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Developmental consequences of defective Atg7-mediated autophagy in humans

Lookup NU author(s): Jack Collier, Dr Monika Olahova, Dr Nuria Martinez Lopez, Dr Tuomo Polvikoski, Dr Andrew Schaefer, Dr Angela Pyle, Professor Bobby McFarland, Professor Robert Taylor

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Abstract

Copyright © 2021 Massachusetts Medical Society.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. (Funded by the Wellcome Centre for Mitochondrial Research and others.


Publication metadata

Author(s): Collier JJ, Guissart C, Olahova M, Sasorith S, Piron-Prunier F, Suomi F, Zhang D, Martinez-Lopez N, Leboucq N, Bahr A, Azzarello-Burri S, Reich S, Schols L, Polvikoski TM, Meyer P, Larrieu L, Schaefer AM, Alsaif HS, Alyamani S, Zuchner S, Barbosa IA, Deshpande C, Pyle A, Rauch A, Synofzik M, Alkuraya FS, Rivier F, Ryten M, McFarland R, Delahodde A, McWilliams TG, Koenig M, Taylor RW

Publication type: Article

Publication status: Published

Journal: New England Journal of Medicine

Year: 2021

Volume: 384

Issue: 25

Pages: 2406-2417

Print publication date: 24/06/2021

Acceptance date: 02/04/2018

ISSN (print): 0028-4793

ISSN (electronic): 1533-4406

Publisher: Massachussetts Medical Society

URL: https://doi.org/10.1056/NEJMoa1915722

DOI: 10.1056/NEJMoa1915722


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