Transcriptomic Analysis of GLUT10 Deficiency in Arterial Tortuosity Syndrome

Abstract Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder caused by mutations in the SLC2A10 gene encoding the glucose transporter GLUT10. GLUT10 deficiency leads to the accumulation of reactive oxygen species (ROS), resulting in oxidative stress, extracellular matrix (ECM) disorganization, and dysregulated signaling that compromise vascular integrity. This study aimed to characterize transcriptomic alterations in fibroblasts derived from ATS patients to elucidate molecular mechanisms underlying the disease and identify potential compensatory responses to ECM disruption. Fibroblasts from two ATS patients carrying homozygous SLC2A10 missense variants were analyzed by RNA sequencing (RNA-seq). Differential gene expression (DEG) analysis was followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses to identify altered biological processes. Functional categorization focused on gene sets related to vascular integrity, ECM organization, and cardiovascular function. RNA-seq revealed significant transcriptional dysregulation in ATS fibroblasts compared to controls. Genes involved in Wnt signaling, angiogenesis, and vascular remodeling were significantly upregulated, suggesting potential compensatory mechanisms against ECM disorganization. In contrast, genes related to cardiovascular integrity, ECM-receptor interaction, and basement membrane stability were markedly downregulated. KEGG pathway analysis showed suppression of critical cardiovascular pathways, including hyper-trophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), ECM-receptor interaction, and complement and coagulation cascades. Conversely, the upregulation of cell adhesion molecules (CAMs) indicated potential adaptive responses to vascular abnormalities. Our findings demonstrate that SLC2A10 mutations impair ECM integrity and vascular remodeling, contributing to the molecular pathology of ATS. The observed transcriptional signatures highlight both disrupted pathways and compensatory responses, providing novel insights into ATS pathophysiology and suggesting potential therapeutic targets for future intervention.