- Affinity purification mass spectrometry mapped PPIs for 100 high-confidence ASD genes, revealing over 1,800 protein interactions.
- Pathogenic missense mutations cause convergent rewiring of PPIs, affecting shared protein complexes across independent mutations.
- Patient-derived FOXP1 variants disrupt FOXP4 interactions, altering cortical neurogenesis and neural activity in human brain organoids.
Science. 2026 Aug 27;393(6814):eady4523. doi: 10.1126/science.ady4523. Epub 2026 Aug 27.
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 spectrometry, we systematically mapped PPIs for 100 high-confidence ASD genes, uncovering more than 1800 interactions. By assessing the impact of pathogenic missense mutations, leveraging AlphaFold, and validating key findings in human-derived model systems, we identified 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.
PMID:42658940 | DOI:10.1126/science.ady4523
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