Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development - Sorbonne Université
Journal Articles Neuron Year : 2020

Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

Lydie Burglen
  • Function : Author
Nataliya Di Donato
  • Function : Author
A. Micheil Innes
  • Function : Author
Boris Keren
  • Function : Author
Amy Kimball
  • Function : Author
Eric Klee
  • Function : Author
Paul Kuentz
  • Function : Author
Sébastien Küry
  • Function : Author
Dominique Martin-Coignard
  • Function : Author
Ghayda Mirzaa
  • Function : Author
Noriko Miyake
  • Function : Author
Naomichi Matsumoto
  • Function : Author
Atsushi Fujita
  • Function : Author
Mathilde Nizon
  • Function : Author
Diana Rodriguez
  • Function : Author
Lot Snijders Blok
  • Function : Author
Christel Thauvin-Robinet
  • Function : Author
Julien Thevenon
  • Function : Author
Marie Vincent
  • Function : Author
Alban Ziegler
  • Function : Author
William Dobyns
  • Function : Author
Linda Richards
  • Function : Author
A. James Barkovich
  • Function : Author
Stephen Floor
  • Function : Author
Elliott Sherr
  • Function : Author

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 = 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 highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

Dates and versions

hal-04586582 , version 1 (24-05-2024)

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Cite

Ashley Lennox, Mariah Hoye, Ruiji Jiang, Bethany Johnson-Kerner, Lindsey Suit, et al.. Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. Neuron, 2020, 106 (3), pp.404-420.e8. ⟨10.1016/j.neuron.2020.01.042⟩. ⟨hal-04586582⟩
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