Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue 
disorder caused by loss-of-function mutations in SLC2A10, which encodes 
facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS 
pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose 
and/or dehydroascorbic acid, have not been clearly elucidated. To discern the 
molecular mechanisms underlying the ATS aetiology, we performed gene expression 
profiling and biochemical studies on skin fibroblasts. Transcriptome analyses 
revealed the dysregulation of several genes involved in TGFβ signalling and 
extracellular matrix (ECM) homeostasis as well as the perturbation of specific 
pathways that control both the cell energy balance and the oxidative stress 
response. Biochemical and functional studies showed a marked increase in 
ROS-induced lipid peroxidation sustained by altered PPARγ function, which 
contributes to the redox imbalance and the compensatory antioxidant activity of 
ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFβ 
signalling due to TGFBRI disorganization, the upregulation of TGFBRII and 
connective tissue growth factor, and the activation of the αvβ3 integrin 
transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 
expression in patients' fibroblasts normalized redox homeostasis and PPARγ 
activity, rescued canonical TGFβ signalling and induced partial ECM 
re-organization. These data add new insights into the ATS dysregulated 
biological pathways and definition of the pathomechanisms involved in this 
disorder.