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

TitlePathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development
Authors
Keywordscortical development
corpus callosum
DDX3X
helicase
intellectual disability
Issue Date2020
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/neuron
Citation
Neuron, 2020, Epub 2020-03-01, v. 106, p. 1-17 How to Cite?
AbstractDe 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.
Persistent Identifierhttp://hdl.handle.net/10722/281700
ISSN
2019 Impact Factor: 14.415
2015 SCImago Journal Rankings: 11.464

 

DC FieldValueLanguage
dc.contributor.authorLennox, AL-
dc.contributor.authorHoye, ML-
dc.contributor.authorJiang, R-
dc.contributor.authorJohnson-Kerner, BL-
dc.contributor.authorSuit, LA-
dc.contributor.authorVenkataramanan, S-
dc.contributor.authorSheehan, CJ-
dc.contributor.authorAlsina, FC-
dc.contributor.authorFregeau, B-
dc.contributor.authorAldinger, KA-
dc.contributor.authorMoey, C-
dc.contributor.authorLobach, I-
dc.contributor.authorAfenjar, A-
dc.contributor.authorBabovic-Vuksanovic, D-
dc.contributor.authorBezieau, S-
dc.contributor.authorBlackburn, PR-
dc.contributor.authorBunt, J-
dc.contributor.authorBurglen, L-
dc.contributor.authorCampeau, PM-
dc.contributor.authorCharles, P-
dc.contributor.authorChung, BHY-
dc.contributor.authorCogne, B-
dc.contributor.authorCurry, C-
dc.contributor.authorD'Agostino, MD-
dc.contributor.authorDi Donato, N-
dc.contributor.authorFaivre, L-
dc.contributor.authorHeron, D-
dc.contributor.authorInnes, AM-
dc.contributor.authorIsidor, B-
dc.contributor.authorKeren, B-
dc.contributor.authorKimball, A-
dc.contributor.authorKlee, EW-
dc.contributor.authorKuentz, P-
dc.contributor.authorKury, S-
dc.contributor.authorMartin-Coignard, D-
dc.contributor.authorMirzaa, G-
dc.contributor.authorMignot, C-
dc.contributor.authorMyake, N-
dc.contributor.authorMatsumoto, N-
dc.contributor.authorFujita, A-
dc.contributor.authorNava, C-
dc.contributor.authorNizon, M-
dc.contributor.authorRodriguez, D-
dc.contributor.authorBlok, LS-
dc.contributor.authorThauvin-Robinet, C-
dc.contributor.authorThevenon, J-
dc.contributor.authorVincent, M-
dc.contributor.authorZiegler, A-
dc.contributor.authorDobyns, W-
dc.contributor.authorRichards, LJ-
dc.contributor.authorBarkovich, AJ-
dc.contributor.authorFloor, SN-
dc.contributor.authorSilver, DL-
dc.contributor.authorSherr, EH-
dc.date.accessioned2020-03-22T04:18:29Z-
dc.date.available2020-03-22T04:18:29Z-
dc.date.issued2020-
dc.identifier.citationNeuron, 2020, Epub 2020-03-01, v. 106, p. 1-17-
dc.identifier.issn0896-6273-
dc.identifier.urihttp://hdl.handle.net/10722/281700-
dc.description.abstractDe 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.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/neuron-
dc.relation.ispartofNeuron-
dc.subjectcortical development-
dc.subjectcorpus callosum-
dc.subjectDDX3X-
dc.subjecthelicase-
dc.subjectintellectual disability-
dc.titlePathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.neuron.2020.01.042-
dc.identifier.hkuros309464-
dc.identifier.volumeEpub 2020-03-01, v. 106-
dc.identifier.spage1-
dc.identifier.epage17-
dc.publisher.placeUnited States-

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