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

Abstract

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.