Understanding the IDH1 missense SNPs on expression of genes involved in Glioblastoma multiforme

The IDH1 gene encodes isocitrate dehydrogenase 1 enzyme (IDH1), crucial in the citric acid cycle that converts isocitrate to alpha-ketoglutarate. Mutations in IDH1 at R132 lead to the production of the oncometabolite 2-hydroxyglutarate, which impacts cellular metabolism, differentiation, and epigenetic regulation, and is associated with GBM. This study utilized in silico methods (SIFT, PROVEAN, PolyPhen2, Predict SNP, MutPred2, InterPro, MusiteDeep, I-Mutant 3.0, MUpro, and INSP-MD) to identify high-risk missense SNPs in IDH1, located in highly conserved regions and overlapping with protein-ligand and PTM sites and assessed their impact on the structure and function of IDH1 protein. A total of 12 high-risk missense SNPs were found at T77, N96, S94, and K260 leading to the gain or loss of catalytic and allosteric sites, alteration in the metal binding site, as well as the gain or loss of PTMs such as acetylation, methylation, N-linked glycosylation, and ubiquitylation at different residues within the active sites of mutated IDH1 enzymes. These changes may significantly impact the structure and function of the IDH1 protein. Furthermore, GEPIA and survival analysis were performed to evaluate IDH1 expression in GBM and LGG and survival outcomes. GEPIA analysis showed significant (p < 0.05) upregulation of IDH1 expression in GBM and LGG. Survival analysis indicated that GBM patients with low IDH1 expression group had better survival outcomes, while LGG patients with low IDH1 expression group showed poorer survival rates. Overall, this study highlights the diagnostic and prognostic potential biomarker of IDH1 in glioblastoma. However, additional in vitro and in vivo studies will be valuable in confirming the role of IDH1 proteins in GBM.