Alternative titles; symbols
HGNC Approved Gene Symbol: CHD3
SNOMEDCT: 1179408008;
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:7,884,796-7,912,755 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Snijders Blok-Campeau syndrome | 618205 | Autosomal dominant | 3 |
The CHD3 gene encodes an ATP-dependent chromatin remodeling protein that regulates chromatin structure, thereby modulating gene expression. CHD3, together with CHD4 (603277) and CDH5 (610771), form the nucleosome remodeling and histone deacetylase (NURD) repressor complex, which is involved in genomic integrity, cell cycle progression, and cell differentiation. CHD3 has been shown to play a part during cortical development in the mouse brain (summary by Snijders Blok et al., 2018).
Anti-Mi2 autoantibody is strongly associated with dermatomyositis and is found in sera of 20% of dermatomyositis patients. Mi2 antigen consists of at least 8 components. By immunoscreening human thymocyte and HeLa cell cDNA expression libraries with anti-Mi2 patient sera, Ge et al. (1995) isolated a partial cDNA encoding Mi2-alpha, or CHD3. The deduced partial protein contains 4 potential zinc finger domains. Antibodies against recombinant Mi2-alpha reacted with a 240-kD HeLa cell protein. Northern blot analysis detected a single 7.5- to 8.0-kb Mi2-alpha transcript in HeLa cells.
Woodage et al. (1997) characterized the CHD3 gene. The predicted 1,944-amino acid protein shares 22.9% identity and 34.5% similarity overall with the mouse Chd1 gene product.
Aubry et al. (1998) cloned full-length human CHD3, which they called ZFH. The deduced 2,000-amino acid ZFH protein has a calculated molecular mass of 226.6 kD. It contains 7 domains conserved among helicase superfamily II members and 4 potential zinc fingers motifs. In addition, ZFH has an N-terminal nuclear localization signal, a bipartite nuclear targeting sequence, and 2 putative casein kinase II (see 115440) phosphorylation sites. Northern blot analysis detected several ZFH transcripts of 7.5 to 9 kb expressed at various levels in human tissues, suggesting the existence of multiple ZHF variants.
Woodage et al. (1997) mapped the CHD3 gene to 17p13 by PCR screening of the Genebridge 4 radiation hybrid mapping panel.
Using in situ hybridization, Aubry et al. (1998) mapped the CHD3 gene to chromosome 17p13-p12.
Seelig et al. (1996) noted that the Mi2-alpha and Mi2-beta (CHD4; 603277) proteins react with most or all dermatomyositis patient anti-Mi2 sera. While these proteins are distinct, they have stretches of identical sequence that could result in shared epitopes.
Using yeast 2-hybrid and coimmunoprecipitation analyses, Saether et al. (2007) found that Mi2-alpha interacted with human MYB (189990). MYB and Mi2-alpha had 2 interaction surfaces: one linking the MYB DNA-binding domain to the N-terminal region of Mi2-alpha, and the other linking the C-terminal region of Mi2-alpha with the FAETL region of MYB. Functional analysis following coexpression of Mi2-alpha and MYB in CV-1 cells revealed that Mi2-alpha had both a helicase-dependent repressive function and helicase-independent activating function, and that MYB exploited the activating function of Mi2-alpha. Knockdown of Mi2-alpha in MYB-expressing human erythroleukemia K562 cells demonstrated that Mi2-alpha could coactivate transcription of endogenous MYB target genes. Mi2-alpha coactivation was exerted primarily on nonsumoylated MYB. Mi2-alpha was also able to enhance MYB-p300 (EP300; 602700) transactivational activity.
In a patient (proband 01) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Eising et al. (2019) identified a de novo heterozygous missense mutation in the CHD3 gene (R1228W; 602120.0001). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation occurred at a highly conserved residue in the helicase domain. The patient was from a cohort of 19 probands with childhood apraxia of speech (CAS), which is a disorder of language development characterized by difficulties with sequencing speech sounds into syllables, words, and sentences. Eising et al. (2019) noted that CHD3 is an interacting partner with FOXP2 (605317) (Estruch et al., 2016), a well-established gene causing a different form of CAS (SPCH1; 602081). Expression data showed that CHD3 is expressed in the brain and is part of a module of functionally connected genes that are highly expressed during early human brain development.
In 35 patients from 33 unrelated families with SNIBCPS, Snijders Blok et al. (2018) identified 23 different de novo heterozygous mutations in the CHD3 gene (see, e.g., 602120.0002-602120.0005). Among the patients, there was a set of monozygotic twins and 2 sibs whose mother was mosaic for the mutation. Except for 4 individuals who carried predicted loss-of-function mutations, all patients carried missense mutations. There were 2 recurrent mutations affecting the same residue: R985W (602120.0002), found in 6 children from 5 families, and R985Q, found in 2 unrelated patients. Seventeen of the 19 missense mutations occurred in and around the ATPase/helicase motif of the protein, which is a functional domain that provides energy for nucleosome remodeling through its ATPase activity. The patients were ascertained from several research and clinical centers through the GeneMatcher program. The mutations, which were found by exome sequencing, were not found in the gnomAD database. In vitro functional expression studies of 6 of the mutations in HEK293 cells showed that 3 (R1121P; R1172Q, 602120.0003; and N1159K) impaired ATP hydrolysis activity, 1 (L915F, 602120.0004) increased activity, and 2 (R1187P; and W1158R, 602120.0005) had no effect. In contrast, further studies showed that 5 of the mutations disturbed chromatin remodeling capacities as measured by restriction enzyme accessibility to nucleosomal DNA, including 4 that severely compromised this ability (R1172Q, R1121P, W1158R, and N1159K), 1 that (L915F) increased it; and 1 (R1187P) that had no significant effect. The findings indicated that chromatin remodeling factors, and specifically CHD3, have an important role in human brain development.
