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Enrichment of sarm1 alleles encoding variants with constitutively hyperactive nadase in patients with als and other motor nerve disorders

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Jonathan Gilley, Oscar Jackson, Menelaos Pipis, Mehrdad A. Estiar, Ammar Al-Chalabi, Matt C. Danzi, Kristel R. van Eijk, Stephen A. Goutman, Matthew B. Harms, Henry Houlden, Alfredo Iacoangeli, Julia Kaye, Leandro Lima, Queen Square Genomics, John Ravits, Guy A. Rouleau, Rebecca Schüle, Jishu Xu, Stephan Züchner, Johnathan Cooper-Knock & 3 more Ziv Gan-Or, Mary M. Reilly, Michael P. Coleman

Original languageEnglish
Article numbere70905
JournaleLife
Volume10
Early online date19 Nov 2021
DOIs
E-pub ahead of print19 Nov 2021
PublishedNov 2021

Bibliographical note

Funding Information: This work was supported by a grant from the Robert Packard Center for ALS Research at Johns Hopkins (to M.P.C, also supporting J.G.) and in part by data provided by the Answer ALS Consortium ? also administered by the Robert Packard Center. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of The Johns Hopkins University or any grantor proving funds to its Robert Packard Center for ALS Research. Parts of this work were also supported by UK Biotechnology and Biological Sciences Research Council (BBSRC) / AstraZeneca Industrial Partnership award BB/S009582/1 (to M.P.C, also supporting J.G., O.J.) and Wellcome Trust Collaborative award 220906/Z/20/Z (to M.P.C and M.M.R, also supporting J.G., O.J., M.P.). Additional support was provided by UK Medical Research Council (MRC) awards MR/L501529/1 and MR/R024804/1 and the UK Economic and Social Research Council (ESRC) award ES/L008238/1 under the aegis of the EU Joint Programme-Neurodegenerative Disease Research (JPND) (www.jpnd.eu) (to A.A-C.), the Motor Neurone Disease (MND) Association and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King?s College London (A.A-C., A.I.), National Institute of Neurological Diseases and Stroke (NINDS) and office of Rare Diseases awards U54NS065712 (to M.M.R., also supporting M.P.), and 5R01NS072248-10 and 5R01NS105755-03 (to S.Z., also supporting M.C.D.), National Institute of Environmental Health Sciences (NIEHS) award K23ES027221 (to S.A.G.), and Wellcome Trust award 216596/Z/19/Z (to J.C.K.). Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. Sample management was undertaken by Biobanking Solutions funded by the MRC at the Centre for Integrated Genomic Medical Research, University of Manchester. Whole-genome sequencing of the Lothian Birth Cohorts was funded by the Biotechnology and Biological Sciences Research Council. Anne Segonds-Pichon kindly helped with statistical analyses. Funding Information: This work was supported by a grant from the Robert Packard Center for ALS Research at Funding Information: Research. Parts of this work were also supported by UK Biotechnology and Biological Funding Information: Johns Hopkins (to M.P.C, also supporting J.G.) and in part by data provided by the Answer Funding Information: a smaller majority are expected to be of European origin. This is broadly supported by the Funding Information: support was provided by UK Medical Research Council (MRC) awards MR/L501529/1 and Funding Information: MR/R024804/1 and the UK Economic and Social Research Council (ESRC) award Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.

King's Authors

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.

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