ABSTRACT
The pathogenesis of schizophrenia (SCZ) is heavily influenced by genetic factors. Ring finger protein 4 (RNF4) and squamous cell carcinoma antigen recognized by T cells 3 (SART3) are thought to be involved in nervous system growth and development via oxidative stress pathways. Moreover, they have previously been linked to SCZ. Yet the role of RNF4 and SART3 in SCZ remains unclear. Here, we investigated how these two genes are involved in SCZ by studying their variants observed in patients. We first observed significantly elevated mRNA levels of RNF4 and SART3 in the peripheral blood in both first-episode (n = 30) and chronic (n = 30) SCZ patients compared to controls (n = 60). Next, we targeted-sequenced three single nucleotide polymorphisms (SNPs) in SART3 and six SNPs in RNF4 for association with SCZ using the genomic DNA extracted from peripheral blood leukocytes from SCZ participants (n = 392) and controls (n = 572). We observed a combination of SNPs that included rs1203860, rs2282765 (both in RNF4), and rs2287550 (in SART3) was associated with increased risk of SCZ, suggesting common pathogenic mechanisms between these two genes. We then conducted experiments in HEK293T cells to better understand the interaction between RNF4 and SART3. We observed that SART3 lowered the expression of RNF4 through ubiquitination and downregulated the expression of nuclear factor E2-related factor 2 (NRF2), a downstream factor of RNF4, implicating the existence of a possible shared regulatory mechanism for RNF4 and SART3. In conclusion, our study provides evidence that the interaction between RNF4 and SART3 contributes to the risk of SCZ. The findings shed light on the underlying molecular mechanisms of SCZ and may lead to the development of new therapies and interventions for this disorder.
Subject(s)
Depression/metabolism , Depression/rehabilitation , Metabolome , Mindfulness/methods , Adolescent , Adult , Aged , Apolipoproteins B/metabolism , Apolipoproteins E/metabolism , Blood Glucose/metabolism , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Triglycerides/metabolism , Uric Acid/metabolism , Young AdultABSTRACT
OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in cyclic adenosine monophosphate response element-binding protein(CREB1) gene and major depressive disorder (MDD). METHODS: We recruited 105 parent-offspring trios of Chinese descent, extracted whole blood genomic DNA, and genotyped the SNPs in rs10932201 and rs6740584 loci. Single-marker transmission disequilibrium test (TDT), pairwise SNP linkage disequilibrium(LD) and haplotype-based TDT were performed. RESULTS: No significant association with MDD was observed for SNPs rs10932201 and rs6740584 (P=0.1004 and P=0.4986). However, there was strong positive association between the rs10932201-rs6740584 haplotype and MDD (P=0.00003241), and both haplotypes of A-C and A-T were significantly associated with MDD (P=0.020 and P=0.00022). CONCLUSION: The rs10932201-rs6740584 haplotype of the CREB1 gene may play an important role in the pathogenesis of MDD.
Subject(s)
Cyclic AMP Response Element-Binding Protein/genetics , Depressive Disorder, Major/genetics , Polymorphism, Single Nucleotide/genetics , Female , Genetic Predisposition to Disease , Haplotypes , Humans , MaleABSTRACT
A lymphocyte cDNA library of normal human was constructed in order to obtain specific gene and prepare lymphocyte gene chips to detect the relative genes between psychiatric diseases and immunity. The lymphocyte was abstracted from fresh normal human blood and cultured in vitro. Total RNA of lymphocyte was extracted from the cultured cells and then mRNA was extracted further. Moreover,single-strand cDNA and double-strand cDNA were synthesized in turn. The double-strand cDNAs were ligated to SalI and NotI adaptor,which were later ligated to arms of gammaZipLox. Ligated-cDNAs were packed in vitro, and then infected E. coli Y1090. Titering the phage and amplifying the library. The lymphocyte cDNA library consisted of 2.6 x 10(6) recombinants with the length of 1-5 kb and the cloning efficiency was 5 x 10(12) recombinants/g cDNA. The amplified library was 3 x 10(7) recombinants/microl in concentration and the number of bacteriophage plagues was the most suitable in density after it was diluted to 10(-6) in concentration. The constructed cDNA library of normal human lymphocyte would be helpful to further detecting target genes and preparing gene chips etc.
