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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
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Snijders Blok, Lot; Rousseau, Justine; Twist, Joanna; Ehresmann, Sophie; Takaku, Motoki; Venselaar, Hanka; Rodan, Lance,; Nowak, Catherine,; Douglas, Jessica; Swoboda, Kathryn,; Steeves, Marcie,; Sahai, Inderneel; Stumpel, Connie; Stegmann, Alexander; Wheeler, Patricia; Willing, Marcia; Fiala, Elise; Kochhar, Aaina; Gibson, William,; Cohen, Ana,; Agbahovbe, Ruky; Innes, A. Micheil; Au, P.,; Rankin, Julia; Anderson, Ilse,; Skinner, Steven,; Louie, Raymond,; Warren, Hannah,; Afenjar, Alexandra; Keren, Boris; Nava, Caroline; Buratti, Julien; Isapof, Arnaud; Rodriguez, Diana; Lewandowski, Raymond; Propst, Jennifer; Van Essen, Ton; Choi, Murim; Lee, Sangmoon; Chae, Jong,; Price, Susan; Schnur, Rhonda,; Douglas, Ganka; Wentzensen, Ingrid,; Zweier, Christiane; Reis, André; Bialer, Martin,; Moore, Christine; Koopmans, Marije; Brilstra, Eva; Monroe, Glen,; van Gassen, Koen,; Van Binsbergen, Ellen; Newbury-Ecob, Ruth; Bownass, Lucy; Bader, Ingrid; Mayr, Johannes,; Wortmann, Saskia; Jakielski, Kathy,; Strand, Edythe,; Kloth, Katja; Bierhals, Tatjana; Roberts, John,; Petrovich, Robert,; Machida, Shinichi; Kurumizaka, Hitoshi; Lelieveld, Stefan; Pfundt, Rolph; Jansen, Sandra; Deriziotis, Pelagia; Faive, Laurence; Thevenon, Julien; Assoum, Mirna; Shriberg, Lawrence; Kleefstra, Tjitske; Brunner, Han,; Wade, Paul,; Fisher, Simon; Campeau, Philippe
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In: ISSN: 2041-1723 ; EISSN: 2041-1723 ; Nature Communications ; https://hal.sorbonne-universite.fr/hal-01922858 ; Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.4619. ⟨10.1038/s41467-018-06014-6⟩ (2018)
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Abstract:
International audience ; Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
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Keyword:
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry; [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Molecular Biology/Structural Biology [q-bio.BM]
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URL: https://hal.sorbonne-universite.fr/hal-01922858
https://doi.org/10.1038/s41467-018-06014-6
https://hal.sorbonne-universite.fr/hal-01922858/document
https://hal.sorbonne-universite.fr/hal-01922858/file/s41467-018-06014-6.pdf
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