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DOI 10.1038/s41467-018-06014-6

Медицинская библиотека · Nature communications · 2018

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

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, 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

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Аннотация

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.

Для цитирования: 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, 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. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.. Nature communications. 2018. DOI: 10.1038/s41467-018-06014-6.

Предметные рубрики MeSH

Adenosine TriphosphatasesChild, PreschoolChromatin Assembly and DisassemblyDNA HelicasesDevelopmental DisabilitiesFemaleGene ExpressionGenotypeHEK293 CellsHumansIntellectual DisabilityLanguage DisordersMaleMegalencephalyMi-2 Nucleosome Remodeling and Deacetylase ComplexModels, MolecularMutation, MissenseNeurodevelopmental DisordersPhenotypeProtein DomainsSpeech DisordersWhole Genome Sequencing
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