Over 200 genes are associated with autism spectrum disorder (ASD). Chromatin regulators are strongly represented in this list, leading to the suggestion that ASD is largely underpinned by dysregulated gene expression. However, some of these chromatin regulators are known to also modulate tubulin, and previous work from Helen Rankin Willsey and colleagues has implicated mitotic spindle defects in ASD. Here, Willsey and her team focus on the five chromatin regulators most strongly associated with ASD, including CHD2. They find that all five proteins localise to the mitotic spindle in both Xenopus embryos and human cells. By contrast, a missense mutation observed in an individual with ASD leads to failure of CHD2 to localise to the spindle during mitosis, and CHD2 depletion in human neural progenitors results in spindle abnormalities alongside increased cell cycle stalling, DNA damage and cell death. Interrogating protein-protein interaction network datasets from human cells, including neurons, reveals that ASD-associated proteins are enriched in tubulin-associated proteomes. Together, these data are consistent with a role for tubulin biology in ASD pathogenesis and suggest that ASD-associated chromatin regulators can have pleiotropic effects. This latter point illustrates the potential limitations of relying too strongly on gene annotations to infer the molecular mechanisms that underly disease.
