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000163536 041__ $$aEnglish
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000163536 1001_ $$00000-0002-9510-7956$$aGilley, Jonathan$$b0
000163536 245__ $$aEnrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
000163536 260__ $$aCambridge$$beLife Sciences Publications$$c2021
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000163536 520__ $$aSARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.
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000163536 650_7 $$2Other$$aALS
000163536 650_7 $$2Other$$aNADase
000163536 650_7 $$2Other$$aSARM1
000163536 650_7 $$2Other$$agenetics
000163536 650_7 $$2Other$$agenomics
000163536 650_7 $$2Other$$ahuman
000163536 650_7 $$2Other$$aneuroscience
000163536 650_7 $$2Other$$arisk allele
000163536 650_7 $$2NLM Chemicals$$aArmadillo Domain Proteins
000163536 650_7 $$2NLM Chemicals$$aCytoskeletal Proteins
000163536 650_7 $$2NLM Chemicals$$aSARM1 protein, human
000163536 650_7 $$01094-61-7$$2NLM Chemicals$$aNicotinamide Mononucleotide
000163536 650_7 $$0EC 3.2.2.5$$2NLM Chemicals$$aNAD+ Nucleosidase
000163536 650_2 $$2MeSH$$aAdult
000163536 650_2 $$2MeSH$$aAged
000163536 650_2 $$2MeSH$$aAlleles
000163536 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000163536 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000163536 650_2 $$2MeSH$$aAnimals
000163536 650_2 $$2MeSH$$aArmadillo Domain Proteins
000163536 650_2 $$2MeSH$$aCytoskeletal Proteins
000163536 650_2 $$2MeSH$$aFemale
000163536 650_2 $$2MeSH$$aHumans
000163536 650_2 $$2MeSH$$aMale
000163536 650_2 $$2MeSH$$aMice
000163536 650_2 $$2MeSH$$aMiddle Aged
000163536 650_2 $$2MeSH$$aMotor Neuron Disease: genetics
000163536 650_2 $$2MeSH$$aMotor Neuron Disease: metabolism
000163536 650_2 $$2MeSH$$aNAD+ Nucleosidase: metabolism
000163536 650_2 $$2MeSH$$aNicotinamide Mononucleotide: metabolism
000163536 7001_ $$00000-0002-1825-9331$$aJackson, Oscar$$b1
000163536 7001_ $$aPipis, Menelaos$$b2
000163536 7001_ $$aEstiar, Mehrdad A$$b3
000163536 7001_ $$aAl-Chalabi, Ammar$$b4
000163536 7001_ $$aDanzi, Matt C$$b5
000163536 7001_ $$avan Eijk, Kristel R$$b6
000163536 7001_ $$aGoutman, Stephen A$$b7
000163536 7001_ $$aHarms, Matthew B$$b8
000163536 7001_ $$aHoulden, Henry$$b9
000163536 7001_ $$aIacoangeli, Alfredo$$b10
000163536 7001_ $$aKaye, Julia$$b11
000163536 7001_ $$aLima, Leandro$$b12
000163536 7001_ $$aGenomics, Queen Square$$b13$$eCollaboration Author
000163536 7001_ $$aRavits, John$$b14
000163536 7001_ $$aRouleau, Guy A$$b15
000163536 7001_ $$0P:(DE-2719)2812018$$aSchüle, Rebecca$$b16
000163536 7001_ $$0P:(DE-2719)9002275$$aXu, Jishu$$b17$$udzne
000163536 7001_ $$aZüchner, Stephan$$b18
000163536 7001_ $$aCooper-Knock, Johnathan$$b19
000163536 7001_ $$aGan-Or, Ziv$$b20
000163536 7001_ $$aReilly, Mary M$$b21
000163536 7001_ $$aColeman, Michael P$$b22
000163536 773__ $$0PERI:(DE-600)2687154-3$$a10.7554/eLife.70905$$gVol. 10, p. e70905$$pe70905$$teLife$$v10$$x2050-084X$$y2021
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