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

Ashley Lennox; Mariah Hoye; Ruiji Jiang; Bethany Johnson-Kerner; Lindsey Suit; Srivats Venkataramanan; Charles Sheehan; Fernando Alsina; Brieana Fregeau; Kimberly Aldinger; Ching Moey; Iryna Lobach; Alexandra Afenjar; Dusica Babovic-Vuksanovic; Stéphane Bézieau; Patrick Blackburn; Jens Bunt; Lydie Burglen; Philippe Campeau; Perrine Charles; Brian H.Y. Chung; Benjamin Cogné; Cynthia Curry; Maria Daniela D’agostino; Nataliya Di Donato; Laurence Faivre; Delphine Héron; A. Micheil Innes; Bertrand Isidor; Boris Keren; Amy Kimball; Eric Klee; Paul Kuentz; Sébastien Küry; Dominique Martin-Coignard; Ghayda Mirzaa; Cyril Mignot; Noriko Miyake; Naomichi Matsumoto; Atsushi Fujita; Caroline Nava; Mathilde Nizon; Diana Rodriguez; Lot Snijders Blok; Christel Thauvin-Robinet; Julien Thevenon; Marie Vincent; Alban Ziegler; William Dobyns; Linda Richards; A. James Barkovich; Stephen Floor; Debra Silver; Elliott Sherr

doi:10.1016/j.neuron.2020.01.042

Journal Articles Neuron Year : 2020

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

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Ashley Lennox

Function : Author

Duke University Medical Center

Mariah Hoye

Function : Author

Duke University Medical Center

Ruiji Jiang

Function : Author

University of California [San Francisco]

Bethany Johnson-Kerner

Function : Author

University of California [San Francisco]

Lindsey Suit

Function : Author

University of California [San Francisco]

Srivats Venkataramanan

Function : Author

University of California [San Francisco]

Charles Sheehan

Function : Author

Duke University Medical Center

Fernando Alsina

Function : Author

Duke University Medical Center

Brieana Fregeau

Function : Author

University of California [San Francisco]

Kimberly Aldinger

Function : Author

Seattle Children’s Hospital

Ching Moey

Function : Author

The University of Queensland

Iryna Lobach

Function : Author

University of California [San Francisco]

Alexandra Afenjar

Function : Author

Hôpital Trousseau

Dusica Babovic-Vuksanovic

Function : Author

Mayo Clinic [Rochester]

Stéphane Bézieau

Function : Author

Centre Hospitalier Universitaire de Nantes = Nantes University Hospital

Patrick Blackburn

Function : Author

Mayo Clinic [Rochester]

Jens Bunt

Function : Author

The University of Queensland

Lydie Burglen

Function : Author

Hôpital Trousseau

Philippe Campeau

Function : Author

CHU Sainte Justine [Montréal]

Perrine Charles

Function : Author
PersonId : 1364656
ORCID : 0000-0002-3108-2171
IdRef : 09424524X

CHU Pitié-Salpêtrière [AP-HP]

Hôpital Trousseau

Brian H.Y. Chung

Function : Author

The University of Hong Kong

Benjamin Cogné

Function : Author

Centre Hospitalier Universitaire de Nantes = Nantes University Hospital

Cynthia Curry

Function : Author

University of California [San Francisco]

Maria Daniela D’agostino

Function : Author

McGill University = Université McGill [Montréal, Canada]

Nataliya Di Donato

Function : Author

Laurence Faivre

Function : Author

Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)

Delphine Héron

Function : Author

Institut du Cerveau = Paris Brain Institute

A. Micheil Innes

Function : Author

Bertrand Isidor

Function : Author

Centre Hospitalier Universitaire de Nantes = Nantes University Hospital

Boris Keren

Function : Author

Amy Kimball

Function : Author

Eric Klee

Function : Author

Paul Kuentz

Function : Author

Sébastien Küry

Function : Author

Dominique Martin-Coignard

Function : Author

Ghayda Mirzaa

Function : Author

Cyril Mignot

Function : Author

Institut du Cerveau = Paris Brain Institute

Noriko Miyake

Function : Author

Naomichi Matsumoto

Function : Author

Atsushi Fujita

Function : Author

Caroline Nava

Function : Author

Institut du Cerveau = Paris Brain Institute

Mathilde Nizon

Function : Author

Diana Rodriguez

Function : Author

Lot Snijders Blok

Function : Author

Christel Thauvin-Robinet

Function : Author

Julien Thevenon

Function : Author

Marie Vincent

Function : Author

Alban Ziegler

Function : Author

William Dobyns

Function : Author

Linda Richards

Function : Author

A. James Barkovich

Function : Author

Stephen Floor

Function : Author

Debra Silver

Function : Author

Duke University Medical Center

Elliott Sherr

Function : Author

Abstract

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.

Keywords

DDX3X autism corpus callosum cortical development helicase intellectual disability polymicrogyria radial glial progenitor stress granule translation.

Domains

Human health and pathology

Gestionnaire HAL 2 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04586582

Submitted on : Friday, May 24, 2024-11:16:58 AM

Last modification on : Thursday, September 5, 2024-10:26:44 AM

Dates and versions

hal-04586582 , version 1 (24-05-2024)

Identifiers

HAL Id : hal-04586582 , version 1
DOI : 10.1016/j.neuron.2020.01.042
PUBMED : 32135084
PUBMEDCENTRAL : PMC7331285

Cite

Ashley Lennox, Mariah Hoye, Ruiji Jiang, Bethany Johnson-Kerner, Lindsey Suit, et al.. Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. Neuron, 2020, 106 (3), pp.404-420.e8. ⟨10.1016/j.neuron.2020.01.042⟩. ⟨hal-04586582⟩

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

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