CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.
Nat Commun
; 9(1): 4619, 2018 11 05.
Article
en 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
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Trastornos del Habla
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Discapacidades del Desarrollo
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ADN Helicasas
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Mutación Missense
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Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2
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Megalencefalia
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Trastornos del Neurodesarrollo
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Dominios Proteicos
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Trastornos del Lenguaje
Límite:
Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Países Bajos