Arterial Tortuosity Syndrome: a vitamin C compartmentation disease?

Arterial tortuosity syndrome (ATS) is a rare connective tissue disorder with vascular, cutaneous and musculoskeletal involvement. ATS is characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation, vascular dissection, and stenosis of the pulmonary arteries. ATS is transmitted in an autosomal recessive manner and is caused by mutations in the SLC2A10 gene, encoding the facilitative glucose transporter 10 (GLUT10). So far, 20 different SLC2A10 loss-of-function mutations have been reported in 34 families with 80 cases. The role of GLUT10 in the pathogenesis of the disorder is still unknown, but SLC2A10 mutations lead to disarray and reduction of the extracellular matrix (ECM) of the arteries and other connective tissues. It was reported that GLUT10 facilitates the uptake of glucose and derivatives in experimental systems. Recently, a new activity for this protein has been proposed given that it can act as a transporter of dehydroascorbate (DHA), the oxidized form of ascorbic acid (AA) or vitamin C. The aim of this project is to clarify the etiopathogenesis of ATS unraveling the relationship between GLUT10 deficiency, AA homeostasis, and the disarray of ECM components. Although this project will not directly lead to therapeutic treatments, it also aims to investigate the effect of in vitro treatment of ATS cells with vitamin C analogues that should restore a control phenotype; these molecules might then be considered as candidates for in vivo therapeutic approaches.