title: GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts.
abstract: 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.
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Chiarelli
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cinquina
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ritelli
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy marina.colombi@unibs.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
mesh_terms: D001158:Arteries / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D020869:Gene Expression Profiling; D051246:Glucose Transport Proteins, Facilitative / Q000172:deficiency* / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007593:Joint Instability / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D018384:Oxidative Stress; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000503:physiopathology; D012873:Skin Diseases, Genetic / Q000378:metabolism* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D054079:Vascular Malformations / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D039302:Integrin alphaVbeta3; C430746:SLC2A10 protein, human; D016212:Transforming Growth Factor beta