Comprehensive analysis predicting effects of deleterious SNPs of human progesterone receptor gene on its structure and functions: a computational approach

Abstract

Progesterone receptor plays a crucial role in the development of the mammary gland and breast cancer. Single nucleotide polymorphisms (SNPs) within its gene, PGR, are associated with the risk of miscarriages and preterm birth as well as many cancers across different populations. The main aim of this work is to investigate the most deleterious SNPs in the PGR gene to identify potential biomarkers for various disease susceptibility and treatments. Both sequence and structure-based computational approaches were adopted and in total 11 nsSNPs have been filtered out of 674 nsSNPs along with seven non-coding SNPs. R740Q, I744T and D746E belonged to a mutation cluster. R740Q, D746E along with S865L altered H-bond interactions within the receptor. The same mutations have been found to be associated with several cancers including uterine and breast cancer among others. It is, therefore, possible that the high-risk SNPs associated with cancers may exert their effect by causing changes in the protein structure, particularly in its bonding patterns, and thus affecting its function. In addition, seven non-coding SNPs that were located in the UTR region created a new miRNA site while three SNPs disrupted a conserved miRNA site. These high-risk SNPs can play an instrumental role in generating a dataset of the PGR gene’s SNPs. Thus, the present study may pave the way to design and develop novel therapeutics for overcoming the challenges associated with certain cancers and pregnancy that result from a change in the protein structure and function due to the SNP mutations in the PGR gene. Communicated by Ramaswamy H. Sarma