univ. of California, Los Angeles) and X.-D. Fu (Univ. of California, San Diego) for gifts of plasmids and advice on mammalian cell culture. Thanks to B. Chabot and J. Sanford for critical reading of the manuscript. This work was primarily supported by US National Institutes of Health grant GM084317 to M.A., with additional support from US National Institutes of Health grant GM040478 (to M.A.), US National Institutes of Health grant AR046799 (to M.S.S.) and US National Institutes of Health grant AR046806 and Muscular Dystrophy Center grant U54NS048843 (to C.A.T.). M.P.H. acknowledges the California Institute of Regenerative Medicine for postdoctoral support.

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Affiliations

  1. RNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, USA.

    • Hongqing Du
    • , Melissa S Cline
    • , John Paul Donohue
    • , Megan P Hall
    • , Lily Shiue
    •  & Manuel Ares Jr
  2. Neuromuscular Disease Center, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.

    • Robert J Osborne
    •  & Charles A Thornton
  3. Department of Molecular Genetics & Microbiology, University of Florida, College of Medicine, Gainesville, Florida, USA.

    • Daniel L Tuttle
    •  & Maurice S Swanson
  4. Affymetrix Inc. Santa Clara, California, USA.

    • Tyson A Clark

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Contributions

M.A., H.D., M.S.S. and C.A.T. designed the experiments; H.D., R.J.O., D.L.T. and M.P.H. performed the experiments; T.A.C. provided materials and data analysis; M.S.C., J.P.D. and L.S. performed data analysis; M.A., H.D. and M.S.C. wrote the paper.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Manuel Ares Jr.

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https://doi.org/10.1038/nsmb.1720

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