Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans
| Autor: | Monika Oláhová, Michel Koenig, Hessa S Alsaif, Selina Reich, Claire Guissart, Silvia Azzarello-Burri, Ludger Schöls, Anita Rauch, Tuomo M Polvikoski, Pierre Meyer, Matthis Synofzik, Jack J Collier, Nicolas Leboucq, Fumi Suomi, François Rivier, Mina Ryten, Nuria Martinez-Lopez, Lise Larrieu, Suad Alyamani, Fowzan S Alkuraya, Angela Bahr, Souphatta Sasorith, Stephan Zuchner, Angela Pyle, Charu Deshpande, Inês A Barbosa, David Zhang, Andrew M. Schaefer, Thomas G McWilliams, Florence Piron-Prunier, Robert McFarland, Agnès Delahodde, Robert W. Taylor |
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| Přispěvatelé: | Newcastle University [Newcastle], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University College of London [London] (UCL), Albert Einstein College of Medicine [New York], Universität Zürich [Zürich] = University of Zurich (UZH), University of Tübingen, University of Miami Leonard M. Miller School of Medicine (UMMSM), King‘s College London, Guy's and St Thomas' Hospital [London], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
metabolism [Muscle Skeletal] Developmental Disabilities [SDV]Life Sciences [q-bio] medicine.disease_cause Autophagy-Related Protein 7 physiology [Autophagy-Related Protein 7] pathology [Muscle Skeletal] 0302 clinical medicine genetics [Nervous System Malformations] Cerebellum Missense mutation ComputingMilieux_MISCELLANEOUS Cells Cultured 0303 health sciences Mutation Atg7 protein human General Medicine genetics [Ataxia] Phenotype 3. Good health Cell biology genetics [Developmental Disabilities] Pedigree Female Intracellular Adult Adolescent genetics [Autophagy] physiology [Autophagy] Mutation Missense Genes Recessive Nervous System Malformations genetics [Abnormalities Multiple] 03 medical and health sciences genetics [Autophagy-Related Protein 7] medicine Autophagy Humans Abnormalities Multiple Computer Simulation ddc:610 Muscle Skeletal Gene 030304 developmental biology abnormalities [Face] business.industry Infant Fibroblasts Embryonic stem cell abnormalities [Cerebellum] Face Ataxia Perinatal lethal business 030217 neurology & neurosurgery |
| Zdroj: | The New England journal of medicine 384(25), 2406-2417 (2021). doi:10.1056/NEJMoa1915722 New England Journal of Medicine New England Journal of Medicine, 2021, 384 (25), pp.2406-2417. ⟨10.1056/NEJMoa1915722⟩ New England Journal of Medicine, Massachusetts Medical Society, 2021, 384 (25), pp.2406-2417. ⟨10.1056/NEJMoa1915722⟩ |
| ISSN: | 0028-4793 1533-4406 |
| DOI: | 10.1056/NEJMoa1915722 |
| Popis: | 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.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.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.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.). |
| Databáze: | OpenAIRE |
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