Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder.
Overview
and 21 other authors
Annapurna Sudarsanam20, Katherine Foster21, Pradeep Vasudevan22, Rajib Samanta23, Fatima Rahman24, Shazia Maqbool24, Vrajesh Udani25,26, Stephanie Efthymiou27, Henry Houlden27, Robert McFarland1,28, Jack J. Collier29, Reza Maroofian27, Wyatt W. Yue11, Gaurav K. Varshney7, Daniel J. Klionsky3, Renaud Legouis7,8, Thomas G. McWilliams4,5, Noboru Mizushima2,30, Monika Oláhová1,31, Charlotte L. Alston1,28, Robert W. Taylor1,2831 affiliations
- Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Department of Molecular, Cellular and Developmental Biology, and Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Translational Stem Cell Biology & Metabolism Program, Research Programs Unit, University of Helsinki, 00290 Helsinki, Finland
- Department of Anatomy, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
- Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRS, 91198 Gif-sur-Yvette, France
- INSERM U1280, 91198 Gif-sur-Yvette, France
- Leeds Clinical Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK
- Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK
- Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway
- Department for Specialised Paediatrics, Oslo University Hospital, 0450 Oslo, Norway
- Department of Paediatric Rehabilitation, University Hospital of North Norway, 9019 Tromsø, Norway
- Research Group for Child and Adolescent Health, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
- Department of Paediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway
- West Midlands Clinical Genetics Unit, Birmingham Women’s and Children’s Hospital, Birmingham B15 2TG, UK
- Department of Neurology, Birmingham Women’s and Children’s Hospital, Birmingham B15 2TG, UK
- Department of Radiology, Birmingham Children’s Hospital, Birmingham B4 6NH, UK
- Department of Clinical Genetics, University Hospitals Leicester NHS Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK
- Department of Paediatric Neurology, University Hospitals Leicester NHS Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK
- Department of Developmental-Behavioral Pediatrics, The Children’s Hospital and University of Child Health Sciences, Lahore, Pakistan
- P.D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai 400 016, India
- Bai Jerbai Wadia Hospital for Children, Acharya Donde Marg, Parel, Mumbai 400012, India
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
- NHS Highly Specialised Rare Mitochondrial Disorders Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
- Department of Clinical Neuroscience, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Tokyo, Japan
- School of Geography and Natural Sciences, Faculty of Science and Environment, Northumbria University, Newcastle upon Tyne NE1 8SG, UK
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.
The paper's code and data availability statement is in the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.
Data
No dataset and no data link were found in the paper.
Data and code availability
The exome datasets supporting this study have not been deposited in a public repository because of ethical restrictions but are available upon reasonable request. The ATG12 variants identified have been submitted to ClinVar (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 41 authors, 5 keywords, 18 MeSH terms, 22 funders, 57 references, 1 RRID.
Cite
This paper
Lambton, J., Asano, S., Huang, Y., Suomi, F., Eguchi, T., Petree, C., Huang, K., Prigent, M., Imam, A., McCorvie, T. J., Warren, D., Hobson, E., McCullagh, H., Misceo, D., Bjerre, A., Smeland, M. F., Klingenberg, C., Frengen, E., Naik, S., . . . Taylor, R. W. (2026). Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder. American journal of human genetics, 113(5), 1090-1107. https://
BibTeX
@article{lambton2026bi,
author = {Lambton, James and Asano, Shotaro and Huang, Yuxiang and Suomi, Fumi and Eguchi, Tomoya and Petree, Cassidy and Huang, Kevin and Prigent, Magali and Imam, Aliza and McCorvie, Thomas J. and Warren, Daniel and Hobson, Emma and McCullagh, Helen and Misceo, Doriana and Bjerre, Anna and Smeland, Marie F. and Klingenberg, Claus and Frengen, Eirik and Naik, Swati and Ryan, Gavin and Sudarsanam, Annapurna and Foster, Katherine and Vasudevan, Pradeep and Samanta, Rajib and Rahman, Fatima and Maqbool, Shazia and Udani, Vrajesh and Efthymiou, Stephanie and Houlden, Henry and McFarland, Robert and Collier, Jack J. and Maroofian, Reza and Yue, Wyatt W. and Varshney, Gaurav K. and Klionsky, Daniel J. and Legouis, Renaud and McWilliams, Thomas G. and Mizushima, Noboru and Oláhová, Monika and Alston, Charlotte L. and Taylor, Robert W.},
title = {{Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder}},
journal = {American journal of human genetics},
year = {2026},
month = mar,
volume = {113},
number = {5},
pages = {1090--1107},
publisher = {Elsevier},
issn = {0002-9297},
doi = {10.1016/
url = {https://
pmid = {41895291},
pmcid = {PMC13277686}
}
RIS
TY - JOUR
AU - Lambton, James
AU - Asano, Shotaro
AU - Huang, Yuxiang
AU - Suomi, Fumi
AU - Eguchi, Tomoya
AU - Petree, Cassidy
AU - Huang, Kevin
AU - Prigent, Magali
AU - Imam, Aliza
AU - McCorvie, Thomas J.
AU - Warren, Daniel
AU - Hobson, Emma
AU - McCullagh, Helen
AU - Misceo, Doriana
AU - Bjerre, Anna
AU - Smeland, Marie F.
AU - Klingenberg, Claus
AU - Frengen, Eirik
AU - Naik, Swati
AU - Ryan, Gavin
AU - Sudarsanam, Annapurna
AU - Foster, Katherine
AU - Vasudevan, Pradeep
AU - Samanta, Rajib
AU - Rahman, Fatima
AU - Maqbool, Shazia
AU - Udani, Vrajesh
AU - Efthymiou, Stephanie
AU - Houlden, Henry
AU - McFarland, Robert
AU - Collier, Jack J.
AU - Maroofian, Reza
AU - Yue, Wyatt W.
AU - Varshney, Gaurav K.
AU - Klionsky, Daniel J.
AU - Legouis, Renaud
AU - McWilliams, Thomas G.
AU - Mizushima, Noboru
AU - Oláhová, Monika
AU - Alston, Charlotte L.
AU - Taylor, Robert W.
TI - Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder
T2 - American journal of human genetics
J2 - Am J Hum Genet
PY - 2026
DA - 2026/
VL - 113
IS - 5
SP - 1090
EP - 1107
SN - 0002-9297
PB - Elsevier
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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