Autism mutations rewire protein interaction networks to drive neurodevelopmental pathology.

Authors

Belinda Wang, Rasika Vartak, Kelsey M Hennick, Yefim Zaltsman, Zun Zar Chi Naing, Benjamin J Polacco, Ali Bashir, Manon Eckhardt, Mehdi Bouhaddou, Jiewei Xu, Nawei Sun, Micaela C Lasser, Yuan Zhou, Justin McKetney, Keelan Z Guiley, Pawel Gniewek, Una Chan, Naufa Amirani, Owen Griffiths, Nishant Chadha, Reshmi Tognatta, Merve Cakir, Martin Gordon, Prachi Khare, Sam Drake, Vanessa Drury, David F Burke, Silvano Gonzalez, Sahar Alkhairy, Reuben Thomas, Stephanie Lam, Montana Morris, Ethel Bader, Mélanie Dos Santos, Anastassia V Komarova, Maxwell Bennett, Craig Ennis, Octavio Castillo, Yvonne Lim, Robert Martin, Meghan Seyler, Tierney Baum, Rebecca Krasnoff, George Wang, Sagnik Middya, Sheng Wang, Presley Pham, Juan Arbelaez, Dexter Pratt, Sofia Bali, Shivali Chag, Julia A Kaye, Nadir Mahmood, Lee Spraggon, Thomas Rolland, Shawn Hervey-Jumper, James S Fraser, Thomas Bourgeron, Steven Finkbeiner, Caroline Demeret, Danielle L Swaney, Sourav Bandyopadhyay, Trey Ideker, Pedro Beltrao, Helen Rankin Willsey, Ruth Hüttenhain, Kirsten Obernier, Tomasz J Nowakowski, Matthew W State, A Jeremy Willsey, Nevan J Krogan

Published in

Science (New York, N.Y.). Volume 393. Issue 6814. Pages eady4523. Aug 27, 2026. Epub Aug 27, 2026.

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
Bibliographic data and abstract were imported from PubMed on 28 Aug 2026.

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