Abstract
CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.
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Data availability
All sequence data have been deposited in GEO under the accession number GSE227579.
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Acknowledgements
We thank K. Tsunematsu and the Research Promotion Unit of the Medical Institute of Bioregulation at Kyushu University for technical assistance as well as A. Ohta for help with preparation of the manuscript. We also thank U. Kiyoe (Chiba University) for technical guidance on chromatin-remodeling assays and Y. Takamiya (Fujita Health University) for the assistance with behavioral analyses. Computations were performed in part on the NIG supercomputer at ROIS National Institute of Genetics. This research was supported in part by KAKENHI grants from the Japan Society for the Promotion of Science (JSPS) to K.I.N. (JP23H00378) and to T.M. (JP16H06276 and JP22H04922), as well as by a grant from MEXT Promotion of Distinctive Joint Research Center Program to H.S. (JPMXP0621467949) and that from the Japan Agency for Medical Research and Development (AMED) to K.I.N. (23wm0425002).
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T. Shiraishi performed experiments and wrote the manuscript. YK, MN, and AM conceived and supervised experimental design. T. Mizoo, HS, and T. Miyakawa performed behavioral tests for Chd8 mutant mice. AH, T. Shirai, and KM performed analysis of CHD8 mutations. KIN coordinated the study and wrote the manuscript.
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Shiraishi, T., Katayama, Y., Nishiyama, M. et al. The complex etiology of autism spectrum disorder due to missense mutations of CHD8. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02491-y
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DOI: https://doi.org/10.1038/s41380-024-02491-y