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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
- Source :
- Nature Communications, 9. Nature Publishing Group, Nature Communications, Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.4619. ⟨10.1038/s41467-018-06014-6⟩, Nature Communications, Vol 9, Iss 1, Pp 1-12 (2018), Nature Communications, 9, 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, 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 2018, ' CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language ', Nature Communications, vol. 9, 4619 . https://doi.org/10.1038/s41467-018-06014-6, Nature Communications, 9(1):4619. Nature Publishing Group, Nat. Commun. 9:4619 (2018), Nature Communications, 9:4619. Nature Publishing Group
- Publication Year :
- 2018
-
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.<br />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.
- Subjects :
- 0301 basic medicine
DISORDER
INTELLECTUAL DISABILITY
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
General Physics and Astronomy
EXOME
Language in Interaction
fluids and secretions
0302 clinical medicine
Intellectual disability
Missense mutation
lcsh:Science
Exome
reproductive and urinary physiology
Genetics
Multidisciplinary
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
Phenotype
FAMILY
DEACETYLASE COMPLEX
NURD
medicine.symptom
Neuroinformatics
Science
Biology
DIAGNOSIS
Article
General Biochemistry, Genetics and Molecular Biology
Chromatin remodeling
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
mental disorders
medicine
CHROMATIN REMODELING COMPLEX
Gene
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
Macrocephaly
Helicase
General Chemistry
medicine.disease
GENE
030104 developmental biology
[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
DE-NOVO MUTATIONS
biology.protein
lcsh:Q
Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications, 9. Nature Publishing Group, Nature Communications, Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.4619. ⟨10.1038/s41467-018-06014-6⟩, Nature Communications, Vol 9, Iss 1, Pp 1-12 (2018), Nature Communications, 9, 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, 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 2018, ' CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language ', Nature Communications, vol. 9, 4619 . https://doi.org/10.1038/s41467-018-06014-6, Nature Communications, 9(1):4619. Nature Publishing Group, Nat. Commun. 9:4619 (2018), Nature Communications, 9:4619. Nature Publishing Group
- Accession number :
- edsair.doi.dedup.....325d5a18f088fcfe443dd33cf44f0b27