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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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).
The authors declare no competing interests.
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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