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

Ashley L. Lennox; Mariah L. Hoye; Ruiji Jiang; Bethany L. Johnson-Kerner; Lindsey A. Suit; Srivats Venkataramanan; Charles J. Sheehan; Fernando C. Alsina; Brieana Fregeau; Kimberly A. Aldinger; Ching Moey; Iryna Lobach; Alexandra Afenjar; Dusica Babovic-Vuksanovic; Stéphane Bézieau; Patrick R. Blackburn; Jens Bunt; Lydie Burglen; Philippe M. 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 W. 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 J. Richards; A. James Barkovich; Stephen N. Floor; Debra L. Silver; Elliott H. Sherr

doi:10.1016/j.neuron.2020.01.042

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

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

Ashley L. Lennox, Mariah L. Hoye, Ruiji Jiang, Bethany L. Johnson-Kerner, Lindsey A. Suit, Srivats Venkataramanan, Charles J. Sheehan, Fernando C. Alsina, Brieana Fregeau, Kimberly A. Aldinger, …

Neuron (Cambridge, Mass.), Vol.106(3), pp.404-420.e8

06/05/2020

DOI: https://doi.org/10.1016/j.neuron.2020.01.042

PMID: 32135084

Résumé

autism

corpus callosum

cortical development

DDX3X

helicase

intellectual disability

polymicrogyria

radial glial progenitor

stress granule

translation

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.

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Titre: Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development
Créateurs - sans rôle: Ashley L. Lennox - Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Mariah L. Hoye - Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Ruiji Jiang - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Bethany L. Johnson-Kerner - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Lindsey A. Suit - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Srivats Venkataramanan - Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94158, USA
Charles J. Sheehan - Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Fernando C. Alsina - Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Brieana Fregeau - University of California, San Francisco
Kimberly A. Aldinger - Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Ching Moey - The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia
Iryna Lobach - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA
Alexandra Afenjar - Hôpital Armand-Trousseau
Dusica Babovic-Vuksanovic - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Stéphane Bézieau - Université de Nantes
Patrick R. Blackburn - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Jens Bunt - The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia
Lydie Burglen - Hôpital Armand-Trousseau
Philippe M. Campeau - Centre Hospitalier Universitaire Sainte-Justine
Perrine Charles - Sorbonne Université
Brian H.Y. Chung - University of Hong Kong
Benjamin Cogné - Université de Nantes
Cynthia Curry - Genetic Medicine, University of California San Francisco/Fresno, Fresno, CA 93701, USA
Maria Daniela D’Agostino - Division of Medical Genetics, Departments of Specialized Medicine and Human Genetics, McGill University, Montreal, QC, Canada
Nataliya Di Donato - Technische Universität Dresden
Laurence Faivre - Centre de référence Anomalies du Développement et Syndromes Malformatifs, INSERM UMR 1231 GAD, CHU de Dijon et Université de Bourgogne, Dijon, France
Delphine Héron - APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
A. Micheil Innes - University of Calgary
Bertrand Isidor - Université de Nantes
Boris Keren - APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
Amy Kimball - Harvey Institute of Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, USA
Eric W. Klee - Mayo Clinic
Paul Kuentz - Université de Bourgogne
Sébastien Küry - Université de Nantes
Dominique Martin-Coignard - Service de Génétique, Centre hospitalier du Mans, Le Mans, France
Ghayda Mirzaa - Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Cyril Mignot - Sorbonne Université
Noriko Miyake - Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
Naomichi Matsumoto - Yokohama City University
Atsushi Fujita - Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
Caroline Nava - APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
Mathilde Nizon - Université de Nantes
Diana Rodriguez - Hôpital Armand-Trousseau
Lot Snijders Blok - Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
Christel Thauvin-Robinet - Centre de référence Déficience Intellectuelle, INSERM UMR 1231 GAD, CHU de Dijon et Université de Bourgogne, Dijon, France
Julien Thevenon - CHU Dijon Bourgogne
Marie Vincent - Université de Nantes
Alban Ziegler - Service de Génétique, CHU d’Angers, Angers, France
William Dobyns - Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Linda J. Richards - The University of Queensland
A. James Barkovich - University of California, San Francisco
Stephen N. Floor - Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94158, USA
Debra L. Silver - Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Elliott H. Sherr - University of California, San Francisco
Détails de publication: Neuron (Cambridge, Mass.), Vol.106(3), pp.404-420.e8
Éditeur: Elsevier Inc
Identifiants: 99158779509311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article