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A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity

Molecular Psychiatry volume 27, pages 2777–2786 (2022)Cite this article

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Abstract

ARID4A plays an important role in regulating gene expression and cell proliferation. ARID4A belongs to the AT-rich interaction domain (ARID)-containing family, and a PWWP domain immediately precedes its ARID region. The molecular mechanism and structural basis of ARID4A are largely unknown. Whole-exome sequencing (WES) revealed that a novel heterozygous missense variant, ARID4A c.1231 C > G (p.His411Asp), was associated with schizophrenia (SCZ) in this study. We determined the crystal structure of the PWWP-ARID tandem at 2.05 Å, revealing an unexpected mode in which ARID4A assembles with its PWWP and ARID from a structural and functional supramodule. Our results further showed that compared with the wild type, the p.His411Asp ARID mutant protein adopts a less compact conformation and exhibits a weaker dsDNA-binding ability. The p.His411Asp mutation decreased the number of cells that were arrested in the G0-G1 phase and caused more cells to progress to the G2-M phase. In addition, the missense mutation promoted the proliferation of HEK293T cells. In conclusion, our data provide evidence that ARID4A p.His411Asp could cause a conformational change in the ARID4A ARID domain, influence the DNA binding function, and subsequently disturb the cell cycle arrest in the G1 phase. ARID4A is likely a susceptibility gene for SCZ; thus, these findings provide new insight into the role of ARID4A in psychiatric disorders.

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Fig. 1: Genetic and burden analysis of ARID4A in mental disorders.
Fig. 2: The overall structure of the ARID4A PWWP-ARID domain.
Fig. 3: Biochemical characterization of disease mutation.
Fig. 4: ARID4A p. His411Asp promotes the proliferation and cell cycle progression of HEK293T cells.

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Acknowledgements

This project is supported by the National Key Research and Development Program (2016YFC0906400, 2018YF1410600), Innovation Funding in Shanghai (20JC1418600, 18JC1413100), the National Natural Science Foundation of China (82071262, 81671326, 19Z103150073), Natural Science Foundation of Shanghai (20ZR1427200, 20511101900), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Shanghai Leading Academic Discipline Project (B205).

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  1. These authors contributed equally: Decheng Ren, Xiaoxi Wei, Lin Lin.

Authors and Affiliations

  1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China

    Decheng Ren, Xiaoxi Wei, Lin Lin, Fan Yuan, Yan Bi, Zhenming Guo, Liangjie Liu, Lei Ji, Xiao Yang, Ke Han, Fengping Yang, Xi Wu, Xingwang Li, Weidong Li, Lin He, Daizhan Zhou, Tao Yu, Yi Shi, Qing Lu & Guang He

  2. The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China

    Decheng Ren, Xiaoxi Wei, Lin Lin, Fan Yuan, Yan Bi, Zhenming Guo, Liangjie Liu, Lei Ji, Xiao Yang, Ke Han, Fengping Yang, Xi Wu, Xingwang Li, Weidong Li, Lin He, Daizhan Zhou, Tao Yu, Yi Shi, Qing Lu & Guang He

  3. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Decheng Ren, Xiaoxi Wei, Lin Lin, Fan Yuan, Yan Bi, Zhenming Guo, Liangjie Liu, Lei Ji, Xiao Yang, Ke Han, Fengping Yang, Xi Wu, Xingwang Li, Zhenghui Yi, Yifeng Xu, Weidong Li, Lin He, Daizhan Zhou, Tao Yu, Yi Shi, Qing Lu & Guang He

  4. Wuhu Fourth People’s Hospital, Wuhu, Anhui, China

    Changqun Cai & Peng Wang

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Contributions

GH and QL conceived the concept; DR, GH and QL designed experiments; GH led the project with assistance from DR, LL, LH, YS and QL; ZY, YX, CC, PW, DZ, XW and TY collected samples; DR performed experiments with assistance from XW, FY, YB, ZG, LL, LJ, XY, KH and WL; DR, LL, FY and QL analyzed data; DR, LL, QL and GH wrote the manuscript with input from all coauthors.

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Correspondence to Qing Lu or Guang He.

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Ren, D., Wei, X., Lin, L. et al. A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity. Mol Psychiatry 27, 2777–2786 (2022). https://doi.org/10.1038/s41380-022-01530-w

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