Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.

ABSTRACT: De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including DDX3X syndrome and autism spectrum disorder. Amongst ~200 mutations identified to date, half are missense. While DDX3X loss of function is known to impair neural cell fate, how the landscape of missense mutations impacts neurodevelopment is almost entirely unknown. Here, we integrate transcriptomics, proteomics, and live imaging to demonstrate clinically diverse DDX3X missense mutations perturb neural development via distinct cellular and molecular mechanisms. Using mouse primary neural progenitors, we investigate four recurrently mutated DDX3X missense variants, spanning clinically severe (2) to mild (2). While clinically severe mutations impair neurogenesis, mild mutations have only a modest i

SUBMITTER: Mosti F 

PROVIDER: S-EPMC11771946 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature