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Autism mutations rewire protein interaction networks to drive neurodevelopmental pathology

ABSTRACT: Systematic mapping of protein-protein interaction (PPI) networks and determining how causal mutations rewire them in autism spectrum disorder (ASD) provide a powerful framework for uncovering disease mechanisms and therapeutic opportunities. Using affinity purification-mass spectroscopy (AP-MS), we systematically mapped PPIs for 100 high-confidence ASD genes, uncovering over 1,800 interactions. By assessing the impact of pathogenic missense mutations, leveraging AlphaFold, and validating key findings in human-derived model systems, we identify marked convergence onto shared protein complexes in the wild-type state and convergent PPI rewiring driven by independent mutations. For example, distinct patient-derived variants in FOXP1 disrupt its interactions with FOXP4, leading to changes in cortical neurogenesis and neural activity in brain organoids. Overall, these findings link genetic variation to protein networks and convergent neurodevelopmental dysfunction in ASD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285270 | GEO | 2024/12/25

REPOSITORIES: GEO

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A foundational atlas of autism protein interactions reveals molecular convergence [CUT&Tag]

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