학술논문
CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
Document Type
Original Paper
Author
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; Anderson, Ilse J.; Skinner, Steven A.; Louie, Raymond J.; Warren, Hannah E.; 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 H.; Price, Susan; Schnur, Rhonda E.; Douglas, Ganka; Wentzensen, Ingrid M.; Zweier, Christiane; Reis, André; Bialer, Martin G.; Moore, Christine; Koopmans, Marije; Brilstra, Eva H.; Monroe, Glen R.; van Gassen, Koen L. I.; van Binsbergen, Ellen; Newbury-Ecob, Ruth; Bownass, Lucy; Bader, Ingrid; Mayr, Johannes A.; Wortmann, Saskia B.; Jakielski, Kathy J.; Strand, Edythe A.; Kloth, Katja; Bierhals, Tatjana; The DDD study; Roberts, John D.; Petrovich, Robert M.; Machida, Shinichi; Kurumizaka, Hitoshi; Lelieveld, Stefan; Pfundt, Rolph; Jansen, Sandra; Deriziotis, Pelagia; Faivre, Laurence; Thevenon, Julien; Assoum, Mirna; Shriberg, Lawrence; Kleefstra, Tjitske; Brunner, Han G.; Wade, Paul A.; Fisher, Simon E.; Campeau, Philippe M.
Source
Nature Communications. 9(1)
Subject
Language
English
ISSN
2041-1723
Abstract
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.
Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.
Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.