Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder

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.

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Journal
The American Journal of Human Genetics
Published
2026-03-01
DOI
https://doi.org/10.1016/j.ajhg.2026.03.002
Primary Topic
Cellular transport and secretion
Type
article
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article

Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder

Gavin Ryan, Wyatt W. Yue, Gaurav K. Varshney, Fumi Suomi et al.
The American Journal of Human Genetics
Cellular transport and secretion
article

Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder

Gavin Ryan, Wyatt W. Yue, Gaurav K. Varshney, Fumi Suomi, Annapurna Sudarsanam, Pradeep Vasudevan, Thomas J. McCorvie, Tomoya Eguchi, Shotaro Asano, Fatima Rahman, Magali Prigent, Rajib Samanta, Anna Bjerre, Eirik Frengen, Helen McCullagh, Monika Oláhová, Marie Falkenberg Smeland, Vrajesh Udani, Jack J. Collier, Robert McFarland, Renaud Legouis, Charlotte L. Alston, Thomas G. McWilliams, Aliza Imam, Daniel Warren, Doriana Misceo, Cassidy Petree, Katherine Foster, Claus Klingenberg, James Lambton, Emma Hobson, Stephanie Efthymiou, Shazia Maqbool, Reza Maroofian, Henry Houlden, Kevin Huang, Robert W. Taylor, Daniel J. Klionsky, Swati Naik, Yuxiang Huang, Noboru Mizushima
article en

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.

The American Journal of Human Genetics
Oslo University Hospital (NO), Centre National de la Recherche Scientifique (FR), University Hospital of North Norway (NO), University of Helsinki (FI), Inserm (FR), University of Oslo (NO), University of Cambridge (GB), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University of Michigan (US), Chapel Allerton Hospital (GB), Leeds Teaching Hospitals NHS Trust (GB), P. D. Hinduja Hospital and Medical Research Centre (IN), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), University Hospitals of Leicester NHS Trust (GB), University of Health Sciences Lahore (PK), Oklahoma Medical Research Foundation (US), Northumbria University (GB), Birmingham Women's Hospital (GB), Birmingham Children's Hospital (GB), Institut de Biologie Intégrative de la Cellule (FR), Bai Jerbai Wadia Hospital for Children (IN), CEA Paris-Saclay (FR), Institute for Molecular Medicine Finland (FI), Wellcome Centre for Mitochondrial Research (GB), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), The University of Tokyo (JP), Newcastle University (GB)
Openalex Percentile: Top 8%
Cellular transport and secretion
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