Warning: This is a preliminary report that has not been peer-reviewed. It should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

Wang B, Vartak R, Zaltsman Y, Naing ZZC, Hennick KM, Polacco BJ, Bashir A, Eckhardt M, Bouhaddou M, Xu J, Sun N, Lasser M, Zhou Y, Guiley KZ, Chan U, Kaye JA, Khare P, Drake S, Drury V, Burke DF, Gonzalez S, Alkhairy S, Morris M, Baum T, Krasnoff R, Wang S, Pham P, Arbalaez J, Pratt D, Chag S, Rolland T, Bourgeron T, Finkbeiner S, Bandyopadhay S, Ideker T, Beltrao P, Willsey HR, Obernier K, Nowakowski TJ, Huttenhain R, State MW, Willsey AJ, Krogan NJ

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 ...

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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.

Date: Dec. 09, 2023

Status: Preliminary Report

View Source: doi: 10.1101/2023.12.03.569805

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