6533b826fe1ef96bd1283cb0
RESEARCH PRODUCT
Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development.
Dominique Martin-coignardSébastien KüryBenjamin CognéLot Snijders BlokPatrick R. BlackburnMathilde NizonDiana RodriguezChing MoeyBethany L. Johnson-kernerNoriko MiyakePhilippe M. CampeauDelphine HéronElliott H. SherrNataliya Di DonatoIryna LobachDusica Babovic-vuksanovicCaroline NavaAlexandra AfenjarA. Micheil InnesRuiji JiangNaomichi MatsumotoStéphane BézieauAmy S. KimballMarie VincentJens BuntKimberly A. AldingerChristel Thauvin-robinetJulien ThevenonStephen N. FloorBrian H.y. ChungAlban ZieglerMaria Daniela D'agostinoGhayda M. MirzaaGhayda M. MirzaaPaul KuentzLaurence FaivreCyril MignotWilliam B. DobynsWilliam B. DobynsBoris KerenBrieana FregeauLindsey SuitLydie BurglenMariah L. HoyeAtsushi FujitaDebra L. SilverCharles J. SheehanA. James BarkovichFernando C. AlsinaSrivats VenkataramananBertrand IsidorPerrine CharlesEric W. KleeLinda J. RichardsAshley L. LennoxCynthia J. Currysubject
0301 basic medicineMaleNeurogenesisMutation MissenseBiologyPathogenesisDEAD-box RNA Helicases03 medical and health sciencesMice0302 clinical medicineGermline mutationStress granuleCell Line TumorPolymicrogyriamedicineMissense mutationAnimalsHumansCells CulturedGeneticsCerebral CortexGeneral NeuroscienceNeurogenesismedicine.diseaseRNA Helicase AMice Inbred C57BL030104 developmental biologyNeurodevelopmental DisordersRNAFemaleDDX3X030217 neurology & neurosurgerydescription
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 = 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-05-01 | Neuron |