In 24 patients with SNIBCPS, including one pair of monozygotic twins, Drivas et al. (2020) identified heterozygous mutations in the CHD3 gene. Nineteen of the mutations were either missense mutations or in-frame deletions; of these, 14 of were located in the helicase domain and 4 remaining missense mutations were located outside of the helicase domain. Five patients had mutations that were predicted to result in loss of function. One patient (patient 18) had a nonsense mutation (W1427X; 602120.0006), 1 patient (patient 21) had a splicing mutation (602120.0007), 2 patients had frameshift mutations, and 1 patient had a 0.5-Mb deletion that included the entire CHD3 gene as well as the MPDU1 (604041), TP53 (191170), and WRAP53 (612661) genes. One additional patient (patient 23) had a 6.5-Mb duplication that included the entire CHD3 gene as well as the CHRNB1 (100710), MPDU1, TP53, and WRAP53 genes. There were no phenotypic differences between patients with missense mutations in the CHD3 helicase domain or missense mutations outside of this domain. Furthermore, there was not a significant phenotypic difference between patients with missense mutations, gene deletions or duplications, or loss-of-function mutations.
In affected members of 21 families with SNIBCPS, van der Spek et al. (2022) identified 21 heterozygous inherited mutations (13 missense and 8 protein-truncating) in the CHD3 gene. Most variants in the cohort (71%) were maternally inherited. Heterozygous parents were not affected or were mildly affected compared to probands, suggesting variable expressivity. Seven of the protein-truncating mutations were due to a single-nucleotide change, whereas one was due to an intragenic deletion with a predicted loss-of-function effect. Lower levels of CHD3 transcript and protein were seen in a family with a CHD3 protein-truncating mutation, confirming the loss-of-function effect of the variant. Among the inherited missense mutations in the cohort, no clustering in the ATPase-helicase domain or elsewhere was seen. The identification of 8 families with an inherited loss-of-function mutation and the lack of clustering of inherited missense mutations supports a loss-of-function effect as the main mechanism for inherited cases.
In a patient (proband 01) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Eising et al. (2019) identified a de novo heterozygous c.3682C-T transition (c.3682C-T, ENST00000380358) in the CHD3 gene, resulting in an arg1228-to-trp (R1228W) substitution at a highly conserved residue in the helicase domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project, Exome Variant Server, and ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In 4 unrelated patients (patients 6, 9, 10, and 11) and 2 sibs (patients 7 and 8) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Snijders Blok et al. (2018) identified a heterozygous c.2953C-T transition (c.2953C-T, NM_001005273.2) in the CHD3 gene, resulting in an arg985-to-trp (R985W) substitution at a highly conserved residue in the helicase domain. The mutation occurred de novo in the 4 unrelated patients and was inherited from a mother who was mosaic for the mutation in the 2 sibs. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 3 unrelated patients (patients 26, 27, and 28) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Snijders Blok et al. (2018) identified a de novo heterozygous c.3515G-A transition (c.3515G-A, NM_001005273.2) in the CHD3 gene, resulting in an arg1172-to-gln (R1172Q) substitution at a highly conserved residue in the helicase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the R1172Q mutation impaired ATP hydrolysis activity and impaired chromatin remodeling capacities as measured by restriction enzyme accessibility to nucleosomal DNA compared to wildtype.
In a 4-year-old girl (patient 3) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Snijders Blok et al. (2018) identified a de novo heterozygous c.2745G-T transversion (c.2745G-T, NM_001005273.2) in the CHD3 gene, resulting in a leu915-to-phe (L915F) substitution at a highly conserved residue in the ATPase/helicase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the L915F mutation increased ATP hydrolysis activity and increased restriction enzyme accessibility to nucleosomal DNA compared to wildtype.
In a 21-year-old woman (patient 18) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Snijders Blok et al. (2018) identified a de novo heterozygous c.3472T-C transition (c.3472T-C, NM_001005273.2) in the CHD3 gene, resulting in a trp1158-to-arg (W1158R) substitution at a highly conserved residue in the helicase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro functional expression studies showed that the W1158R mutation had no effect on ATP hydrolysis activity, but impaired chromatin remodeling capacities as measured by restriction enzyme accessibility to nucleosomal DNA compared to wildtype.
In a patient (patient 18) and her mother with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Drivas et al. (2020) identified heterozygosity for a c.4280G-A transition (c.4280G-A, NM_001005273.2) in the CHD3 gene, resulting in a trp1427-to-ter (W1427X) substitution. The mutation was predicted to result in loss of function.
In a patient (patient 21) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Drivas et al. (2020) identified a de novo heterozygous 76-bp deletion (c.4073-3_4078del, NM_001005273.2) affecting the splice acceptor site for exon 27 in the CHD3 gene, predicted to cause a splicing abnormality. The mutation was predicted to result in exclusion of exon 27 and a frameshift.
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