Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2020-05, Vol.106 (3), p.404-420.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Discovery of 107 mutations in the RNA helicase DDX3X causing cortical malformations•Clinical severity is linked to reduced helicase activity and RNA-protein granules•Ddx3x is required in neural progenitors to produce cortical neurons during development•Severe missense mutations cause polymicrogyria and impair translation of targets Using human and mouse genetics, Lennox et al. identify 107 mutations in DDX3X, demonstrating DDX3X is essential for cortical development. A striking correlation between the severity of clinical mutations and abnormal RNA metabolism highlights unappreciated mechanisms of DDX3X syndrome.