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Snijders Blok, L.* ; Rousseau, J.* ; Twist, J.* ; Ehresmann, S.* ; Takaku, M.* ; Venselaar, H.* ; Rodan, L.H.* ; Nowak, C.B.* ; Douglas, J.* ; Swoboda, K.J.* ; Steeves, M.A.* ; Sahai, I.* ; Stumpel, C.T.R.M.* ; Stegmann, A.P.A.* ; Wheeler, P.* ; Willing, M.C.* ; Fiala, E.* ; Kochhar, A.* ; Gibson, W.T.* ; Cohen, A.S.A.* ; Agbahovbe, R.* ; Innes, A.M.* ; Au, P.Y.B.* ; Rankin, J.* ; Anderson, I.J.* ; Skinner, S.A.* ; Louie, R.J.* ; Warren, H.E.* ; Afenjar, A.* ; Keren, B.* ; Nava, C.* ; Buratti, J.* ; Isapof, A.* ; Rodriguez, D.* ; Lewandowski, R.* ; Propst, J.* ; van Essen, T.* ; Choi, M.* ; Lee, S.* ; Chae, J.H.* ; Price, S.* ; Schnur, R.E.* ; Douglas, G.* ; Wentzensen, I.M.* ; Zweier, C.* ; Reis, A.* ; Bialer, M.G.* ; Moore, C.* ; Koopmans, M.* ; Brilstra, E.H.* ; Monroe, G.R.* ; van Gassen, K.L.I.* ; van Binsbergen, E.* ; Newbury-Ecob, R.* ; Bownass, L.* ; Bader, I.* ; Mayr, J.A.* ; Wortmann, S.B. ; Jakielski, K.J.* ; Strand, E.A.* ; Kloth, K.* ; Bierhals, T.* ; Roberts, J.D.* ; Petrovich, R.M.* ; Machida, S.* ; Kurumizaka, H.* ; Lelieveld, S.* ; Pfundt, R.* ; Jansen, S.* ; Deriziotis, P.* ; Faive, L.* ; Thevenon, J.* ; Assoum, M.* ; Shriberg, L.* ; Kleefstra, T.* ; Brunner, H.G.* ; Wade, P.A.* ; Fisher, S.E.* ; Campeau, P.M.*

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

Nat. Commun. 9:4619 (2018)
Publ. Version/Full Text Research data DOI
Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords De-novo Mutations; Chromatin Remodeling Complex; Intellectual Disability; Deacetylase Complex; Exome; Disorder; Family; Gene; Nurd; Diagnosis
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 9, Issue: 1, Pages: , Article Number: 4619 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed