Kavli Affiliate: Jeremy Willsey
| Authors: Belinda Wang, Rasika Vartak, Yefim Zaltsman, Zun Zar Chi Naing, Kelsey M Hennick, Benjamin J Polacco, Ali Bashir, Manon Eckhardt, Mehdi Bouhaddou, Jiewei Xu, Nawei Sun, Micaela Lasser, Yuan Zhou, Keelan Z Guiley, Una Chan, Julia A Kaye, Prachi Khare, Sam Drake, Vanessa Drury, David F Burke, Silvano Gonzalez, Sahar Alkhairy, Montana Morris, Tierney Baum, Rebecca Krasnoff, Sheng Wang, Presley Pham, Juan Arbalaez, Dexter Pratt, Shivali Chag, Thomas Rolland, Thomas Bourgeron, Steven Finkbeiner, Sourav Bandyopadhay, Trey Ideker, Pedro Beltrao, Helen Rankin Willsey, Kirsten Obernier, Tomasz J Nowakowski, Ruth Huttenhain, Matthew W State, A. Jeremy Willsey and Nevan J Krogan
| Summary:
Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.