Fiche publication
Date publication
février 2020
Journal
Neuron
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
,
Pr THAUVIN-ROBINET Christel
,
Pr KUENTZ Paul
Tous les auteurs :
Lennox AL, Hoye ML, Jiang R, Johnson-Kerner BL, Suit LA, Venkataramanan S, Sheehan CJ, Alsina FC, Fregeau B, Aldinger KA, Moey C, Lobach I, Afenjar A, Babovic-Vuksanovic D, Bézieau S, Blackburn PR, Bunt J, Burglen L, Campeau PM, Charles P, Chung BHY, Cogné B, Curry C, D'Agostino MD, Di Donato N, Faivre L, Héron D, Innes AM, Isidor B, Keren B, Kimball A, Klee EW, Kuentz P, Küry S, Martin-Coignard D, Mirzaa G, Mignot C, Miyake N, Matsumoto N, Fujita A, Nava C, Nizon M, Rodriguez D, Blok LS, Thauvin-Robinet C, Thevenon J, Vincent M, Ziegler A, Dobyns W, Richards LJ, Barkovich AJ, Floor SN, Silver DL, Sherr EH
Lien Pubmed
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.
Mots clés
DDX3X, autism, corpus callosum, cortical development, helicase, intellectual disability, polymicrogyria, radial glial progenitor, stress granule, translation
Référence
Neuron. 2020 Feb 28;:
