Paper - Review

DOI: 10.1016/j.neuron.2020.01.042

Graphical Abstract

In Brief

1⃣ human 2⃣ mouse genetics
∴ Identify 107 mutations ← in DDX3X
∴ DDX3X is essential → for cortical development

❗: A striking correlation
← between 1⃣ the severity of clinical mutations 2⃣ abnormal RNA metabolism
→ highlights unappreciated mechanisms ← of DDX3X syndrome

Summary

De novo germline mutations ← in the RNA helicase DDX4X
→ account → for < 3% of unexplained intellectual disability cases in females
→ are associated ← with 1⃣ autism 2⃣ brain malformations 3⃣ epilepsy

❓: the developmental & molecular mechanisms
← by which DDX3X mutations impair brain function
→ are unknown

❗: use → 1⃣ (human & mouse) genetics 2⃣ cell (biological & biochemical) approches
→ to elucidate mechanisms
← by which pathogenic DDX3X variants disrupt brain development

❗: report → the largest clinical cohort → to date with DDX3X mutations
∴ a striking correlation
← between 1⃣ recurrent dominant missense mutations 2⃣ polymicrogyria 3⃣ the most severe clinical outcomes

∴ ddx3x → controls cortical development
← by regulating neuron generation

❗: Severe DDX3X missens mutations
→ disrupt RNA helicase activity
→ induce ectopic RNA-protein granules ← in neural progenitors & neurons
→ impair translation

∴ these results
→ uncover key mechanisms ← underlying DDX3X syndrome
→ highlight aberrant RNA metabolism
← in the pathogenesis of neurodevelopmental disease

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