1. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder
- Author
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Naomi Meeks, Stefan Kindler, Anya Revah-Politi, Alexander P.A. Stegmann, Vinodh Narayanan, Dominique Bonneau, Claudia Schob, Jill A. Rosenfeld, Jennifer E. Posey, Tim M. Strom, LaDonna Immken, Tjitske Kleefstra, Jolanda H. Schieving, Katherine L. Helbig, Estelle Colin, Magalie Barth, Tamar Harel, Matthew J. Huentelman, James R. Lupski, Benjamin Cogné, Han G. Brunner, Yaping Yang, Sébastien Küry, Jenny Morton, Erica H. Gerkes, Keri Ramsey, Marine Tessarech, Zeynep Coban-Akdemir, Shimon Edvardson, Hans-Jürgen Kreienkamp, Nelly Oundjian, Davor Lessel, Christian Kubisch, Thomas Besnard, Jonas Denecke, Orly Elpeleg, Ana M. Claasen, Kelsey Zegar, Mohammad K. Eldomery, Sandra Mercier, Margot R.F. Reijnders, Stéphane Bézieau, Univ Angers, Okina, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Central Nervous System ,Male ,DISRUPTION ,INTELLECTUAL DISABILITY ,Developmental Disabilities ,PROTEIN ,DISEASE ,0302 clinical medicine ,Neurodevelopmental disorder ,Intellectual disability ,Missense mutation ,Global developmental delay ,Amino Acids ,Child ,Genetics (clinical) ,Genetics ,Adenosine Triphosphatases ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Translation (biology) ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,3. Good health ,FAMILY ,Child, Preschool ,Female ,RNA Helicases ,MODULE ,Adolescent ,Mutation, Missense ,RNA GRANULES ,Biology ,Article ,Cell Line ,03 medical and health sciences ,Stress granule ,Cell Line, Tumor ,medicine ,Humans ,HELICASE ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,STRESS GRANULES ,Helicase ,RNA ,Correction ,medicine.disease ,GENE ,030104 developmental biology ,HEK293 Cells ,biology.protein ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Contains fulltext : 182457.pdf (Publisher’s version ) (Open Access) DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.
- Published
- 2017
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