期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06014-6
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资金
- Netherlands Organization for Scientific Research (NWO) Gravitation Grant [24.001.006]
- Max Planck Society
- National Institute on Deafness and Other Communication Disorders Grant [DC000496]
- National Institute of Child Health and Human Development [U54 HD090256]
- Canadian Institutes of Health Research [MOP-119595, PJT-148830]
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome Trust
- Department of Health
- Wellcome Trust Sanger Institute [WT098051, GEN/284/12]
- National Institute for Health Research through Comprehensive Clinical Research Network
- Cambridge South REC [10/H0305/83]
- Republic of Ireland REC [GEN/284/12]
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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