Autism mutations rewire protein interaction networks to drive neurodevelopmental pathology
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.
Authors
- Ali Bashir (ORCID: https://orcid.org/0000-0002-5240-9604)
- Matthew W. State (ORCID: https://orcid.org/0000-0003-1624-8302)
- Yefim Zaltsman (ORCID: https://orcid.org/0000-0002-2979-8197)
- Zun Zar Chi Naing (ORCID: https://orcid.org/0000-0002-6320-5084)
- Sahar Alkhairy (ORCID: https://orcid.org/0000-0003-1457-9802)
- Kirsten Obernier (ORCID: https://orcid.org/0000-0002-4025-1299)
- Anastassia V. Komarova (ORCID: https://orcid.org/0000-0002-9998-8447)
- Paweł Gniewek (ORCID: https://orcid.org/0000-0002-2102-9297)
- Tomasz J. Nowakowski (ORCID: https://orcid.org/0000-0003-2345-4964)
- Nevan J. Krogan (ORCID: https://orcid.org/0000-0003-4902-337X)
- Sourav Bandyopadhyay (ORCID: https://orcid.org/0000-0003-3120-923X)
- Reuben Thomas (ORCID: https://orcid.org/0000-0003-3176-7303)
- Manon Eckhardt (ORCID: https://orcid.org/0000-0001-8143-6129)
- Caroline Demeret (ORCID: https://orcid.org/0000-0002-1103-6805)
- Silvano Gonzalez
- Mélanie Dos Santos (ORCID: https://orcid.org/0000-0001-6501-9675)
- Belinda Wang (ORCID: https://orcid.org/0000-0001-5563-894X)
- Rebecca Krasnoff
- Dexter Pratt (ORCID: https://orcid.org/0000-0002-1471-9513)
- Shawn L. Hervey‐Jumper (ORCID: https://orcid.org/0000-0003-4699-260X)
- Meghan Seyler
- Craig L. Ennis (ORCID: https://orcid.org/0000-0001-6497-0397)
- Kelsey M. Hennick (ORCID: https://orcid.org/0000-0002-6127-2400)
- Keelan Z. Guiley (ORCID: https://orcid.org/0000-0002-8149-4262)
- Justin McKetney (ORCID: https://orcid.org/0000-0002-2405-8288)
- Prachi Khare
- Pedro Beltrão (ORCID: https://orcid.org/0000-0002-2724-7703)
- James S. Fraser (ORCID: https://orcid.org/0000-0002-5080-2859)
- Mehdi Bouhaddou (ORCID: https://orcid.org/0000-0002-9526-1427)
- Lee Spraggon (ORCID: https://orcid.org/0000-0003-3438-4180)
- Vanessa Drury
- Naufa Amirani
- Helen Rankin Willsey (ORCID: https://orcid.org/0000-0001-8404-3291)
- Thomas Rolland (ORCID: https://orcid.org/0000-0001-6468-8391)
- Steven M. Finkbeiner (ORCID: https://orcid.org/0000-0002-3480-394X)
- Reshmi Tognatta (ORCID: https://orcid.org/0000-0001-7460-1843)
- Stephanie Lam
- Yuan Zhou (ORCID: https://orcid.org/0000-0002-1393-5476)
- Rasika Vartak (ORCID: https://orcid.org/0009-0006-7568-7726)
- P Pham (ORCID: https://orcid.org/0000-0003-3328-2836)
- Jiewei Xu (ORCID: https://orcid.org/0000-0002-8647-4172)
- Octavio Castillo (ORCID: https://orcid.org/0009-0002-9396-7140)
- Sam Drake
- Julia Kaye (ORCID: https://orcid.org/0000-0001-7442-0882)
- Benjamin J. Polacco (ORCID: https://orcid.org/0000-0003-1570-9234)
- David F. Burke (ORCID: https://orcid.org/0000-0001-8830-3951)
- Robert Martin
- Sofia Bali (ORCID: https://orcid.org/0000-0002-4046-7081)
- Micaela Lasser (ORCID: https://orcid.org/0000-0002-4737-1197)
- Merve Çakır (ORCID: https://orcid.org/0000-0003-1803-5693)
- Thomas Bourgeron (ORCID: https://orcid.org/0000-0001-8164-9220)
- Ruth Hüttenhain (ORCID: https://orcid.org/0000-0002-0896-5910)
- A. Jeremy Willsey (ORCID: https://orcid.org/0000-0002-9922-3612)
- Danielle L. Swaney (ORCID: https://orcid.org/0000-0001-6119-6084)
- Trey Ideker (ORCID: https://orcid.org/0000-0002-1708-8454)
- Sagnik Middya
- Úna Chan
- Ethel Bader
- Sheng Wang (ORCID: https://orcid.org/0000-0002-1809-3116)
- Martin Gordon (ORCID: https://orcid.org/0009-0009-5253-6505)
- Nadir Mahmood
- Nishant Chadha
- Montana Morris
- Nawei Sun
- George Wang (ORCID: https://orcid.org/0009-0005-7879-3519)
- Juan Arbelaez
- Tierney Baum
- Owen Griffiths
- Maxwell Bennett (ORCID: https://orcid.org/0009-0004-1318-3026)
- Yvonne Lim (ORCID: https://orcid.org/0009-0007-4769-2031)
- Shivali Chag
Institutions
- Centre National de la Recherche Scientifique (FR)
- European Bioinformatics Institute (GB)
- Gladstone Institutes (US)
- Institut Pasteur (FR)
- University of California, San Francisco (US)
- Université Paris Cité (FR)
- Langley Porter Psychiatric Hospital and Clinics (US)
- ETH Zurich (CH)
- University of California San Diego (US)
- Rapt Therapeutics (United States) (US)
- Quantitative BioSciences (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Gènes, synapses et cognition (FR)
- Broad Center (US)
- Taube Koret Center (US)
- Neurological Surgery (US)
Publication Details
- Journal
- Science
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1126/science.ady4523
- Primary Topic
- Bioinformatics and Genomic Networks
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Schmidt Futures
- William K. Bowes, Jr. Foundation
- National Institutes of Health