Home > Publications Database > Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders. > print

001     163536
005     20230915092422.0
024 7 _ |a 10.7554/eLife.70905
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037 _ _ |a DZNE-2022-00296
041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Gilley, Jonathan
|0 0000-0002-9510-7956
|b 0
245 _ _ |a Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
260 _ _ |a Cambridge
|c 2021
|b eLife Sciences Publications
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 7 |a ALS
|2 Other
650 _ 7 |a NADase
|2 Other
650 _ 7 |a SARM1
|2 Other
650 _ 7 |a genetics
|2 Other
650 _ 7 |a genomics
|2 Other
650 _ 7 |a human
|2 Other
650 _ 7 |a neuroscience
|2 Other
650 _ 7 |a risk allele
|2 Other
650 _ 7 |a Armadillo Domain Proteins
|2 NLM Chemicals
650 _ 7 |a Cytoskeletal Proteins
|2 NLM Chemicals
650 _ 7 |a SARM1 protein, human
|2 NLM Chemicals
650 _ 7 |a Nicotinamide Mononucleotide
|0 1094-61-7
|2 NLM Chemicals
650 _ 7 |a NAD+ Nucleosidase
|0 EC 3.2.2.5
|2 NLM Chemicals
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Alleles
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Armadillo Domain Proteins
|2 MeSH
650 _ 2 |a Cytoskeletal Proteins
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Motor Neuron Disease: genetics
|2 MeSH
650 _ 2 |a Motor Neuron Disease: metabolism
|2 MeSH
650 _ 2 |a NAD+ Nucleosidase: metabolism
|2 MeSH
650 _ 2 |a Nicotinamide Mononucleotide: metabolism
|2 MeSH
700 1 _ |a Jackson, Oscar
|0 0000-0002-1825-9331
|b 1
700 1 _ |a Pipis, Menelaos
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700 1 _ |a Estiar, Mehrdad A
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700 1 _ |a Al-Chalabi, Ammar
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700 1 _ |a Danzi, Matt C
|b 5
700 1 _ |a van Eijk, Kristel R
|b 6
700 1 _ |a Goutman, Stephen A
|b 7
700 1 _ |a Harms, Matthew B
|b 8
700 1 _ |a Houlden, Henry
|b 9
700 1 _ |a Iacoangeli, Alfredo
|b 10
700 1 _ |a Kaye, Julia
|b 11
700 1 _ |a Lima, Leandro
|b 12
700 1 _ |a Genomics, Queen Square
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700 1 _ |a Ravits, John
|b 14
700 1 _ |a Rouleau, Guy A
|b 15
700 1 _ |a Schüle, Rebecca
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700 1 _ |a Xu, Jishu
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700 1 _ |a Züchner, Stephan
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700 1 _ |a Cooper-Knock, Johnathan
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700 1 _ |a Gan-Or, Ziv
|b 20
700 1 _ |a Reilly, Mary M
|b 21
700 1 _ |a Coleman, Michael P
|b 22
773 _ _ |a 10.7554/eLife.70905
|g Vol. 10, p. e70905
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