UCSF

Agenesis of the corpus callosum (ACC) is one of the of the most common defects of the central nervous system with an incidence of 1/20000-30000 live births, putting it behind only spinal cord defects in terms of prevalence. While many candidate genes have been identified in patients with ACC, only 30% of all cases of ACC with a suspected genetic cause have an identified candidate gene. Patients with ACC rarely have ACC in isolation and usually have other neurologic (epilepsy, intellectual disability, cortical malformations), and neurodevelopmental (autism spectrum disorder, mood disorders) problems as well. Genes implicated in agenesis of the corpus callosum vary wildly from genes implicated in neurogenesis(PAX6, DISC1), axonal targeting and interaction(L1CAM), neuronal specification(SATB2), and neuronal survival. Identifying and characterizing potential genes in ACC gives us insight into neurodevelopment as a whole. My thesis work focused on two genes implicated in agenesis of the corpus callosum whose role in brain development was heretofore unknown, DEAD-box Helicase 3 X-linked (DDX3X), an RNA helicase, and C12ORF57 which we have tentatively named Camkinin a gene which had no previously known function. My work has shown that a subset of missense mutations in DDX3X completely inhibit its RNA helicase activity, which correlates with striking brain anatomy changes and more severe clinical outcomes. I have also reported the first evidence that demonstrates a likely function for the novel protein Camkinin, suggesting that it regulates the kinase CamKIV and through that controls synaptic scaling in excitatory neurons. Thus, through the two arms of my research we were able to further elucidate the brain specific function of these proteins and discover potential therapeutic avenues for patients.