PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

Abstract

De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

Nucleocytoplasmic Transport of RNA-Binding Proteins Regulates Neural Stem Cell Fates 

“…3E). For example, disruption of FMR1 and DDX3X that are involved in RNA metabolisms leads to impaired neurogenesis and is linked to intellectual disability (ID) and cortical malformations (Lennox et al, 2020;Mila et al, 2018;Snijders Blok et al, 2015;Tervonen et al, 2009). Veleva-Rotse and Barnes, 2014).…”

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

“…Affected individuals can have low body weight, hypotonia and/or hypertonia with spasticity, microcephaly, seizures, movement disorders, gait anomalies, and behavioral problems. Brain malformations (e.g., agenesis of the corpus callosum and polymicrogyria) are also common (1, 3, 4).…”

“…DDX3X facilitates the ATP-dependent unwinding of RNA secondary structures. Therefore, it is broadly implicated in RNA metabolism, especially mRNA translation (3, 8–10). DDX3X is located on the X chromosome but it escapes X chromosome inactivation (11, 12).…”

“…Females with DDX3X syndrome carry de novo mutations, either loss-of-function mutations plausibly leading to haploinsufficiency or missense/in-frame mutations (1–3). Genotype-phenotype analyses have shown that missense/in-frame mutations are associated with more severe phenotypes than loss-of-function mutations.…”

“…Genotype-phenotype analyses have shown that missense/in-frame mutations are associated with more severe phenotypes than loss-of-function mutations. For example, polymicrogyria has not been detected in individuals with loss-of-function mutations but only in a subset of females with missense/in-frame mutations, and this group is more delayed developmentally (3). Only a few affected males—all carrying missense mutations—have been identified (1, 3, 15, 16).…”