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RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression

Nature Genetics volume 40, pages 61–68 (2008)Cite this article

Abstract

Myotonic muscular dystrophy (DM1) is the most common inherited neuromuscular disorder in adults and is considered the first example of a disease caused by RNA toxicity. Using a reversible transgenic mouse model of RNA toxicity in DM1, we provide evidence that DM1 is associated with induced NKX2-5 expression. Transgene expression resulted in cardiac conduction defects, increased expression of the cardiac-specific transcription factor NKX2-5 and profound disturbances in connexin 40 and connexin 43. Notably, overexpression of the DMPK 3′ UTR mRNA in mouse skeletal muscle also induced transcriptional activation of Nkx2-5 and its targets. In human muscles, these changes were specific to DM1 and were not present in other muscular dystrophies. The effects on NKX2-5 and its downstream targets were reversed by silencing toxic RNA expression. Furthermore, using Nkx2-5+/− mice, we show that NKX2-5 is the first genetic modifier of DM1-associated RNA toxicity in the heart.

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Figure 1: Cardiac conduction abnormalities.
Figure 2: NKX2-5 expression is induced by RNA toxicity in the heart.
Figure 3: NKX2-5 is ectopically induced in skeletal muscle.
Figure 4: NKX2-5 downstream targets are affected by induction of transgene expression.
Figure 5: NKX2-5 is sufficient to transcriptionally activate downstream targets in skeletal myoblasts.
Figure 6: NKX2-5 is expressed in muscle tissue from individuals with DM1.
Figure 7: Reversal of RNA toxicity and molecular changes.
Figure 8: Nkx2-5 haploinsufficiency protects against cardiac conduction defects induced by DMPK 3′ UTR mRNA.

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Acknowledgements

We thank P. Mahadevan for critically reading the manuscript. Human tissues were purchased from the University of Miami Brain and Tissue Bank. Transgenic mice were generated by the University of Wisconsin-Madison Transgenic Core Facility. All studies were done under the auspices of the University of Virginia Animal Care and Use Committee and Institutional Review Board. This work was supported by the Muscular Dystrophy Association (grant 3889) and by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR052771).

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  1. Ramesh S Yadava and Mani S Mahadevan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of Virginia, Charlottesville, 22908, Virginia, USA

    Ramesh S Yadava, Carla D Frenzel-McCardell, Qing Yu, Varadamurthy Srinivasan & Mani S Mahadevan

  2. Department of Medicine, University of Virginia, Charlottesville Virginia 22908, USA.,

    Amy L Tucker

  3. Human Genetics Research Unit, Laval University, Quebec City, G1V 4G2, Quebec, Canada

    Jack Puymirat

  4. Department of Neurology, University of Rochester, Rochester, 14642, New York, USA

    Charles A Thornton

  5. The Victor Chang Cardiac Research Institute, Darlinghurst, 2010, New South Wales, Australia

    Owen W Prall & Richard P Harvey

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Contributions

M.S.M. discovered NKX2-5 induction and performed mouse phenotypic analyses, immunohistochemistry and protein blotting. R.S.Y. performed molecular analyses and transfection assays. Q.Y. managed the mouse colony and performed mouse phenotypic analyses and tissue collection. C.D.F.-M. performed RT-PCR assays and analyses, and V.S. performed mouse experimental work and tissue staining. J.P. and C.A.T. provided human tissues. A.L.T. provided ECG machines and assistance in performing and analyzing ECGs. O.W.P. and R.P.H. provided Nkx2-5LacZ/+ mice and gave experimental advice, critical insight and comments. M.S.M. was responsible for conceptual design and execution.

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Correspondence to Mani S Mahadevan.

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Yadava, R., Frenzel-McCardell, C., Yu, Q. et al. RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nat Genet 40, 61–68 (2008). https://doi.org/10.1038/ng.2007.28

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