In:
Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-11-05)
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
2041-1723
DOI:
10.1038/s41467-018-06014-6
Sprache:
Englisch
Verlag:
Springer Science and Business Media LLC
Publikationsdatum:
2018
ZDB Id:
2553671-0
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