NEJM:ATG7介导的人类自噬功能缺陷可导致严重的复杂神经发育障碍

2021-06-26 MedSci原创 MedSci原创

研究人员确认了与核心自噬相关基因缺陷有关的严重神经发育障碍,患者ATG7酶活严重缺失或完全缺失

自噬是哺乳动物细胞内主要的降解途径,小鼠核心自噬相关(ATG)基因的系统性消融可导致胚胎或幼体围产期死亡,有模型研究显示ATG异常与神经退行性变异相关。自噬功能损伤与一系列复杂的人类疾病有关,然而先天性自噬障碍却很少见。

近日研究人员对五个复杂神经发育障碍家庭进行了基因、临床和神经影像学分析,并使用患者来源的成纤维细胞、骨骼肌活检标本以及小鼠胚胎成纤维细胞和酵母进行了机制研究

研究人员在人ATG7中发现了有害的隐性变异,ATG7是一个核心自噬相关基因,编码一种对经典的降解性自噬不可或缺的蛋白质。来自5个不同ATG7变异家族的12名患者患有复杂的神经发育障碍,包括大脑、肌肉和内分泌受累。患者有小脑和胼胝体异常,以及不同程度的面部畸形。ATG7蛋白减少或缺失导致自噬通路异常,但患者得以存活。虽然自噬通路受抑制,但在ATG7缺失的成纤维细胞和骨骼肌中发现了基础自噬的证据。与野生型ATG7相比,有害的ATG7变异对不同模型系统的互补导致自噬功能差或缺失。

患有共济失调、发育迟缓和有害的双等位基因ATG7变异家族

研究人员确认了与核心自噬相关基因缺陷有关的严重神经发育障碍,患者ATG7酶活严重缺失或完全缺失

原始出处:

Jack J. Collier et al. Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans. N Engl J Med,June 24,2021.

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    2021-06-28 neurowu
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    2021-06-26 旺医

    顶刊就是顶刊,谢谢梅斯带来这么高水平的研究报道,我们科里同事经常看梅斯,分享梅斯上的信息

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