Abstract
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 TGFβ 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 diabetes4,5. Our data could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggest that therapeutic compounds intervening with TGFβ signaling represent a new treatment strategy.
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Acknowledgements
We are indebted to the families and patients for their interest and cooperation. We thank C.E. Catsman-Berrevoets for referring family 1. We thank P. Van Acker and L.A. Myers for technical assistance. This study was supported by the Fund for Scientific Research, Flanders (Belgium); Ghent University; the Ministero dell'Istruzione, dell'Università e della Ricerca, Fondo per gli Investimenti della Ricerca di Base 2001; Fondazione Cariplo; Fondazione Berlucchi; the William Smilow Center for Marfan Syndrome Research; the Howard Hughes Medical Institute and the US National Institutes of Health. B.C. and B.L. are research assistant and senior clinical investigator, respectively, and are supported by the Fund for Scientific Research, Flanders. J.D.B. is a research fellow from Ghent University.
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Supplementary Table 1
Primer sequences and annealing temperatures used for the amplification of each exon of SLC2A10. (PDF 30 kb)
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Coucke, P., Willaert, A., Wessels, M. et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet 38, 452–457 (2006). https://doi.org/10.1038/ng1764
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DOI: https://doi.org/10.1038/ng1764