Saad Mona, Mehawej Cybel, Faour Wissam H
Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
Heliyon. 2023 Sep 15;9(9):e20233. doi: 10.1016/j.heliyon.2023.e20233. eCollection 2023 Sep.
Nephrotic Syndrome is the most widespread pediatric kidney disorder. Genetic alterations in podocyte genes are thought to be responsible for the disease. G-quadruplexes are non-conventional guanine-rich DNA and RNA structures, which are commonly found in regulatory regions. This study examined the potential G-quadruplexes forming sequences in the promoters and gene bodies of podocyte-marker genes. High G-quadruplexes density was found in the , cluster of differentiation-151, integrin subunit beta-4, metalloendopeptidase, Wilms tumor-1, integrin subunit beta-3, synaptopodin, and nephrin promoters. , cluster of differentiation-151 and integrin subunit beta-4 had the highest G-quadruplexes density in their gene bodies and promoters. Additionally, highly stable G-quadruplexes forming sequences were identified within all podocyte-marker genes. Furthermore, it is hypothesized that Wilms tumor-1 is capable of controlling the transcription of podocalyxin by binding to two possible G-quadruplexes forming motifs. We next analyzed the most frequently reported genetic mutations in the selected genes for their effect on DNA G-quadruplexes formation, and the thermodynamic stability of predicted RNA G-quadruplexes, using RNAfold. Importantly, the missense mutation c.121_122del in the nephrin gene reported in patients with NS type 1 affected DNA G-quadruplexes formation in this region as well as the thermodynamic stability of the corresponding RNA G-quadruplexes. Overall, we report the potential regulatory roles of G-quadruplexes in the etiology of nephrotic syndrome and their possible use as drug targets to treat kidney diseases.
肾病综合征是最常见的儿科肾脏疾病。足细胞基因的遗传改变被认为是该疾病的病因。G-四链体是富含鸟嘌呤的非常规DNA和RNA结构，常见于调控区域。本研究检测了足细胞标记基因启动子和基因体内潜在的G-四链体形成序列。在分化簇-151、整合素亚基β-4、金属内肽酶、威尔姆斯瘤-1、整合素亚基β-3、突触足蛋白和nephrin启动子中发现了高G-四链体密度。分化簇-151和整合素亚基β-4在其基因体和启动子中具有最高的G-四链体密度。此外，在所有足细胞标记基因中都鉴定出了高度稳定的G-四链体形成序列。此外，据推测威尔姆斯瘤-1能够通过结合两个可能的G-四链体形成基序来控制足细胞蛋白的转录。接下来，我们使用RNAfold分析了所选基因中最常报道的基因突变对DNA G-四链体形成的影响以及预测的RNA G-四链体的热力学稳定性。重要的是，1型肾病综合征患者中报道的nephrin基因错义突变c.121_122del影响了该区域的DNA G-四链体形成以及相应RNA G-四链体的热力学稳定性。总体而言，我们报道了G-四链体在肾病综合征病因中的潜在调控作用及其作为治疗肾脏疾病药物靶点的可能用途。
