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The complex etiology of autism spectrum disorder due to missense mutations of CHD8

Molecular Psychiatry (2024)Cite this article

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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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Fig. 1: Missense mutations of CHD8 in ASD patients show a score distribution distinct from that for SNPs of CHD8 in healthy individuals.
Fig. 2: The chromatin-remodeling activity of CHD8 is impaired by missense mutations associated with ASD.
Fig. 3: Molecular dysfunction of CHD8 gives rise to embryonic mortality in mice.
Fig. 4: Molecular dysfunction of CHD8 results in ASD-like behavior in mice.
Fig. 5: Neural differentiation–related gene expression is downregulated in both Chd8+/− and Chd8+/R1242Q NPCs.
Fig. 6: The L1072F mutation results in ectopic binding of CHD8 to DNA in ESCs and ASD-like behavior in mice.
Fig. 7: Molecular basis for ASD etiology due to missense mutations of the CHD8 gene.

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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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Authors and Affiliations

  1. Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka, Fukuoka, 812-8582, Japan

    Taichi Shiraishi, Yuta Katayama, Taisuke Mizoo & Keiichi I. Nakayama

  2. Department of Histology and Cell Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan

    Masaaki Nishiyama

  3. Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Hirotaka Shoji & Tsuyoshi Miyakawa

  4. Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, 464-8602, Japan

    Akinobu Matsumoto

  5. School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Atsushi Hijikata

  6. Department of Computer Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-Cho, Nagahama, Shiga, 526-0829, Japan

    Tsuyoshi Shirai

  7. Department of Drug Discovery Structural Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, Fukuoka, 812-8582, Japan

    Kouta Mayanagi

  8. Anticancer Strategies Laboratory, TMDU Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Keiichi I. Nakayama

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Contributions

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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Correspondence to Keiichi I. Nakayama.

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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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