Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

Jessica L. Childs-Disney; Ewa Stepniak-Konieczna; Tuan Tran; Ilyas Yildirim; Ha Jeung Park; Catherine Z. Chen; Jason Hoskins; Noel Southall; Juan J. Marugan; Samarjit Patnaik; Wei Zheng; Chris P. Austin; George C. Schatz; Krzysztof Sobczak; Charles A. Thornton; Matthew D. Disney

doi:10.1038/ncomms3044

Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

Jessica L. Childs-Disney, Ewa Stepniak-Konieczna, Tuan Tran, Ilyas Yildirim, Ha Jeung Park, Catherine Z. Chen, Jason Hoskins, Noel Southall, Juan J. Marugan, Samarjit Patnaik, Wei Zheng, Chris P. Austin, George C. Schatz, Krzysztof Sobczak, Charles A. Thornton, Matthew D. Disney^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)^exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)^exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)^exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)^exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.

Original language	English (US)
Article number	2044
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3044
State	Published - Jun 28 2013

Funding

We thank Don Mackenzie from the Marigold Foundation for his support of this research project in particular and DM1 research in general and Amit Kumar for preliminary studies; and Professor Glenn E. Morris (Wolfson Centre for Inherited Neuromuscular Disease) for generously providing the MB1a antibody (anti-MBNL1). Funding for this work was provided by the Scripps Research Institute, the Muscular Dystrophy Association (158552 to MDD), the National Institutes of Health (3R01GM079235-02S1 and 1R01GM079235-01A2 to MDD; AR049077 and U54NS48843 to CAT), the Molecular Libraries Initiative of the NIH Roadmap for Medical Research, the Marigold Foundation postdoctoral fellowship, the PS-OC Center of the NIH/NCI (grant 1U54CA143869-01; I.Y. and G.C.S.), and the Foundation for Polish Science—TEAM programme co-financed by the European Union within the European Regional Development Fund (E.S-K and K.S.).

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Childs-Disney, J. L., Stepniak-Konieczna, E., Tran, T., Yildirim, I., Park, H. J., Chen, C. Z., Hoskins, J., Southall, N., Marugan, J. J., Patnaik, S., Zheng, W., Austin, C. P., Schatz, G. C., Sobczak, K., Thornton, C. A., & Disney, M. D. (2013). Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. Nature communications, 4, Article 2044. https://doi.org/10.1038/ncomms3044

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title = "Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules",

abstract = "The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.",

author = "Childs-Disney, {Jessica L.} and Ewa Stepniak-Konieczna and Tuan Tran and Ilyas Yildirim and Park, {Ha Jeung} and Chen, {Catherine Z.} and Jason Hoskins and Noel Southall and Marugan, {Juan J.} and Samarjit Patnaik and Wei Zheng and Austin, {Chris P.} and Schatz, {George C.} and Krzysztof Sobczak and Thornton, {Charles A.} and Disney, {Matthew D.}",

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Childs-Disney, JL, Stepniak-Konieczna, E, Tran, T, Yildirim, I, Park, HJ, Chen, CZ, Hoskins, J, Southall, N, Marugan, JJ, Patnaik, S, Zheng, W, Austin, CP, Schatz, GC, Sobczak, K, Thornton, CA & Disney, MD 2013, 'Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules', Nature communications, vol. 4, 2044. https://doi.org/10.1038/ncomms3044

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T1 - Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

AU - Childs-Disney, Jessica L.

AU - Stepniak-Konieczna, Ewa

AU - Tran, Tuan

AU - Yildirim, Ilyas

AU - Park, Ha Jeung

AU - Chen, Catherine Z.

AU - Hoskins, Jason

AU - Southall, Noel

AU - Marugan, Juan J.

AU - Patnaik, Samarjit

AU - Zheng, Wei

AU - Austin, Chris P.

AU - Schatz, George C.

AU - Sobczak, Krzysztof

AU - Thornton, Charles A.

AU - Disney, Matthew D.

PY - 2013/6/28

Y1 - 2013/6/28

N2 - The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.

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Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

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