Abstract
Nephropathic cystinosis is a rare, inherited metabolic disease caused by functional defects of cystinosin associated with mutations in the CTNS gene. The mechanisms underlying the phenotypic alterations associated with this disease are not well known. In this study, gene expression profiles in peripheral blood of nephropathic cystinosis patients (N = 7) were compared with controls (N = 7) using microarray technology. In unsupervised hierarchical clustering analysis, cystinosis samples co-clustered, and 1,604 genes were significantly differentially expressed between both groups. Gene ontology analysis revealed that differentially expressed genes in cystinosis were enriched in cell organelles such as mitochondria, lysosomes, and endoplasmic reticulum (p ≤ 0.030). The majority of the differentially regulated genes were involved in oxidative phosphorylation, apoptosis, mitochondrial dysfunction, endoplasmic reticulum stress, antigen processing and presentation, B-cell-receptor signaling, and oxidative stress (p ≤ 0.003). Validation of selected genes involved in apoptosis and oxidative phosphorylation was performed by quantitative real-time polymerase chain reaction (PCR). Electron microscopy and confocal imaging of cystinotic renal proximal tubular epithelial cells further confirmed anomalies in the cellular organelles and pathways identified by microarray analysis. Further analysis of these genes and pathways may offer critical insights into the clinical spectrum of cystinosis patients and ultimately lead to novel links for targeted therapy.