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

Published

Conference Paper

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.

Full Text

Duke Authors

Cited Authors

  • Lennox, AL; Hoye, ML; Jiang, R; Johnson-Kerner, BL; Suit, LA; Venkataramanan, S; Sheehan, CJ; Alsina, FC; Fregeau, B; Aldinger, KA; Moey, C; Lobach, I; Afenjar, A; Babovic-Vuksanovic, D; Bézieau, S; Blackburn, PR; Bunt, J; Burglen, L; Campeau, PM; Charles, P; Chung, BHY; Cogné, B; Curry, C; D'Agostino, MD; Di Donato, N; Faivre, L; Héron, D; Innes, AM; Isidor, B; Keren, B; Kimball, A; Klee, EW; Kuentz, P; Küry, S; Martin-Coignard, D; Mirzaa, G; Mignot, C; Miyake, N; Matsumoto, N; Fujita, A; Nava, C; Nizon, M; Rodriguez, D; Blok, LS; Thauvin-Robinet, C; Thevenon, J; Vincent, M; Ziegler, A; Dobyns, W; Richards, LJ; Barkovich, AJ; Floor, SN; Silver, DL; Sherr, EH

Published Date

  • May 6, 2020

Published In

Volume / Issue

  • 106 / 3

Start / End Page

  • 404 - 420.e8

PubMed ID

  • 32135084

Pubmed Central ID

  • 32135084

Electronic International Standard Serial Number (EISSN)

  • 1097-4199

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2020.01.042

Conference Location

  • United States