Fig. 2
Schematic view of CHD3 transcript and protein with de novo mutations. a Schematic view of CHD3 exons (transcript 1, NM_001005273.2) with the splice site mutation c.4073-2A>G shown that most likely leads to skipping of exon 27 (22 amino acids), while preserving the reading frame. Exon 27 is part of the beginning of the second DUF domain (DUF 1086). Colors of the domains in a match with colors of domains in b and c. Five different types of domains are specified: plant homeodomains (PHD), chromodomains (Chromo), a Helicase domain consisting of two parts (Helicase ATP-binding and Helicase C-terminal), domains of unknown function (DUF), and a C-terminal 2 domain. b Schematic view of linear CHD3 protein (transcript 1, NM_001005273.2) with all mutations, except for the splice site mutation that is shown in a, found in our cohort. Almost all missense mutations cluster in or around the Helicase domain of the CHD3 protein. c Overview of one of the two CHD3-models used in this study, based on the 3MWY protein structure. This figure shows the different domains of the protein in their three-dimensional conformation: chromo domain 1 494–595 (magenta), chromo domain 2 631–673 (red), helicase ATP binding domain (yellow), helicase C-terminal domain (green), ATP binding residues 761–768 (cyan). ATP is orange, and gray residues do not belong to an indicated domain. Colors of the domains in c match with colors of domains in a and b. d The same structure as c, but in this figure the positions of the mutated residues are indicated in red, the sidechains of these residues are shown as red balls. The ATP molecule is shown in yellow. This figure illustrates the clustering of mutations on specific sites within the Helicase ATP-binding domain and Helicase C-terminal domain. A more detailed analysis of the different missense mutations in our cohort can be found in Supplementary Note 1
