Browse by author
Lookup NU author(s): Dr James Lambton, Dr Thomas McCorvieORCiD, Professor Bobby McFarlandORCiD, Professor Wyatt YueORCiD, Dr Monika Olahova, Dr Charlotte Alston, Professor Robert TaylorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s).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.
Author(s): Lambton J, Asano S, Huang Y, Suomi F, Eguchi T, Petree C, Huang K, Prigent M, Imam A, McCorvie TJ, Warren D, Hobson E, McCullagh H, Misceo D, Bjerre A, Smeland MF, Klingenberg C, Frengen E, Naik S, Ryan G, Sudarsanam A, Foster K, Vasudevan P, Samanta R, Rahman F, Maqbool S, Udani V, Efthymiou S, Houlden H, McFarland R, Collier JJ, Maroofian R, Yue WW, Varshney GK, Klionsky DJ, Legouis R, McWilliams TG, Mizushima N, Olahova M, Alston CL, Taylor RW
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2026
Volume: 113
Issue: 5
Pages: 1090-1107
Print publication date: 07/05/2026
Online publication date: 26/03/2026
Acceptance date: 02/03/2026
Date deposited: 18/05/2026
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2026.03.002
DOI: 10.1016/j.ajhg.2026.03.002
Data Access Statement: 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://www.ncbi.nlm.nih.gov/clinvar/) with the accession numbers SCV007432508, SCV007432509, SCV007432510, SCV007432511, and SCV007432512.
PubMed id: 41895291
Altmetrics provided by Altmetric
