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Snijders Blok, Lot; Rousseau, Justine; Twist, Joanna; Ehresmann, Sophie; Takaku, Motoki; Venselaar, Hanka; Rodan, Lance H.; Nowak, Catherine B.; Douglas, Jessica; Swoboda, Kathryn J.; Steeves, Marcie A.; Sahai, Inderneel; Stumpel, Connie T. R. M.; Stegmann, Alexander P. A.; Wheeler, Patricia; Willing, Marcia; Fiala, Elise; Kochhar, Aaina; Gibson, William T.; Cohen, Ana S. A.; Agbahovbe, Ruky; Innes, A. Micheil; Au, P. Y. Billie; Rankin, Julia; [...]

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

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  • Medientyp: E-Artikel
  • Titel: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
  • Beteiligte: Snijders Blok, Lot; Rousseau, Justine; Twist, Joanna; Ehresmann, Sophie; Takaku, Motoki; Venselaar, Hanka; Rodan, Lance H.; Nowak, Catherine B.; Douglas, Jessica; Swoboda, Kathryn J.; Steeves, Marcie A.; Sahai, Inderneel; Stumpel, Connie T. R. M.; Stegmann, Alexander P. A.; Wheeler, Patricia; Willing, Marcia; Fiala, Elise; Kochhar, Aaina; Gibson, William T.; Cohen, Ana S. A.; Agbahovbe, Ruky; Innes, A. Micheil; Au, P. Y. Billie; Rankin, Julia; [...]
  • Erschienen: Springer Science and Business Media LLC, 2018
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-018-06014-6
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>CHD3</jats:italic>, 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 <jats:italic>CHD3</jats:italic> 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 <jats:italic>CHD3</jats:italic> mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.</jats:p>
  • Zugangsstatus: Freier Zugang