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.

SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We describe eight rare missense or in-frame microdeletion human SARM1 variant alleles, in patients with amyotrophic lateral sclerosis (ALS), hereditary spastic paraparesis (HSP), or other motor nerve disorders, that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activities of six of the variants are at least as high as that of SARM1 lacking the entire ARM domain and greatly exceed the basal 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, we provide evidence that these gain-of-function alleles are enriched in ALS and HSP patients compared to matched individuals without these conditions within ALS and other motor nerve disorder databases. Together, these data suggest these are risk alleles for ALS and other motor nerve disorders. The broad phenotypic heterogeneity and variable age-of-onset in patients with these alleles raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

No abstract