John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, United Kingdom.
Elife. 2021 Nov 19;10:e70905. doi: 10.7554/eLife.70905.
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 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 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.
SARM1 是一种具有关键 NADase 活性的蛋白质，是轴突退化的保守程序中的核心执行者。我们在肌萎缩侧索硬化症（ALS）或其他运动神经疾病患者中报告了七个罕见的错义或框内微缺失的人类变异等位基因，这些变异改变了 SARM1 自身抑制的 ARM 结构域并持续过度激活 SARM1 NADase 活性。这七种变体的组成型 NADase 活性与缺乏整个 ARM 结构域的 SARM1 相似，甚至在烟酰胺单核苷酸（NMN）存在的情况下，其生理激活剂，其活性大大超过野生型 SARM1 的活性。这种组成型活性的增加本身足以促进神经元退化，而无需其他非有害的轻度应激。重要的是，在研究的队列中，这些强功能获得等位基因完全是患者特异性的，并且在单基因水平上与疾病具有高度显著的相关性。这些与 SARM1 功能改变相关的疾病相关编码变异的发现，以前曾报道过与 ALS 相关的邻近、更常见的内含子单核苷酸多态性（SNP）具有全基因组显著相关性，支持 SARM1 在这些疾病中的作用。这些等位基因的患者表现出广泛的表型异质性和可变的发病年龄，这也提出了关于过度活跃的 SARM1 变体的致病机制的有趣问题。
