TY  - JOUR
AU  - Gilley, Jonathan
AU  - Jackson, Oscar
AU  - Pipis, Menelaos
AU  - Estiar, Mehrdad A
AU  - Al-Chalabi, Ammar
AU  - Danzi, Matt C
AU  - van Eijk, Kristel R
AU  - Goutman, Stephen A
AU  - Harms, Matthew B
AU  - Houlden, Henry
AU  - Iacoangeli, Alfredo
AU  - Kaye, Julia
AU  - Lima, Leandro
AU  - Ravits, John
AU  - Rouleau, Guy A
AU  - Schüle, Rebecca
AU  - Xu, Jishu
AU  - Züchner, Stephan
AU  - Cooper-Knock, Johnathan
AU  - Gan-Or, Ziv
AU  - Reilly, Mary M
AU  - Coleman, Michael P
TI  - Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
JO  - eLife
VL  - 10
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DZNE-2022-00296
SP  - e70905
PY  - 2021
AB  - 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.
KW  - Adult
KW  - Aged
KW  - Alleles
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Animals
KW  - Armadillo Domain Proteins
KW  - Cytoskeletal Proteins
KW  - Female
KW  - Humans
KW  - Male
KW  - Mice
KW  - Middle Aged
KW  - Motor Neuron Disease: genetics
KW  - Motor Neuron Disease: metabolism
KW  - NAD+ Nucleosidase: metabolism
KW  - Nicotinamide Mononucleotide: metabolism
KW  - ALS (Other)
KW  - NADase (Other)
KW  - SARM1 (Other)
KW  - genetics (Other)
KW  - genomics (Other)
KW  - human (Other)
KW  - neuroscience (Other)
KW  - risk allele (Other)
KW  - Armadillo Domain Proteins (NLM Chemicals)
KW  - Cytoskeletal Proteins (NLM Chemicals)
KW  - SARM1 protein, human (NLM Chemicals)
KW  - Nicotinamide Mononucleotide (NLM Chemicals)
KW  - NAD+ Nucleosidase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34796871
C2  - pmc:PMC8735862
DO  - DOI:10.7554/eLife.70905
UR  - https://pub.dzne.de/record/163536
ER  -