CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

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.

Download full-text PDF

Source
http://www.nature.com/articles/s41467-018-06014-6
Publisher Site
http://dx.doi.org/10.1038/s41467-018-06014-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218476PMC
November 2018
436 Reads
10.742 Impact Factor

Publication Analysis

Top Keywords

chromatin remodeling
12
impaired speech
8
novo chd3
8
chd3 mutations
8
alterations chromatin
8
speech language
8
macrocephaly impaired
8
mutations
5
individuals novo
4
mutations overlapping
4
phenotypes mutations
4
domain encoded
4
encoded protein
4
atpase/helicase domain
4
cluster atpase/helicase
4
characterizing individuals
4
mutations cluster
4
overlapping phenotypes
4
approach collecting
4
gain comprehensive
4

References

(Supplied by CrossRef)

CG Marfella et al.
Mutat. Res. 2007

DC Hargreaves et al.
Cell Res. 2011

L Ho et al.
Nature 2010

GL Carvill et al.
Nat. Genet. 2013

LE Vissers et al.
Nat. Genet. 2004

BJ O'Roak et al.
Nature 2012

R Bernier et al.
Cell 2014

K Weiss et al.
Am. J. Hum. Genet. 2016

GO Pilarowski et al.
J. Med. Genet. 2017

Y Zhang et al.
Cell 1998

T Woodage et al.
Proc. Natl. Acad. Sci. U.S.A. 1997

Similar Publications