Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Immunobiology. 2022 Sep;227(5):152242. doi: 10.1016/j.imbio.2022.152242. Epub 2022 Jul 9.
Single nucleotide polymorphisms (SNPs) that do not change the composition of amino acids and cause synonymous mutations (sSNPs) were previously considered to lack any functional roles. However, sSNPs have recently been shown to interfere with protein expression owing to a myriad of factors related to the regulation of transcription, mRNA stability, and protein translation processes. In patients with Chagas disease, the presence of the synonymous mutation rs1129293 in phosphatidylinositol-4,5-bisphosphate 3-kinase gamma (PIK3CG) gene contributes to the development of the chronic Chagas cardiomyopathy (CCC), instead of the digestive or asymptomatic forms. In this study, we aimed to investigate whether rs1129293 is associated with the transcription of PIK3CG mRNA and its activity by quantifying AKT phosphorylation in the heart samples of 26 chagasic patients with CCC. Our results showed an association between rs1129293 and decreased PIK3CG mRNA expression levels in the cardiac tissues of patients with CCC. The phosphorylation levels of AKT, the protein target of PI3K, were also reduced in patients with this mutation, but were not correlated with PI3KCG mRNA expression levels. Moreover, bioinformatics analysis showed that rs1129293 and other SNPs in linkage disequilibrium (LD) were associated with the transcriptional regulatory elements, post-transcriptional modifications, and cell-specific splicing expression of PIK3CG mRNA. Therefore, our data demonstrates that the synonymous SNP rs1129293 is capable of affecting the PIK3CG mRNA expression and PI3Kγ activation.
单核苷酸多态性（SNPs）不改变氨基酸组成并导致同义突变（sSNPs），以前被认为缺乏任何功能作用。然而，最近的研究表明，由于与转录调控、mRNA 稳定性和蛋白质翻译过程相关的多种因素，sSNPs 会干扰蛋白质表达。在恰加斯病患者中，磷脂酰肌醇-4,5-二磷酸 3-激酶γ（PIK3CG）基因中的同义突变 rs1129293 的存在导致慢性恰加斯心肌病（CCC）的发生，而不是消化或无症状形式。在这项研究中，我们旨在通过量化心脏样本中 AKT 的磷酸化来研究 rs1129293 是否与 PIK3CG mRNA 的转录及其活性相关。26 例 CCC 患者的心脏组织。我们的结果表明 rs1129293 与 CCC 患者心脏组织中 PIK3CG mRNA 表达水平降低有关。该突变患者的 AKT（PI3K 的蛋白靶标）磷酸化水平也降低，但与 PI3KCG mRNA 表达水平无关。此外，生物信息学分析表明，rs1129293 及其与其他在连锁不平衡（LD）中的 SNP 与 PIK3CG mRNA 的转录调节元件、转录后修饰和细胞特异性剪接表达有关。因此，我们的数据表明同义 SNP rs1129293 能够影响 PIK3CG mRNA 表达和 PI3Kγ 激活。
