Journal
NEURON
Volume 106, Issue 3, Pages 404-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2020.01.042
Keywords
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Categories
Funding
- NIH [R01NS083897, R21NS098176, R01NS110388, F31NS0933762]
- Regeneration Next Initiative Postdoctoral Fellowship, NIH [F32NS112566, 1R01NS058721, 5R01NS050375, R25]
- DDX3X Foundation
- National Health and Medical Research Council, Australia [GNT1126153]
- NHMRC [GNT1120615]
- UCSF Program for Breakthrough Biomedical Research - Sandler Foundation, California Tobacco-Related Disease Research Grants Program [27KT-0003, NIH DP2GM132932]
- Dandy-Walker Alliance
- HUGODIMS Consortium - French Ministry of Health [RC14_0107]
- Health Regional Agency from Poitou-Charentes
- Health Regional Agency of Poitou-Charentes
- Holland-Trice Foundation
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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 = 107), 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 neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and high-light aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.
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