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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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.

Author information

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alessandra Chesi or Aaron D Gitler.

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DOI

https://doi.org/10.1038/nn.3412

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