Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans.

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. (Funded by the Wellcome Centre for Mitochondrial Research and others.).

• Authors: Jack J Collier, Claire Guissart, Monika Oláhová, Souphatta Sasorith, Florence Piron-Prunier, Fumi Suomi, David Zhang, Nuria Martinez-Lopez, Nicolas Leboucq, Angela Bahr, Silvia Azzarello-Burri, Selina Reich, Ludger Schöls, Tuomo M Polvikoski, Pierre Meyer, Lise Larrieu, Andrew M Schaefer, Hessa S Alsaif, Suad Alyamani, Stephan Zuchner, Inês A Barbosa, Charu Deshpande, Angela Pyle, Anita Rauch, Matthis Synofzik, Fowzan S Alkuraya, François Rivier, Mina Ryten, Robert McFarland, Agnès Delahodde, Thomas G McWilliams, Michel Koenig, Robert W Taylor
• Journal: The New England journal of medicine (N Engl J Med) Vol. 384 Issue 25 Pg. 2406-2417 (06 24 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 34161705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Massachusetts Medical Society.

Chemical References

• ATG7 protein, human
• Autophagy-Related Protein 7

Topics

• Abnormalities, Multiple (genetics)
• Adolescent
• Adult
• Ataxia (genetics)
• Autophagy (genetics, physiology)
• Autophagy-Related Protein 7 (genetics, physiology)
• Cells, Cultured
• Cerebellum (abnormalities)
• Computer Simulation
• Developmental Disabilities (genetics)
• Face (abnormalities)
• Female
• Fibroblasts
• Genes, Recessive
• Humans
• Infant
• Male
• Muscle, Skeletal (metabolism, pathology)
• Mutation, Missense
• Nervous System Malformations (genetics)
• Pedigree
• Phenotype