327: Bi-allelic ATG12 variants impair ATG12-ATG5 conjugation, LC3 lipidation and neural development

Lambton J et al., The American Journal of Human Genetics - Bi-allelic ATG12 variants disrupt ATG12‑ATG5 conjugation and LC3 lipidation, impairing autophagy in patient cells and model systems and causing cerebellar vermis hypoplasia. Key terms: ATG12, autophagy, neurodevelopmental disorder, zebrafish, LC3 lipidation.

Study Highlights:
The study characterized six affected individuals with bi-allelic ATG12 variants using patient fibroblasts, HeLa ATG12 knockout complementation, yeast complementation, and CRISPR zebrafish models. Methods included WES/WGS and Sanger sequencing, immunoblotting, LC3/p62 flux assays, HaloTag-LC3 processing, LDH sequestration, AlphaFold-Multimer structural modeling, yeast GFP-Atg8 assays, and zebrafish behavioral and imaging assays. Structural modeling and biochemical data indicate variants map to ATG12 interfaces with ATG5 and ATG3, destabilize ATG12 or its conjugate with ATG5, reduce LC3/Atg8 lipidation and autophagic flux in a variant-dependent manner. Functionally, ATG12 disruption associates with neurodevelopmental phenotypes including cerebellar vermis hypoplasia, ataxia and seizures in humans, and causes growth, brain-structure and locomotor defects with reduced survival in zebrafish.

Conclusion:
Bi-allelic ATG12 variants impair ATG12 function and autophagy, producing a recessive neurodevelopmental disorder marked by cerebellar vermis hypoplasia and neurological deficits.

Music:
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Article title:
Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder

First author:
Lambton J

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.03.002

Reference:
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, Oláhová M, Alston CL, Taylor RW. Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder. The American Journal of Human Genetics. 2026 May 7;113:1–18. https://doi.org/10.1016/j.ajhg.2026.03.002

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content from the transcript, focusing on the patient cohort, molecular mechanism (ATG12-ATG5 conjugation, LC3 lipidation), structural modeling, model organisms (yeast, zebrafish), and neurological phenotype.
- transcript topics: Bi-allelic ATG12 variants and patient cohort; ATG12-ATG5 conjugation and LC3 lipidation; AlphaFold/structural modeling of ATG12 interactions; Yeast and zebrafish functional assays; Cerebellar involvement and mitophagy; Therapeutic implications of autophagy modulation

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- c...

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