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

• DOI: 10.7554/elife.70905
• Publication Date: 2021-11-19T13:00:13Z
• Authors: 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; ; John Ravits; Guy A Rouleau; Rebecca Schüle; Jishu Xu; Stephan Züchner; Johnathan Cooper-...; Ziv Gan-Or; Mary M Reilly; Michael P Coleman
• Keywords: Adult; Male; SARM1; SARM1 protein, human; metabolism [Nicotinamide Mononucleotide]; QH301-705.5; Science; 610; NADase; neuroscience; Mice; 03 medical and health sciences; NAD+ Nucleosidase; Genetics; genomics; Animals; Humans; genetics; human; Biology (General); Motor Neuron Disease; metabolism [NAD+ Nucleosidase]; Alleles; Nicotinamide Mononucleotide; risk allele; Aged; Armadillo Domain Proteins; 0303 health sciences; metabolism [Amyotrophic Lateral Sclerosis]; Q; Amyotrophic Lateral Sclerosis; R; Genetics and Genomics; Middle Aged; metabolism [Motor Neuron Disease]; 3. Good health; genetics [Amyotrophic Lateral Sclerosis]; Cytoskeletal Proteins; Medicine; genetics [Motor Neuron Disease]; Female; ALS; ddc:600

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.