Analysis of G-quadruplex forming sequences in podocytes-marker genes and their potential roles in inherited...

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 vascular endothelial growth facto, cluster of differentiation-151, integrin subunit beta-4, metalloendopeptidase, Wilms tumor-1, integrin subunit beta-3, synaptopodin, and nephrin promoters. Vascular endothelial growth facto, 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.