Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363:2063–72.

    PubMed  Article  Google Scholar 

  2. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P t. 2014;39:638–45.

    PubMed  PubMed Central  Google Scholar 

  3. Degenhardt F, Priebe L, Meier S, Lennertz L, Streit F, Witt SH, et al. Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets. Transl Psychiatry. 2013;3:e326.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Wu MY, Tsai TF, Beaudet AL. Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain. Genes Dev. 2006;20:2859–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Wu RC, Jiang M, Beaudet AL, Wu MY. ARID4A and ARID4B regulate male fertility, a functional link to the AR and RB pathways. Proc Natl Acad Sci USA. 2013;110:4616–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Wu RC, Zeng Y, Pan IW, Wu MY. Androgen Receptor Coactivator ARID4B Is Required for the Function of Sertoli Cells in Spermatogenesis. Mol Endocrinol. 2015;29:1334–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Wu MY, Eldin KW, Beaudet AL. Identification of chromatin remodeling genes Arid4a and Arid4b as leukemia suppressor genes. J Natl Cancer Inst. 2008;100:1247–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Lai A, Kennedy BK, Barbie DA, Bertos NR, Yang XJ, Theberge MC, et al. RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Mol Cell Biol. 2001;21:2918–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Liang YK, Han ZD, Lu JM, Liu ZZ, Zhuo YJ, Zhu XJ, et al. Downregulation of ARID4A and ARID4B promote tumor progression and directly regulated by microRNA-30d in patient with prostate cancer. J Cell Biochem. 2018;119:7245–55.

    CAS  PubMed  Article  Google Scholar 

  10. Zhang J, Hou S, You Z, Li G, Xu S, Li X, et al. Expression and prognostic values of ARID family members in breast cancer. Aging (Albany NY). 2021;13:5621–37.

    CAS  Article  Google Scholar 

  11. Hurst DR, Xie Y, Vaidya KS, Mehta A, Moore BP, Accavitti-Loper MA, et al. Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells. J Biol Chem. 2008;283:7438–44.

    CAS  PubMed  Article  Google Scholar 

  12. Gong W, Yao X, Liang Q, Tong Y, Perrett S, Feng Y. Resonance assignments for the tandem PWWP-ARID domains of human RBBP1. Biomol NMR Assign. 2019;13:177–81.

    CAS  PubMed  Article  Google Scholar 

  13. Coulson RL, Powell WT, Yasui DH, Dileep G, Resnick J, LaSalle JM. Prader-Willi locus Snord116 RNA processing requires an active endogenous allele and neuron-specific splicing by Rbfox3/NeuN. Hum Mol Genet. 2018;27:4051–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Cataldi M, Arnaldi D, Tucci V, De Carli F, Patti G, Napoli F, et al. Sleep disorders in Prader-Willi syndrome, evidence from animal models and humans. Sleep Med Rev. 2021;57:101432.

    PubMed  Article  Google Scholar 

  15. Systematic single-variant and gene-based association testing of 3,700 phenotypes in 281,850 UK Biobank exomes. https://genebass.org/, 2021, Accessed 2021.

  16. Rusk N. The UK Biobank. Nat Methods. 2018;15:1001.

    CAS  PubMed  Article  Google Scholar 

  17. Patsialou A, Wilsker D, Moran E. DNA-binding properties of ARID family proteins. Nucleic Acids Res. 2005;33:66–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Cajuso T, Hänninen UA, Kondelin J, Gylfe AE, Tanskanen T, Katainen R, et al. Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer. Int J Cancer. 2014;135:611–23.

    CAS  PubMed  Article  Google Scholar 

  19. Wilsker D, Patsialou A, Dallas PB, Moran E. ARID proteins: a diverse family of DNA binding proteins implicated in the control of cell growth, differentiation, and development. Cell Growth Differ. 2002;13:95–106.

    CAS  PubMed  Google Scholar 

  20. Wang X, Nagl NG, Wilsker D, Van Scoy M, Pacchione S, Yaciuk P, et al. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem J. 2004;383:319–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Maulik A, Giri M, Singh M. Molecular determinants of complex formation between DNA and the AT-rich interaction domain of BAF250a. FEBS Lett. 2019;593:2716–29.

    CAS  PubMed  Article  Google Scholar 

  22. Wilsker D, Probst L, Wain HM, Maltais L, Tucker PW, Moran E. Nomenclature of the ARID family of DNA-binding proteins. Genomics. 2005;86:242–51.

    CAS  PubMed  Article  Google Scholar 

  23. Lei M, Feng Y, Zhou M, Yang Y, Loppnau P, Li Y, et al. Crystal structure of chromo barrel domain of RBBP1. Biochem Biophys Res Commun. 2018;496:1344–8.

    CAS  PubMed  Article  Google Scholar 

  24. Ren J, Yao H, Hu W, Perrett S, Gong W, Feng Y. Structural basis for the DNA-binding activity of human ARID4B Tudor domain. J Biol Chem. 2021;296:100506.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Cadet JL, Brannock C, Jayanthi S, Krasnova IN. Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat. Mol Neurobiol. 2015;51:696–717.

