Integrative Transcriptomic and Structural Analysis of Lipoprotein Genes Reveals Potential Therapeutic Targets in Diabetic Retinopathy

Abstract

Lipoprotein dysfunction has been linked to the retinal damage associated with diabetic retinopathy (DR). Despite available data, the molecular pathways associated with abnormal lipid metabolism, neurovascular impairment, and genetic variation are not well elucidated. In this study, we analyzed differentially expressed lipoprotein genes (DELGs) from a DR mouse model by utilizing RNA-Seq data, gene ontology enrichment, PPI network analysis, nsSNP impact prediction, and structural effects of prioritized variants were analyzed using SWISS-MODEL homology modeling, FoldX stability predictions, among others. Ten key hub genes that are crucial for retinal function were discovered to contain nsSNPs that are structurally deleterious. The pathogenic RHO P53R/L variant was confirmed to significantly destabilize rhodopsin structure, aligning with known photoreceptor degeneration. Additional deleterious variants in RET, GNG3, and CNP showed strong destabilizing or functional impacts based on FoldX and I-Mutant. The progression of DR is probably aided by these genetic variations, which impact lipid homeostasis and phototransduction. Our findings suggest that targeting DELGs or correcting deleterious SNP-induced dysfunction could offer new treatment options for DR.