Fig. 1

Identification of dysregulated SARM1 variants found in ALS patients. (A) Schematic representation of the domain structure of SARM1 marked with every rare variant found in ALS patients. Constitutively-active variants are indicated above in red. Bold variants were prioritized because they were identified in multiple ALS patients or were unique to ALS patients. Δ indicates an in-frame deletion. MLS, mitochondrial localization signal; ARM, HEAT/Armadillo motif; SAM, sterile alpha motif; TIR, Toll/interleukin-1 receptor homology domain. (B) The ratio of cADPR/NAD⁺, cADPR, and NAD⁺ levels from cultured Sarm1^−/− DRG neurons infected with human SARM1 constructs carrying every rare variants identified in multiple ALS patients or unique to ALS patients (red), every rare variant found in controls (green), and the most common SARM1 variant, P332Q (gray), relative to the common reference human genome allele of SARM1 (black). *p < 0.05; **p < 0.0005 difference from reference allele. We demonstrate that strongly constitutively active variants predominate among those SARM1 variants identified in multiple ALS patients or unique to ALS patients, while the only two significantly active variants discovered in controls are comparatively weak