Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development.
DDX3X
autism
corpus callosum
cortical development
helicase
intellectual disability
polymicrogyria
radial glial progenitor
stress granule
translation
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
06 05 2020
06 05 2020
Historique:
received:
10
05
2018
revised:
05
11
2019
accepted:
29
01
2020
pubmed:
7
3
2020
medline:
25
8
2020
entrez:
6
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32135084
pii: S0896-6273(20)30099-4
doi: 10.1016/j.neuron.2020.01.042
pmc: PMC7331285
mid: NIHMS1572732
pii:
doi:
Substances chimiques
RNA
63231-63-0
DDX3X protein, human
EC 3.6.1.-
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
404-420.e8Subventions
Organisme : NINDS NIH HHS
ID : R21 NS098176
Pays : United States
Organisme : NIGMS NIH HHS
ID : DP2 GM132932
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007184
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007618
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS112566
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS110388
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS050375
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083897
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS093762
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS058721
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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