Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

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 un...

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Published inbioRxiv
Main Authors Lennox, Ashley L, Jiang, Ruiji, Suit, Lindsey, Fregeau, Brieana, Sheehan, Charles J, Aldinger, Kimberly A, Moey, Ching, Lobach, Iryna, Mirzaa, Ghayda, Afenjar, Alexandra, Babovic-Vuksanovic, Dusica, St phane B zieau, Blackburn, Patrick R, Bunt, Jens, Burglen, Lydie, Perrine, Charles, Chung, Brian Hy, Benjamin Cogn, Debrosse, Suzanne, Nataliya Di Donato, Faivre, Laurence, Delphine H ron, Innes, A Micheil, Bertrand Isidor, Johnson-Kerner, Bethany L, Keren, Boris, Kimball, Amy, Klee, Eric W, Kuentz, Paul, S bastien K ry, Martin-Coignard, Dominique, Mignot, Cyril, Miyake, Noriko, Nava, Caroline, Nizon, Mathilde, Rodriguez, Diana, Lot Snijders Blok, Thauvin, Christel, Thevenon, Julien, Vincent, Marie, Ziegler, Alban, Dobyns, William, Richards, Linda J, Barkovich, A James, Floor, Stephen N, Silver, Debra L, Sherr, Elliott H
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.05.2018
Subjects
Autism
Cortex
DNA helicase
Epilepsy
Fetuses
Missense mutation
Molecular modelling
Mutation
Neural stem cells
Neurodevelopmental disorders
Neurogenesis
Polymicrogyria
RNA helicase
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Summary: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.
DOI:10.1101/317974