Authors
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 Charles, Brian HY 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
Publication date
2020/5/6
Journal
Neuron
Volume
106
Issue
3
Pages
404-420. e8
Publisher
Elsevier
Description
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 …
Scholar articles
AL Lennox, ML Hoye, R Jiang, BL Johnson-Kerner… - Neuron, 2020