1. Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development
- Author
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A. Micheil Innes, Iryna Lobach, Ashley L. Lennox, A. James Barkovich, Caroline Nava, Amy S. Kimball, Sébastien Küry, Julien Thevenon, Benjamin Cogné, Marie Vincent, Debra L. Silver, Bertrand Isidor, Alban Ziegler, Paul Kuentz, Delphine Héron, Kimberly A. Aldinger, Dusica Babovic-Vuksanovic, Elliott H. Sherr, Jens Bunt, Ching Moey, Brieana Fregeau, Lindsey Suit, Diana Rodriguez, Ghayda M. Mirzaa, Patrick R. Blackburn, Noriko Miyake, Cyril Mignot, Brian H.Y. Chung, Alexandra Afenjar, Lot Snijders Blok, Mathilde Nizon, Laurence Faivre, Ruiji Jiang, Nataliya Di Donato, Charles J. Sheehan, Christel Thauvin-Robinet, Boris Keren, Perrine Charles, Bethany L. Johnson-Kerner, Dominique Martin-Coignard, Suzanne DeBrosse, Eric W. Klee, Stéphane Bézieau, Linda J. Richards, Lydie Burglen, Stephen N. Floor, and William B. Dobyns
- Subjects
Genetics ,Pathogenesis ,Germline mutation ,Neurogenesis ,Polymicrogyria ,medicine ,Missense mutation ,Translation (biology) ,Biology ,DDX3X ,medicine.disease ,RNA Helicase A - 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.
- Published
- 2018
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