CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.
Nat Commun
; 9(1): 4619, 2018 11 05.
Article
em En
| MEDLINE
| ID: mdl-30397230
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Distúrbios da Fala
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Deficiências do Desenvolvimento
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DNA Helicases
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Mutação de Sentido Incorreto
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Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase
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Megalencefalia
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Transtornos do Neurodesenvolvimento
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Domínios Proteicos
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Transtornos da Linguagem
Limite:
Child, preschool
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article