RAC1 is a highly conserved Rho GTPase under strict mutational constraint. We describe patients with novel human disorder caused by germline de novo missense RAC1 mutations resulting in varying degrees of developmental delay, brain malformations, and additional phenotypes (1). Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modelling, mouse fibroblasts spreading assays, and in vivo over-expression assays using zebrafish as a surrogate model demonstrated that the some RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, some variants are constitutively active or their effects are context dependent. Currently we are working to expand the known spectrum of germline RAC1 mutations and improve the understanding of the mechanism of the disease. More recently, other Rho GTPases and their regulators have also been implicated in human neurodevelopmental disorders. Overall, these findings highlight the importance of Rho GTPases in normal human neurodevelopment and disease.
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