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

Ashley L. Lennox, Mariah L. Hoye, Ruiji Jiang, Bethany L. Johnson-Kerner, Lindsey A. Suit, Srivats Venkataramanan, Charles J. Sheehan, Fernando C. Alsina, Brieana Fregeau, Kimberly A. Aldinger, Ching Moey, Iryna Lobach, Alexandra Afenjar, Dusica Babovic-Vuksanovic, Stéphane Bézieau, Patrick R. Blackburn, Jens Bunt, Lydie Burglen, Philippe M. Campeau, Perrine CharlesBrian H.Y. Chung, Benjamin Cogné, Cynthia Curry, Maria Daniela D'Agostino, Nataliya Di Donato, Laurence Faivre, Delphine Héron, A. Micheil Innes, Bertrand Isidor, Boris Keren, Amy Kimball, Eric W. Klee, Paul Kuentz, Sébastien Küry, Dominique Martin-Coignard, Ghayda Mirzaa, Cyril Mignot, Noriko Miyake, Naomichi Matsumoto, Atsushi Fujita, Caroline Nava, Mathilde Nizon, Diana Rodriguez, Lot Snijders Blok, Christel Thauvin-Robinet, Julien Thevenon, Marie Vincent, Alban Ziegler, William Dobyns, Linda J. Richards, A. James Barkovich, Stephen N. Floor, Debra L. Silver, Elliott H. Sherr

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)404-420.e8
JournalNeuron
Volume106
Issue number3
DOIs
StatePublished - May 6 2020

Keywords

  • DDX3X
  • autism
  • corpus callosum
  • cortical development
  • helicase
  • intellectual disability
  • polymicrogyria
  • radial glial progenitor
  • stress granule
  • translation

ASJC Scopus subject areas

  • Neuroscience(all)

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