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Link to original content: https://doi.org/10.1038/nn.3412
Exome sequencing to identify de novo mutations in sporadic ALS trios | Nature Neuroscience
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Exome sequencing to identify de novo mutations in sporadic ALS trios

Nature Neuroscience volume 16, pages 851–855 (2013)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, we assessed the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n = 141 exomes). We found that amino acid–altering de novo mutations were enriched in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex (nBAF) component SS18L1 (also known as CREST). CREST mutations inhibited activity-dependent neurite outgrowth in primary neurons, and CREST associated with the ALS protein FUS. These findings expand our understanding of the ALS genetic landscape and provide a resource for future studies into the pathogenic mechanisms contributing to sporadic ALS.

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Figure 1: The SS18L1 de novo mutation (Q388stop) identified in an ALS trio inhibits activity-dependent dendritic outgrowth.
Figure 2: Identification of an additional CREST variant in FALS case and interaction with FUS.

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Acknowledgements

This work was supported by a US National Institutes of Health Director's New Innovator Award 1DP2OD004417 (A.D.G.), grants from the US National Institutes of Health (1R01NS065317 to A.D.G., R01NS046789 to G.R.C. and 5U01NS062713 to N.J.M.) and the Department of Defense ALS Research Program (N.J.M.). A.D.G. received funding from the Biogen Idec ALS genome sequencing consortium. A.D.G. received funding from The Pew Charitable Trusts and the Rita Allen Foundation. G.R.C. receives funding from the Howard Hughes Medical Institute. A.D.G. and J.D.G. are supported by the Packard Center for ALS Research at Johns Hopkins. This work was also supported by the National Health and Medical Research Council of Australia (1004670, 511941) and the Motor Neurone Disease Research Institute of Australia.

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Authors and Affiliations

  1. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Alessandra Chesi, Ana Jovičić, Julien Couthouis, Alya R Raphael & Aaron D Gitler

  2. Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA

    Brett T Staahl, Laura Elias & Gerald R Crabtree

  3. Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Maria Fasolino

  4. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Tomohiro Yamazaki & Robin Reed

  5. Department of Neurology, Emory University, Atlanta, Georgia, USA

    Meraida Polak, Crystal Kelly & Jonathan D Glass

  6. Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps Research Institute, Sydney, Australia

    Kelly L Williams, Jennifer A Fifita, Garth A Nicholson & Ian P Blair

  7. Sydney Medical School, University of Sydney, Sydney, Australia

    Kelly L Williams, Garth A Nicholson & Ian P Blair

  8. Australian School of Advanced Medicine, Macquarie University, Sydney, Australia

    Kelly L Williams, Jennifer A Fifita & Ian P Blair

  9. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicholas J Maragakis

  10. Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Oliver D King

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Contributions

A.C. performed all of the exome sequencing and analysis. B.T.S. and A.J. performed the primary neuron experiments. B.T.S. performed co-immunoprecipitation experiments with direction from G.R.C. J.C., M.F. and A.R.R. performed Sanger sequencing and helped A.C. with exome sequencing. T.Y. and R.R. performed SS18L1-FUS physical association experiments. L.E. performed mass spectrometry analysis. N.J.M. and J.D.G. contributed ALS patient samples, with assistance from M.P. and C.K., and helped to design experiments. K.L.W., J.A.F., G.A.N. and I.P.B. contributed ALS patient samples and performed experiments to identify SS18L1 variants in Australian FALS pedigrees. O.D.K. performed prion-like domain analysis for SS18L1 and SS18. A.D.G. and A.C. wrote the manuscript with input from all of the authors.

Corresponding authors

Correspondence to Alessandra Chesi or Aaron D Gitler.

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The authors declare no competing financial interests.

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Chesi, A., Staahl, B., Jovičić, A. et al. Exome sequencing to identify de novo mutations in sporadic ALS trios. Nat Neurosci 16, 851–855 (2013). https://doi.org/10.1038/nn.3412

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