We studied individuals with mutations in CHD3. They tended to have a delayed development, especially their language development, and later on various degrees of intellectual disability. Some characteristics were in common between many individuals, such as a larger head, a flat facial profile, eyes more set apart, joint laxity and hernias. We studied the effect of the mutations in vitro. Several decreased the ability of CHD3 to remodel nucleosomes, while others had no in vitro effect or in fact increased the activity.
We defined the clinical characteristics of individuals with dysfunctional CHD3, thus allowing us to better know this genetic condition, and also allowing us to start to understand what happens in the cells and eventually in the neurons of such individuals.
We will now try to understand what are the consequences of this CHD3 dysregulation on gene expression and regulation in neurons, and we will continue expanding the phenotypic spectrum of this condition.Dr. Philippe M Campeau, MD, FCCMG
Nat Commun 2018 11 5;9(1):4619. Epub 2018 Nov 5.
CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
Link to publicationChromatin 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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