Insulin gene mutations affect the structure of insulin and are considered a leading cause of neonatal diabetes and permanent neonatal diabetes mellitus PNDM. These mutations can affect the production and secretion of insulin, resulting in inadequate insulin levels and subsequent hyperglycemia. Early discovery or prediction of PNDM can aid in better management and treatment. The current study identified potential deleterious non-synonymous single nucleotide polymorphisms nsSNPs in the INS gene. The analysis of the nsSNPs in the INS gene was conducted using bioinformatics tools by implementing computational algorithms including SIFT, PolyPhen2, SNAP2, SNPs & GO, PhD-SNP, MutPred2, I-Mutant, MuPro, and HOPE tools to investigate the prediction of the potential association between nsSNPs in the INS gene and PNDM. Three mutations, C96Y, P52R, and C96R, were shown to potentially reduce the stability and function of the INS protein. These mutants were subjected to MDSs for structural analysis. Results suggested that these three potential pathogenic mutations may affect the stability and functionality of the insulin protein encoded by the INS gene. Therefore, these changes may influence the development of PNDM. Further researches are required to fully understand the various effects of mutations in the INS gene on insulin synthesis and function. These data can aid in genetic testing for PNDM to evaluate its risk and create treatment and prevention strategies in personalized medicine.

Background: Mutations in the EPOR gene can disrupt its normal signaling pathways, leading to hematological disorders such as polycythemia vera and other myeloproliferative diseases. Methodology: In this study, a range of bioinformatics tools, including SIFT, PolyPhen-2, SNAP2, SNPs & Go, PhD-SNP, I-Mutant2.0, MuPro, MutPred, ConSurf, HOPE, and Interpro were used to assess the deleterious effects of missense nonsynonymous single nucleotide polymorphisms (nsSNPs) on protein structure and function. Furthermore, molecular dynamics simulations (MDS) were conducted to assess the structural deviations of the identified mutant variants in comparison to the wild type. Results: The results identified two nsSNPs, R223P and G302S, as deleterious, significantly affecting protein structure and function. Both substitutions occur in functionally conserved regions and are predicted to be pathogenic, associated with altered molecular mechanisms. The MDSs indicated that while the wild-type EPOR maintained optimal stability, the G302S and R223P variants exhibited substantial deviations, adversely affecting overall protein stability and compactness. Conclusions: The computational analysis of missense nsSNPs in the EPOR gene identified two missense SNPs, R223P and G302S, as deleterious, occurring at highly conserved regions, and having substantial effects on erythropoietin receptor (EPO-R) protein structure and function, suggesting their potential pathogenic consequences.