英国纽卡斯尔大学Robert W. Taylor团队研究了ATG7介导的自噬缺陷对人类发育的影响。2021年6月23日出版的《新英格兰医学杂志》发表了这项成果。

自噬是哺乳动物细胞内的主要降解途径。小鼠核心自噬相关（ATG）基因的系统性消融导致胚胎或围产期死亡，条件模型显示神经退行性变。自噬功能受损与一系列复杂的人类疾病有关，但先天性的自噬障碍非常罕见。

研究组对5个家庭进行了遗传、临床和神经影像学分析。使用患者来源的成纤维细胞、骨骼肌活检标本、小鼠胚胎成纤维细胞和酵母进行了机制研究。

研究人员在人类ATG7中发现了有害的隐性变异，ATG7是一个与自噬相关的核心基因，其编码的蛋白质对经典的降解自噬不可或缺。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、胼胝体异常及不同程度的面部畸形。

ATG7蛋白减少或缺失导致自噬通量受损，这些患者才得以存活。虽然自噬隔离明显减少，但在ATG7缺失的成纤维细胞和骨骼肌中很容易发现基础自噬的证据。与野生型ATG7的再引入相比，由有害ATG7变异引起的不同模型系统的互补导致自噬功能较差或缺失。

综上，研究组发现几名患有神经发育障碍的幸存者ATG7严重缺失或完全缺失。ATG7是一种自噬的必要效应酶，且没有已知的功能类似物。

附：英文原文

Title: Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans

Author: Jack J. Collier, Ph.D.,, Claire Guissart, Pharm.D.,, Monika Oláhová, Ph.D.,, Souphatta Sasorith, Ph.D.,, Florence Piron-Prunier, M.Sc.,, Fumi Suomi, Ph.D.,, David Zhang, M.Sc.,, Nuria Martinez-Lopez, Ph.D.,, Nicolas Leboucq, M.D.,, Angela Bahr, Ph.D.,, Silvia Azzarello-Burri, M.D.,, Selina Reich, M.Sc.,, Ludger Schls, M.D.,, Tuomo M. Polvikoski, Ph.D.,, Pierre Meyer, M.D.,, Lise Larrieu, M.Sc.,, Andrew M. Schaefer, M.R.C.P.,, Hessa S. Alsaif, B.Sc.,, Suad Alyamani, M.D.,, Stephan Zuchner, Ph.D.,, Inês A. Barbosa, Ph.D.,, Charu Deshpande, F.R.C.P.,, Angela Pyle, Ph.D.,, Anita Rauch, M.D.,, Matthis Synofzik, M.D.,, Fowzan S. Alkuraya, M.D.,, Franois Rivier, M.D.,, Mina Ryten, Ph.D.,, Robert McFarland, Ph.D.,, Agnès Delahodde, Ph.D.,, Thomas G. McWilliams, Ph.D.,, Michel Koenig, M.D.,, and Robert W. Taylor, Ph.D.

Issue&Volume: 2021-06-23

Abstract:

BACKGROUND

Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare.

METHODS

We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle–biopsy specimens, mouse embryonic fibroblasts, and yeast.

RESULTS

We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7.

CONCLUSIONS

We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue.

DOI: 10.1056/NEJMoa1915722

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1915722