Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development
Ashley Lennox
(1)
,
Mariah Hoye
(1)
,
Ruiji Jiang
(2)
,
Bethany Johnson-Kerner
(2)
,
Lindsey Suit
(2)
,
Srivats Venkataramanan
(2)
,
Charles Sheehan
(1)
,
Fernando Alsina
(1)
,
Brieana Fregeau
(2)
,
Kimberly Aldinger
(3)
,
Ching Moey
(4)
,
Iryna Lobach
(2)
,
Alexandra Afenjar
(5)
,
Dusica Babovic-Vuksanovic
(6)
,
Stéphane Bézieau
(7)
,
Patrick Blackburn
(6)
,
Jens Bunt
(4)
,
Lydie Burglen
(5)
,
Philippe Campeau
(8)
,
Perrine Charles
(9, 5)
,
Brian H.Y. Chung
(10)
,
Benjamin Cogné
(7)
,
Cynthia Curry
(2)
,
Maria Daniela D’agostino
(11)
,
Nataliya Di Donato
,
Laurence Faivre
(12)
,
Delphine Héron
(13)
,
A. Micheil Innes
,
Bertrand Isidor
(7)
,
Boris Keren
,
Amy Kimball
,
Eric Klee
,
Paul Kuentz
,
Sébastien Küry
,
Dominique Martin-Coignard
,
Ghayda Mirzaa
,
Cyril Mignot
(13)
,
Noriko Miyake
,
Naomichi Matsumoto
,
Atsushi Fujita
,
Caroline Nava
(13)
,
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
(1)
,
Elliott Sherr
1
Duke University Medical Center
2 UC San Francisco - University of California [San Francisco]
3 Seattle Children’s Hospital
4 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
5 Hôpital Trousseau
6 Mayo Clinic [Rochester]
7 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
8 CHU Sainte Justine [Montréal]
9 CHU Pitié-Salpêtrière [AP-HP]
10 HKU - The University of Hong Kong
11 McGill University = Université McGill [Montréal, Canada]
12 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
13 ICM - Institut du Cerveau = Paris Brain Institute
2 UC San Francisco - University of California [San Francisco]
3 Seattle Children’s Hospital
4 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
5 Hôpital Trousseau
6 Mayo Clinic [Rochester]
7 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
8 CHU Sainte Justine [Montréal]
9 CHU Pitié-Salpêtrière [AP-HP]
10 HKU - The University of Hong Kong
11 McGill University = Université McGill [Montréal, Canada]
12 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
13 ICM - Institut du Cerveau = Paris Brain Institute
Perrine Charles
- Function : Author
- PersonId : 1364656
- ORCID : 0000-0002-3108-2171
- IdRef : 09424524X
Nataliya Di Donato
- Function : Author
A. Micheil Innes
- Function : Author
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
Noriko Miyake
- Function : Author
Naomichi Matsumoto
- Function : Author
Atsushi Fujita
- Function : Author
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
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.