Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder
Year: 2026
Type: article
Abstract: Autophagy is an essential developmental and homeostatic process, defined by the endolysosomal degradation of intracellular components and pathogens. Dysfunctional autophagy is implicated in complex human disease, yet reports of congenital autophagy disorders were considered exceedingly rare until the recent report of several unrelated families with bi-allelic variants in the core autophagy effector ATG7, complementing the report of two individuals harboring ATG5 variants. We now report six affected individuals from five families with bi-allelic ATG12 variants with complex neurological phenotypes overlapping those seen in individuals with pathogenic variants in ATG5 and ATG7: developmental delay, intellectual disability, congenital ataxia, hypotonia, and seizures with cerebellar vermis hypoplasia evident on neuroradiological imaging. Structural modeling implicated a potential disruption of the ATG12-ATG5-ATG16N-ATG3 complex. Biochemical analyses of primary fibroblasts confirmed the loss of stable ATG12-ATG5 conjugate in one family and altered autophagic flux in one unrelated family. The HaloTag processing assay in HeLa cells demonstrated a decrease in ATG12-ATG5 conjugate and reduced autophagic flux in response to starvation. Complementation studies demonstrated that equivalent missense atg12 variants were unable to fully recover the biochemical defect in atg12-null yeast, with microscopy analysis demonstrating a reduced delivery of autophagy substrates to the yeast's degradative compartment. Zebrafish studies confirmed that Atg12 is required for normal growth, brain development, and neural function. Collectively, our findings underscore the pivotal role of autophagy in maintaining human neural integrity, emphasize an emerging group of congenital autophagy disorders, and expand our understanding of adaptive homeostasis in human health and disease.
Authors: James Lambton, Shotaro Asano, Yuxiang Huang, Fumi Suomi, Tomoya Eguchi, Cassidy Petree, Kevin Huang, Magali Prigent, Aliza Imam, Thomas J. McCorvie, Daniel Warren, Emma Hobson, Helen McCullagh, Doriana Misceo, Anna Bjerre, Marie F. Smeland, Claus Klingenberg, Eirik Frengen, Swati Naik, Gavin Ryan, Annapurna Sudarsanam, Katherine Foster, Pradeep Vasudevan, Rajib Samanta, Fatima Rahman, Shazia Maqbool, Vrajesh Udani, Stephanie Efthymiou, Henry Houlden, Robert McFarland, Jack J. Collier, Reza Maroofian, Wyatt W. Yue, Gaurav K. Varshney, Daniel J. Klionsky, Renaud Legouis, Thomas G. McWilliams, Noboru Mizushima, Monika Oláhová, Charlotte L. Alston, Robert W. Taylor
Institutions: Newcastle University, The University of Tokyo, University of Michigan, University of Helsinki, Oklahoma Medical Research Foundation, Centre National de la Recherche Scientifique, Inserm, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut de Biologie Intégrative de la Cellule, CEA Paris-Saclay, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Oslo University Hospital, University of Oslo, University Hospital of North Norway, UiT The Arctic University of Norway, Birmingham Women's Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham Children's Hospital, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, University of Child Health Sciences, P. D. Hinduja Hospital and Medical Research Centre, Bai Jerbai Wadia Hospital for Children, UCL Queen Square Institute of Neurology, University College London, Newcastle upon Tyne Hospitals NHS Foundation Trust, University of Cambridge, International Research Center for Neurointelligence, The University of Tokyo, Northumbria University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,150
Funders: Fight for Sight, Helsingin Yliopisto, LifeArc, National Institute for Health and Care Research, Pathological Society of Great Britain and Ireland, Academy of Medical Sciences, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Academy of Finland, Newcastle upon Tyne Hospitals NHS Foundation Trust, Jane ja Aatos Erkon Säätiö, Päivikki ja Sakari Sohlbergin Säätiö, Turun Yliopisto, Anders Jahres Fond til Vitenskapens Fremme, Sigrid Juséliuksen Säätiö, Nanjing Agricultural University, Novo Nordisk Fonden, Mito Foundation, Lily Foundation, National Institutes of Health, Helsinki Institute of Life Science, Helsingin Yliopisto, Medical Research Council, Japan Society for the Promotion of Science, NIHR Newcastle Biomedical Research Centre, Inserm Transfert, National Institute of General Medical Sciences, Office of Research Infrastructure Programs, National Institutes of Health
Awards: Research on intracellular degradation focusing on membranous structures, Development of scalable methods for rapid phenotyping and functional testing of variants, Pleiotropic disorders of mitochondrial translation, Deciphering the autophagy related and unrelated functions of Atg8 repertoire in C. elegans, Can muscle biopsy be avoided for paediatric patients with suspected mitochondrial disease?, G5099844066, The mechanism and regulation of autophagy, G914789958
OpenAlex ID: W7140479934