2. Academic Validation
  3. Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans

Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans

  • N Engl J Med. 2021 Jun 24;384(25):2406-2417. doi: 10.1056/NEJMoa1915722.
Jack J Collier 1,  Claire Guissart 1,  Monika Oláhová 1,  Souphatta Sasorith 1,  Florence Piron-Prunier 1,  Fumi Suomi 1,  David Zhang 1,  Nuria Martinez-Lopez 1,  Nicolas Leboucq 1,  Angela Bahr 1,  Silvia Azzarello-Burri 1,  Selina Reich 1,  Ludger Schöls 1,  Tuomo M Polvikoski 1,  Pierre Meyer 1,  Lise Larrieu 1,  Andrew M Schaefer 1,  Hessa S Alsaif 1,  Suad Alyamani 1,  Stephan Zuchner 1,  Inês A Barbosa 1,  Charu Deshpande 1,  Angela Pyle 1,  Anita Rauch 1,  Matthis Synofzik 1,  Fowzan S Alkuraya 1,  François Rivier 1,  Mina Ryten 1,  Robert McFarland 1,  Agnès Delahodde 1,  Thomas G McWilliams 1,  Michel Koenig 1,  Robert W Taylor 1
Affiliations

Affiliation

  • 1 From the Wellcome Centre for Mitochondrial Research, (J.J.C., M.O., N.M.-L., A.M.S., A.P., R.M., R.W.T.), the Translational and Clinical Research Institute (J.J.C, M.O., T.M.P., A.M.S., A.P., R.M., R.W.T.), and the NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children (A.M.S., R.M., R.W.T.), Newcastle University, Newcastle Upon Tyne, and the Institute of Child Health, Department of Molecular Neuroscience, University College London Institute of Neurology (D.Z., M.R.), the Division of Genetics and Molecular Medicine, Guy's Hospital, King's College London School of Medicine (I.A.B.), and the Clinical Genetics Unit, Guy's and St. Thomas' NHS Foundation Trust (C.D.), London - all in the United Kingdom; Institut Universitaire de Recherche Clinique and Laboratoire de Génétique Moléculaire, University of Montpellier and Centre Hospitalier Universitaire (CHU) de Montpellier (C.G., S.S., L.L., M.K.), Departments of Neuroradiology (N.L.) and Pediatric Neurology (P.M., F.R.) and Reference Center for Neuromuscular Diseases Atlantic-Occitania-Caribbean (AOC) (P.M., F.R.), CHU de Montpellier, and Laboratoire de Physiologie et Médecine Expérimentale du Cœur et des Muscles (PhyMedExp), INSERM, CNRS, University of Montpellier (P.M., F.R.), Montpellier, and the Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Alternative Energies and Atomic Energy Commission (CEA), CNRS Gif-sur-Yvette (F.P.-P., A.D.) - all in France; the Translational Stem Cell Biology and Metabolism Program, Research Programs Unit, and the Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki (F.S., T.G.M.); Radiation Oncology, Albert Einstein College of Medicine, New York (N.M.-L.); the Institute of Medical Genetics, University of Zurich, Zurich, Switzerland (A.B., S.A.-B., A.R.); Hertie Institute for Clinical Brain Research and Center of Neurology, and the German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany (S.R., L.S., M.S.); the Departments of Genetics (H.S.A., F.S.A.) and Neuroscience (S.A.), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and the Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami (S.Z.).
PMID: 34161705 DOI: 10.1056/NEJMoa1915722
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.).

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