Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome

Paul J Coucke¹, Andy Willaert¹, Marja W Wessels², Bert Callewaert¹, Nicoletta Zoppi³, Julie De Backer¹, Joyce E Fox⁴, Grazia M S Mancini², Marios Kambouris⁵, Rita Gardella³, Fabio Facchetti⁶, Patrick J Willems⁷, Ramses Forsyth⁸, Harry C Dietz⁹, Sergio Barlati³, Marina Colombi³, Bart Loeys¹ & Anne De Paepe¹

¹  Center for Medical Genetics, Ghent University, B-9000 Ghent, Belgium.

²  Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.

³  Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia 25123, Italy.

⁴  Department of Pediatrics, North Shore University Hospital, Manhasset, New York 11030, USA.

⁵  Yale University School of Medicine, New Haven, Connecticut 06510, USA.

⁶  Department of Pathology, University of Brescia, Brescia, Italy.

⁷  GENDIA, B-2000 Antwerp, Belgium.

⁸  Department of Pathology, Ghent University, B-9000 Ghent, Belgium.

⁹  McKusick-Nathans Institute of Genetic Medicine and Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore 21205, Maryland, USA.

Arterial tortuosity syndrome (ATS) is an autosomal recessive disorder characterized by tortuosity, elongation, stenosis and aneurysm formation in the major arteries owing to disruption of elastic fibers in the medial layer of the arterial wall¹. Previously, we used homozygosity mapping to map a candidate locus in a 4.1-Mb region on chromosome 20q13.1 (ref. 2). Here, we narrowed the candidate region to 1.2 Mb containing seven genes. Mutations in one of these genes, SLC2A10, encoding the facilitative glucose transporter GLUT10, were identified in six ATS families. GLUT10 deficiency is associated with upregulation of the TGF pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome, in which aortic aneurysms associate with arterial tortuosity³. The identification of a glucose transporter gene responsible for altered arterial morphogenesis is notable in light of the previously suggested link between GLUT10 and type 2 diabetes^{4, 5}. Our data could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggest that therapeutic compounds intervening with TGF signaling represent a new treatment strategy.

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