CHD3, or Chromodomain Helicase DNA Binding Protein 3, is a key component in chromatin remodeling, being involved in the NuRD complex (nucleosome remodeling and deacetylase activities). It functions in modulating chromatin structure and gene expression by deacetylating histones, which is crucial for various biological processes [3,4].

Mutations in CHD3 are associated with Snijders Blok-Campeau syndrome, an autosomal-dominant neurodevelopmental disorder. Probands with inherited CHD3 variants show phenotypes overlapping those with de novo variants, including global developmental delay, intellectual disability, speech and language difficulties, behavioral disorders, and typical dysmorphic features, while heterozygote parents may be mildly or not affected, indicating variable expressivity [1,3,5,7,8]. Computational and experimental studies have shown that mutations in the ATPase/helicase domain of CHD3 can disrupt critical binding and interaction motifs, affecting ATPase activity and chromatin remodeling [2]. Generation of Chd3-floxed allele in mice showed that while CHD3 is dispensable for early vascular development, global deletion of Chd3 led to partial lethality of Chd3Δ/Δ mutants prior to weaning, suggesting its role in embryonic viability [6].

In conclusion, CHD3 is essential for chromatin remodeling and plays a significant role in embryonic viability. Its mutations are strongly associated with Snijders Blok-Campeau syndrome, highlighting the importance of CHD3 functional studies, especially those using mouse models, in understanding neurodevelopmental disorders.

References:

1. van der Spek, Jet, den Hoed, Joery, Snijders Blok, Lot, Fisher, Simon E, Kleefstra, Tjitske. 2022. Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome. In Genetics in medicine : official journal of the American College of Medical Genetics, 24, 1283-1296. doi:10.1016/j.gim.2022.02.014. https://pubmed.ncbi.nlm.nih.gov/35346573/

2. Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Fisher, Simon E, Campeau, Philippe M. 2018. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. In Nature communications, 9, 4619. doi:10.1038/s41467-018-06014-6. https://pubmed.ncbi.nlm.nih.gov/30397230/

3. Pascual, Patricia, Tenorio-Castano, Jair, Mignot, Cyril, Nevado, Julián, Lapunzina, Pablo. 2023. Snijders Blok-Campeau Syndrome: Description of 20 Additional Individuals with Variants in CHD3 and Literature Review. In Genes, 14, . doi:10.3390/genes14091664. https://pubmed.ncbi.nlm.nih.gov/37761804/

4. Hoffmeister, Helen, Fuchs, Andreas, Erdel, Fabian, Rippe, Karsten, Längst, Gernot. . CHD3 and CHD4 form distinct NuRD complexes with different yet overlapping functionality. In Nucleic acids research, 45, 10534-10554. doi:10.1093/nar/gkx711. https://pubmed.ncbi.nlm.nih.gov/28977666/

5. Gao, Yuanyuan, Wang, Pei, Chen, Mengying, Zhang, Hongmei, Zhu, Min. 2024. Novel genotypes and phenotypes in Snijders Blok-Campeau syndrome caused by CHD3 mutations. In Frontiers in genetics, 15, 1347933. doi:10.3389/fgene.2024.1347933. https://pubmed.ncbi.nlm.nih.gov/39050258/

6. Xie, Jun, Gao, Siqi, Schafer, Christopher, Muthukumar, Vijay, Griffin, Courtney T. 2020. The chromatin-remodeling enzyme CHD3 plays a role in embryonic viability but is dispensable for early vascular development. In PloS one, 15, e0235799. doi:10.1371/journal.pone.0235799. https://pubmed.ncbi.nlm.nih.gov/32658897/

7. Chen, Lin, Bu, Yanjiao, Yu, Yuwen, Chen, Yongxing, Lei, Xiaoguang. 2024. CHD3-related Snijders Blok-Campeau syndrome with Spastic Paraplegia, Ataxia, and Situs Inversus. In European journal of medical genetics, 73, 104988. doi:10.1016/j.ejmg.2024.104988. https://pubmed.ncbi.nlm.nih.gov/39709005/

8. LeBreton, Laure, Allain, Eric P, Parscan, Radu Christian, Almaghraby, Abdullah, Ben Amor, Mouna. 2022. A novel CHD3 variant in a patient with central precocious puberty: Expanded phenotype of Snijders Blok-Campeau syndrome? In American journal of medical genetics. Part A, 191, 1065-1069. doi:10.1002/ajmg.a.63096. https://pubmed.ncbi.nlm.nih.gov/36565043/