Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
复制标题
在ALS和其他运动神经疾病患者中，用组成性多动NADase编码变体的SARM1等位基因富集。
DOI：
10.7554/elife.70905
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发表时间：
2021-11-19
期刊：
影响因子：
7.7
通讯作者：
Coleman MP
中科院分区：
文献类型：
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作者：
Gilley J;Jackson O;Pipis M;Estiar MA;Al-Chalabi A;Danzi MC;van Eijk KR;Goutman SA;Harms MB;Houlden H;Iacoangeli A;Kaye J;Lima L;Queen Square Genomics;Ravits J;Rouleau GA;Schüle R;Xu J;Züchner S;Cooper-Knock J;Gan-Or Z;Reilly MM;Coleman MP
SARM 1是一种具有关键NAD酶活性的蛋白质，是轴突变性保守程序的中心执行者。我们报告了肌萎缩侧索硬化症（ALS）或其他运动神经疾病患者中7种罕见的错义或框内微缺失人类SARM 1变体等位基因，这些等位基因改变SARM 1自抑制ARM结构域并组成性过度激活SARM 1 NAD酶活性。这七种变体的组成型NAD酶活性与缺乏整个ARM结构域的SARM 1相似，并且大大超过野生型SARM 1的活性，即使在存在烟酰胺单核苷酸（NMN）的情况下，其生理激活剂也是如此。这种组成性活动的增加本身就足以促进神经元变性，以响应原本无害的轻度应激。重要的是，这些强功能获得性等位基因在研究的队列中完全是患者特异性的，并且在单基因水平上显示出与疾病的高度显著相关性。这些改变SARM 1功能的疾病相关编码变体的发现建立在先前报道的与ALS的邻近的、更常见的SARM 1基因内单核苷酸多态性（SNP）的全基因组显著关联的基础上，以支持SARM 1在这些疾病中的贡献作用。在具有这些等位基因的患者中，广泛的表型异质性和发病年龄的可变性也引起了关于过度活跃的SARM 1变体的致病机制的有趣问题。
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.