ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene.

中文翻译：

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ANXA11 基因筛查揭示了与肌萎缩侧索硬化相关的新突变

先前已在肌萎缩侧索硬化 (ALS) 运动神经元疾病中发现 ANXA11 突变。为了确认 ANXA11 突变对 ALS 的贡献，我们分析了从 330 名法国患者（包括 150 名家族性 ALS 索引病例和 180 名散发性 ALS 病例）获得的大型外显子组数据集，从而在 5 名患者中发现了 3 种罕见的 ANXA11 变异。新型 p.L254V 变体与早发性散发性 ALS 相关。新的 p.D40Y 突变和 p.G38R 变异涉及锥体束主要受累和认知能力下降的患者。p.G38R 携带者的神经病理学发现与脊髓内 ALS 典型包涵体的存在、外侧束大量变性和 A 型额颞叶变性相关。这种膜联蛋白 A11 的突变形式在不同的大脑区域和脊髓运动神经元中积累，尽管它在患者淋巴母细胞中的稳定性降低。由于大多数 ANXA11 内含物不与反式反应 DNA 结合蛋白 43 或 p62 沉积物共定位，因此 ANXA11 聚集似乎并不强制触发神经变性，其他参与者/伴侣蛋白可以干预。