John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
Menelaos Pipis
Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, United Kingdom
Mehrdad A Estiar
Department of Human Genetics, McGill University, Montreal, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada
Ammar Al-Chalabi
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Neurology, King's College Hospital, King’s College London, London, United Kingdom
Matt C Danzi
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States
Kristel R van Eijk
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Stephen A Goutman
Department of Neurology, University of Michigan, Ann Arbor, United States
Matthew B Harms
Institute for Genomic Medicine, Columbia University, New York, United States
Henry Houlden
Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, United Kingdom
Alfredo Iacoangeli
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom
Julia Kaye
Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, United States
Leandro Lima
Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, United States; Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, United States
Queen Square Genomics
Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, United Kingdom
John Ravits
Department of Neurosciences, University of California, San Diego, La Jolla, United States
Guy A Rouleau
Department of Human Genetics, McGill University, Montreal, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
Rebecca Schüle
Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany
Jishu Xu
Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany
Stephan Züchner
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States
Johnathan Cooper-Knock
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
Ziv Gan-Or
Department of Human Genetics, McGill University, Montreal, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
Mary M Reilly
Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, United Kingdom
Michael P Coleman
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
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.
