Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder - PubMed
7 hours ago
- #Autophagy
- #ATG12
- #Neurodevelopmental Disorder
- The study reports six individuals from five families with bi-allelic ATG12 variants, leading to a neurodevelopmental disorder with symptoms including developmental delay, intellectual disability, congenital ataxia, hypotonia, and seizures.
- Structural modeling suggests ATG12 variants disrupt the ATG12-ATG5-ATG16N-ATG3 complex, and biochemical analyses in fibroblasts and HeLa cells show loss of ATG12-ATG5 conjugate and reduced autophagic flux.
- Complementation studies in yeast indicate missense ATG12 variants fail to fully restore autophagy defects, and zebrafish models confirm ATG12's role in growth, brain development, and neural function.
- The findings highlight autophagy's critical role in neural integrity, identify a new congenital autophagy disorder, and expand knowledge of adaptive homeostasis in human health and disease.