UCSF

Mutations in DDX3X are associated with autism spectrum disorder, brain malformations, and epilepsy, and account for up to 3% of cases of females with unexplained intellectual disability. However, little is currently known about the molecular mechanism linking DDX3X mutations to neurodevelopmental disease. DDX3X encodes an RNA helicase of the DEAD-box protein family and has been implicated in many aspects of RNA metabolism, yet we still lack a mechanistic understanding of DDX3X’s role in these processes, as well as how patient mutations in DDX3X affect RNA metabolism.

To address this gap in knowledge of understanding of how DDX3X mutations perturb cellular function and contribute to neurodevelopmental disease, this study investigated the mechanism of how DDX3X regulates its target transcripts at the level of mRNA nuclear export, and how pathogenic mutations in DDX3X alter these processes. In addition to DDX3X’s role in translation, DDX3X has been implicated in nuclear mRNA processing, and our preliminary data show that the genes in the mRNA export pathway are genetic interaction partners of DDX3X. However, we still do not understand what the function of DDX3X is in the nucleus or mRNA export. This study aimed to gain a greater understanding the precise mechanism of how DDX3X regulates RNA metabolism both at the level of translation initiation as well as mRNA export. This knowledge is critical for advancing our knowledge of RNA metabolism, as well as understanding and developing treatments for patients with DDX3X syndrome.