Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

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Author Name

Ashley L. Lennox

Ruiji Jiang

Lindsey Suit

Brieana Fregeau

Ching Moey

Iryna Lobach

Ghayda Mirzaa

Alexandra Afenjar

Jens Bunt

Lydie Burglen

Perrine Charles

Brian H.Y. Chung

Benjamin Cogné

Suzanne DeBrosse

Laurence Faivre

Delphine HĂ©ron

A Micheil Innes

Bertrand Isidor

Boris Keren

Amy Kimball

Eric W Klee

Paul Kuentz

Cyril Mignot

Noriko Miyake

Caroline Nava

Mathilde Nizon

Diana Rodriguez

Lot Snijders Blok

Julien Thevenon

Marie Vincent

Alban Ziegler

William Dobyns

Linda J Richards

Stephen N. Floor

Debra L. Silver

Elliott H. Sherr

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Published in Neuron, 2020-03-04

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=78), 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 neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

Genetics 59 Projects
Ddx3X 1 Project
Helicase 1 Project
Radial Glial
Radial Glial 1 Project
Progenitor 1 Project
Cortical Development
Cortical Development 2 Projects
Migration 1 Project
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Stress Granule 1 Project
Polymicrogyria 1 Project