Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small-alpha helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterised the phenotypes induced by a genetic loss of function (LoF) and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human WT Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterised by Lamin B2 mis-localisation. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS+/-FTD patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.

中文翻译：

---

膜联蛋白 A11 突变与体内和人体组织中的核膜功能障碍相关


膜联蛋白 A11 突变是肌萎缩侧索硬化症 (ALS) 的罕见原因，其中复制蛋白变体 P36R、G38R、D40G 和 D40Y 位于长而无序的 N 末端的小 α 螺旋中。为了阐明疾病机制，我们对体内遗传功能丧失 (LoF) 以及 G38R 和 D40G 错误表达诱导的表型进行了表征。膜联蛋白 A11 的缺失会导致斑马鱼纯合敲除幼虫出现低渗透行为表型和异常轴突形态，而人类 WT 膜联蛋白 A11 可以挽救这一现象。膜联蛋白 A11 敲除/下调和 ALS 变体都会引发以核纤层蛋白 B2 错误定位为特征的核功能障碍。 Lamin B2 特征还存在于来自具有 G38R 和 D40G 蛋白变体的死后 ALS+/-FTD 患者组织的前角、脊髓神经元中。这些发现表明突变型膜联蛋白 A11 充当显性失活，揭示了潜在的早期核病，突出了动物模型中行为异常之前的核包膜异常。