Autism Genes Converge on the Same Protein Partners, a New Map Finds

Researchers at the University of California, San Francisco have mapped the protein partners of 100 genes strongly associated with autism spectrum disorder and report more than 1,800 interactions among them, in a paper published Aug. 27 in Science.

The map was built with affinity purification-mass spectrometry, a method that pulls a target protein out of cells along with whatever is bound to it, the paper states.

Two patterns are reported. In the unmutated state, proteins made by different autism genes converged on shared complexes, so that products of genes with no obvious link sit in the same molecular assemblies. Independent mutations in different genes then rewired those interactions in similar ways, which the authors call convergent rewiring.

The researchers assessed the effect of pathogenic missense mutations (single-letter changes in a protein's sequence) and used the structure-prediction system AlphaFold, according to the paper. Key findings were checked in human-derived model systems.

The worked case is FOXP1. Distinct variants carried by patients disrupt FOXP1's interaction with a related protein, FOXP4, the authors report. That disruption changed cortical neurogenesis, the production of new nerve cells, and neural activity in brain organoids, which are clusters of human brain cells grown in a dish rather than tissue from a person.

The paper says the findings "link genetic variation to protein networks and convergent neurodevelopmental dysfunction in ASD," and describes systematic interaction mapping as "a powerful framework for uncovering disease mechanisms and therapeutic opportunities."