Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

  1. Jonathan Gilley  Is a corresponding author
  2. Oscar Jackson
  3. Menelaos Pipis
  4. Mehrdad A Estiar
  5. Ammar Al-Chalabi
  6. Matt C Danzi
  7. Kristel R van Eijk
  8. Stephen A Goutman
  9. Matthew B Harms
  10. Henry Houlden
  11. Alfredo Iacoangeli
  12. Julia Kaye
  13. Leandro Lima
  14. John Ravits
  15. Guy A Rouleau
  16. Rebecca Schüle
  17. Jishu Xu
  18. Stephan Züchner
  19. Johnathan Cooper-Knock
  20. Ziv Gan-Or
  21. Mary M Reilly
  22. Michael P Coleman  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University College London, United Kingdom
  3. McGill University, Canada
  4. King's College London, United Kingdom
  5. University of Miami Miller School of Medicine, United States
  6. Utrecht University, Netherlands
  7. University of Michigan, United States
  8. Columbia University, United States
  9. Gladstone Institutes, United States
  10. University of California, San Diego, United States
  11. University of Tübingen, Germany
  12. University of Sheffield, United Kingdom

Abstract

SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

Data availability

Genomic data was requested from a variety of previously published datasets from whom interested researchers can request access: Project MinE (https://www.projectmine.com/research/data-sharing/); Answer ALS (https://www.nygenome.org/als-consortium/); GENESIS (https://neuropathycommons.org/genetics/genesis-platform); UCL rare disease (neurology) dataset (available on request from Prof. Henry Houlden); HSP study (available on request from Dr. Rebecca Schüle); Lothian Birth Cohort (https://www.ed.ac.uk/lothian-birth-cohorts/data-access-collaboration). Further information about how to gain access to these datasets and any restrictions on who can gain access to the data is provided on these websites. The specifics of the datasets used are outlined in the Materials and Methods section, and are listed in Tables 1-4. Source data files of processed numerical data and raw blot images have been provided for Figures 2, 3, 4, 5, 6 and 7 and Figure 2 - figure supplement 2, Figure 3 - figure supplement 2 and Figure 6 - figure supplements 1 and 2.

Article and author information

Author details

  1. Jonathan Gilley

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    jg792@cam.ac.uk
    Competing interests
    Jonathan Gilley, Part-funded by AstraZeneca during the past 3 years..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9510-7956
  2. Oscar Jackson

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Oscar Jackson, Currently part-funded by AstraZeneca..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1825-9331
  3. Menelaos Pipis

    Department of Neuromuscular Disease, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Mehrdad A Estiar

    McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  5. Ammar Al-Chalabi

    King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Matt C Danzi

    University of Miami Miller School of Medicine, Miami, United States
    Competing interests
    No competing interests declared.
  7. Kristel R van Eijk

    Department of Neurology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  8. Stephen A Goutman

    Department of Neurology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  9. Matthew B Harms

    Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  10. Henry Houlden

    Department of Molecular Neuroscience, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  11. Alfredo Iacoangeli

    King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  12. Julia Kaye

    Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, United States
    Competing interests
    No competing interests declared.
  13. Leandro Lima

    Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, United States
    Competing interests
    No competing interests declared.
  14. John Ravits

    University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  15. Guy A Rouleau

    McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  16. Rebecca Schüle

    University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  17. Jishu Xu

    University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  18. Stephan Züchner

    University of Miami Miller School of Medicine, Miami, United States
    Competing interests
    No competing interests declared.
  19. Johnathan Cooper-Knock

    University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
  20. Ziv Gan-Or

    McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0332-234X
  21. Mary M Reilly

    MRC Centre for Neuromuscular Diseases, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  22. Michael P Coleman

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    mc469@cam.ac.uk
    Competing interests
    Michael P Coleman, Consults for Nura Bio, but no support provided for this work..

Funding

Biotechnology and Biological Sciences Research Council (BB/S009582/1)

  • Jonathan Gilley
  • Oscar Jackson
  • Michael P Coleman

EU Joint Programme – Neurodegenerative Disease Research

  • Ammar Al-Chalabi

Robert Packard Center for ALS Research, Johns Hopkins University

  • Jonathan Gilley
  • Michael P Coleman

Wellcome Trust (216596/Z/19/Z)

  • Johnathan Cooper-Knock

Wellcome Trust (220906/Z/20/Z)

  • Jonathan Gilley
  • Oscar Jackson
  • Menelaos Pipis
  • Mary M Reilly
  • Michael P Coleman

National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712)

  • Menelaos Pipis
  • Mary M Reilly

National Institute of Neurological Disorders and Stroke (5R01NS072248-10 and 5R01NS105755-03)

  • Matt C Danzi
  • Stephan Züchner

Medical Research Council (MR/L501529/1 and MR/R024804/1)

  • Ammar Al-Chalabi

Economic and Social Research Council (ES/L008238/1)

  • Ammar Al-Chalabi

National Institute of Environmental Health Sciences (K23ES027221)

  • Stephen A Goutman

Motor Neurone Disease Association

  • Ammar Al-Chalabi
  • Alfredo Iacoangeli

NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London

  • Ammar Al-Chalabi
  • Alfredo Iacoangeli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This is a retrospective study using anonymised data so specific consent was not obtained by the authors, but informed consent and consent to publish was obtained at each site that contributed patient information to this study in accordance with their local Institutional Review Boards (IRBs).

Reviewing Editor

  1. J Paul Taylor, St Jude Children's Research Hospital, United States

Version history

  1. Received: June 2, 2021
  2. Preprint posted: June 17, 2021 (view preprint)
  3. Accepted: November 18, 2021
  4. Accepted Manuscript published: November 19, 2021 (version 1)
  5. Accepted Manuscript updated: November 22, 2021 (version 2)
  6. Version of Record published: January 6, 2022 (version 3)

Copyright

© 2021, Gilley et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jonathan Gilley
  2. Oscar Jackson
  3. Menelaos Pipis
  4. Mehrdad A Estiar
  5. Ammar Al-Chalabi
  6. Matt C Danzi
  7. Kristel R van Eijk
  8. Stephen A Goutman
  9. Matthew B Harms
  10. Henry Houlden
  11. Alfredo Iacoangeli
  12. Julia Kaye
  13. Leandro Lima
  14. John Ravits
  15. Guy A Rouleau
  16. Rebecca Schüle
  17. Jishu Xu
  18. Stephan Züchner
  19. Johnathan Cooper-Knock
  20. Ziv Gan-Or
  21. Mary M Reilly
  22. Michael P Coleman
(2021)
Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders
eLife 10:e70905.
https://doi.org/10.7554/eLife.70905

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https://doi.org/10.7554/eLife.70905

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