Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders
- University of Cambridge, United Kingdom
- University College London, United Kingdom
- McGill University, Canada
- King's College London, United Kingdom
- University of Miami Miller School of Medicine, United States
- Utrecht University, Netherlands
- University of Michigan, United States
- Columbia University, United States
- Gladstone Institutes, United States
- University of California, San Diego, United States
- University of Tübingen, Germany
- 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
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).
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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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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