Recently, "Molecular Psychiatry" published online with the title "A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity" by He Guang, Bio-X Institute of Shanghai Jiaotong University.
The research results of the collaborative research between the researcher and Lu Qing, a long-appointed associate professor, are the co-corresponding authors.
The ARID4A p.
His411Asp mutation was identified through whole-exome sequencing analysis of schizophrenia family samples, and the high-resolution crystal of the ARID domain where the mutation site is located was analyzed.
The structure and function of this variant were studied, which provided important information for revealing the molecular mechanism of ARID4A gene action
.
Dr.
Decheng Ren, Dr.
Xiaoxi Wei and Assistant Researcher Lin Lin are the co-first authors of this paper
.
Figure 1 Article home page
Figure 2 Results of functional studies of ARID4A protein analysis and mutation
(a) Ribbon diagram of PWWP-ARID structure; (b) DNA-binding functional analysis of the protein; (c) Effect of gene mutation on cell proliferation and cell cycle
Schizophrenia is a severe chronic mental disorder that severely affects an individual's behavior and its cognitive and emotional processes
.
The main clinical features of the patients included delusions, hallucinations, and speech and behavior disturbances
.
Previous studies have found that genetic factors and a variety of environmental factors play an important role in the occurrence and development of schizophrenia
.
The heritability of schizophrenia is as high as 80%, its genetic basis is extremely complex, and there is strong genetic heterogeneity
.
At present, more than 200 schizophrenia risk loci have been identified based on genome-wide association studies and other methods, but in-depth functional studies of these genes and risk loci are still lacking
.
In the present study, the heterozygous missense variant ARID4A (AT-rich interaction domain 4A) c.
1231C>G (p.
His411Asp) identified by whole-exome sequencing co-segregated with the schizophrenia phenotype
.
The gene mutation is located in the ARID domain of ARID4A protein (which can bind dsDNA), which is an important functional domain of ARID4A
.
Through X-ray diffraction experiments, crystal diffraction data of the ARID4A PWWP-ARID tandem domain with a resolution of 2.
05 Å were obtained, and it was found that the PWWP domain could stabilize the structure of ARID and maintain its function
.
ARID4A p.
His411Asp mutation not only results in conformational changes in the ARID domain, but also affects its binding ability to dsDNA
.
Cell-level findings suggest that ARID4A p.
His411Asp mutation can interfere with the normal cell cycle, resulting in abnormal cell proliferation
.
This study has important theoretical significance for understanding the pathogenesis of schizophrenia
.
Original link: https:// class="Article-source form-horizontal">
