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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., Competing Interests: JG Part-funded by AstraZeneca during the past 3 years, OJ Currently part-funded by AstraZeneca, MP, ME, AA, MD, Kv, SG, MH, HH, AI, JK, LL, JR, GR, RS, JX, SZ, JC, ZG, MR No competing interests declared, MC Consults for Nura Bio, but no support provided for this work, (© 2021, Gilley et al.)

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Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.

Genetic variation occurring within conserved functional protein domains warrants special attention when examining DNA variation in the context of disease causation. Here we introduce a resource, freely available at www.prot2hg.com, that addresses the question of whether a particular variant falls onto an annotated protein domain and directly translates chromosomal coordinates onto protein residues. The tool can perform a multiple-site query in a simple way, and the whole dataset is available for download as well as incorporated into our own accessible pipeline. To create this resource, National Center for Biotechnology Information protein data were retrieved using the Entrez Programming Utilities. After processing all human protein domains, residue positions were reverse translated and mapped to the reference genome hg19 and stored in a MySQL database. In total, 760 487 protein domains from 42 371 protein models were mapped to hg19 coordinates and made publicly available for search or download (www.prot2hg.com). In addition, this annotation was implemented into the genomics research platform GENESIS in order to query nearly 8000 exomes and genomes of families with rare Mendelian disorders (tgp-foundation.org). When applied to patient genetic data, we found that rare (<1%) variants in the Genome Aggregation Database were significantly more annotated onto a protein domain in comparison to common (>1%) variants. Similarly, variants described as pathogenic or likely pathogenic in ClinVar were more likely to be annotated onto a domain. In addition, we tested a dataset consisting of 60 causal variants in a cohort of patients with epileptic encephalopathy and found that 71% of them (43 variants) were propagated onto protein domains. In summary, we developed a resource that annotates variants in the coding part of the genome onto conserved protein domains in order to increase variant prioritization efficiency., Database URL: www.prot2hg.com., (© The Author(s) 2020. Published by Oxford University Press.)

Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion (DRG) sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.