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@ARTICLE{Gilley:163536,
      author       = {Gilley, Jonathan and Jackson, Oscar and Pipis, Menelaos and
                      Estiar, Mehrdad A and Al-Chalabi, Ammar and Danzi, Matt C
                      and van Eijk, Kristel R and Goutman, Stephen A and Harms,
                      Matthew B and Houlden, Henry and Iacoangeli, Alfredo and
                      Kaye, Julia and Lima, Leandro and Ravits, John and Rouleau,
                      Guy A and Schüle, Rebecca and Xu, Jishu and Züchner,
                      Stephan and Cooper-Knock, Johnathan and Gan-Or, Ziv and
                      Reilly, Mary M and Coleman, Michael P},
      collaboration = {Genomics, Queen Square},
      title        = {{E}nrichment of {SARM}1 alleles encoding variants with
                      constitutively hyperactive {NAD}ase in patients with {ALS}
                      and other motor nerve disorders.},
      journal      = {eLife},
      volume       = {10},
      issn         = {2050-084X},
      address      = {Cambridge},
      publisher    = {eLife Sciences Publications},
      reportid     = {DZNE-2022-00296},
      pages        = {e70905},
      year         = {2021},
      abstract     = {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.},
      keywords     = {Adult / Aged / Alleles / Amyotrophic Lateral Sclerosis:
                      genetics / Amyotrophic Lateral Sclerosis: metabolism /
                      Animals / Armadillo Domain Proteins / Cytoskeletal Proteins
                      / Female / Humans / Male / Mice / Middle Aged / Motor Neuron
                      Disease: genetics / Motor Neuron Disease: metabolism / NAD+
                      Nucleosidase: metabolism / Nicotinamide Mononucleotide:
                      metabolism / ALS (Other) / NADase (Other) / SARM1 (Other) /
                      genetics (Other) / genomics (Other) / human (Other) /
                      neuroscience (Other) / risk allele (Other) / Armadillo
                      Domain Proteins (NLM Chemicals) / Cytoskeletal Proteins (NLM
                      Chemicals) / SARM1 protein, human (NLM Chemicals) /
                      Nicotinamide Mononucleotide (NLM Chemicals) / NAD+
                      Nucleosidase (NLM Chemicals)},
      cin          = {AG Maetzler},
      ddc          = {600},
      cid          = {I:(DE-2719)5000024},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34796871},
      pmc          = {pmc:PMC8735862},
      doi          = {10.7554/eLife.70905},
      url          = {https://pub.dzne.de/record/163536},
}