    CAS  PubMed  Article  Google Scholar 

  26. Gong W, Wang J, Perrett S, Feng Y. Retinoblastoma-binding protein 1 has an interdigitated double Tudor domain with DNA binding activity. J Biol Chem. 2014;289:4882–95.

    CAS  PubMed  Article  Google Scholar 

  27. Wu H, Zeng H, Lam R, Tempel W, Amaya MF, Xu C, et al. Structural and histone binding ability characterizations of human PWWP domains. PLoS One. 2011;6:e18919.

    PubMed  PubMed Central  Article  Google Scholar 

  28. Yang C, Wang J, Liu J, Sun Y, Guo Y, Jiang Q, et al. Functional haplotypes of ARID4A affect promoter activity and semen quality of bulls. Anim Reprod Sci. 2018;197:257–67.

    CAS  PubMed  Article  Google Scholar 

  29. Li M, Shen L, Chen L, Huai C, Huang H, Wu X, et al. Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients. Transl Psychiatry. 2020;10:5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Jouan L, Girard SL, Dobrzeniecka S, Ambalavanan A, Krebs MO, Joober R, et al. Investigation of rare variants in LRP1, KPNA1, ALS2CL and ZNF480 genes in schizophrenia patients reflects genetic heterogeneity of the disease. Behav Brain Funct. 2013;9:9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Anticevic A, Repovs G, Corlett PR, Barch DM. Negative and nonemotional interference with visual working memory in schizophrenia. Biol Psychiatry. 2011;70:1159–68.

    PubMed  Article  Google Scholar 

  32. Fan Y, Abrahamsen G, McGrath JJ, Mackay-Sim A. Altered cell cycle dynamics in schizophrenia. Biol Psychiatry. 2012;71:129–35.

    CAS  PubMed  Article  Google Scholar 

  33. Hung PS, Chen CY, Chen WT, Kuo CY, Fang WL, Huang KH, et al. miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma. PLoS One. 2017;12:e0177346.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Chan SW, Hong W. Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription. J Biol Chem. 2001;276:28402–12.

    CAS  PubMed  Article  Google Scholar 

  35. Kim TG, Kraus JC, Chen J, Lee Y. JUMONJI, a critical factor for cardiac development, functions as a transcriptional repressor. J Biol Chem. 2003;278:42247–55.

    CAS  PubMed  Article  Google Scholar 

  36. Wang X, Nagl NG Jr., Flowers S, Zweitzig D, Dallas PB, Moran E. Expression of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors. Int J Cancer. 2004;112:636.

    CAS  PubMed  Article  Google Scholar 

  37. Jung EM, Moffat JJ, Liu J, Dravid SM, Gurumurthy CB, Kim WY. Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. Nat Neurosci. 2017;20:1694–707.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Moffat JJ, Jung EM, Ka M, Smith AL, Jeon BT, Santen GWE, et al. The role of ARID1B, a BAF chromatin remodeling complex subunit, in neural development and behavior. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:30–38.

    CAS  PubMed  Article  Google Scholar 

  39. Smith AL, Jung EM, Jeon BT, Kim WY. Arid1b haploinsufficiency in parvalbumin- or somatostatin-expressing interneurons leads to distinct ASD-like and ID-like behavior. Sci Rep. 2020;10:7834.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Fanous AH, Kendler KS. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry. 2005;10:6–13.

    CAS  PubMed  Article  Google Scholar 

  41. Lefort-Besnard J, Varoquaux G, Derntl B, Gruber O, Aleman A, Jardri R, et al. Patterns of schizophrenia symptoms: hidden structure in the PANSS questionnaire. Transl Psychiatry. 2018;8:237.

    PubMed  PubMed Central  Article  Google Scholar 

  42. Maurer-Stroh S, Dickens NJ, Hughes-Davies L, Kouzarides T, Eisenhaber F, Ponting CP. The Tudor domain ‘Royal Family’: Tudor, plant Agenet, Chromo, PWWP and MBT domains. Trends Biochem Sci. 2003;28:69–74.

    CAS  PubMed  Article  Google Scholar 

  43. Lai A, Lee JM, Yang WM, DeCaprio JA, Kaelin WG Jr, Seto E, et al. RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins. Mol Cell Biol. 1999;19:6632–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Zhang HS, Postigo AA, Dean DC. Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFbeta, and contact inhibition. Cell. 1999;97:53–61.

    CAS  PubMed  Article  Google Scholar 

  45. Allen KM, Fung SJ, Weickert CS. Cell proliferation is reduced in the hippocampus in schizophrenia. Aust N. Z J Psychiatry. 2016;50:473–80.

    PubMed  Article  Google Scholar 

  46. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006;11:514–22.

    CAS  PubMed  Article  Google Scholar 

  47. Hathy E, Szabó E, Varga N, Erdei Z, Tordai C, Czehlár B, et al. Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell-based in vitro disease modeling: convergence of schizophrenia- and autism-related cellular phenotypes. Stem Cell Res Ther. 2020;11:504.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Iannitelli A, Quartini A, Tirassa P, Bersani G. Schizophrenia and neurogenesis: A stem cell approach. Neurosci Biobehav Rev. 2017;80:414–42.

    PubMed  Article  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Qing Lu or Guang He.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01530-w

Search

Quick links