Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome.
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 wall. 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 TGFbeta pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome, in which aortic aneurysms associate with arterial tortuosity. 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. Our data could provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggest that therapeutic compounds intervening with TGFbeta signaling represent a new treatment strategy.
Coucke
Paul J
PJ
Center for Medical Genetics, Ghent University, B-9000 Ghent, Belgium. paul.coucke@ugent.be
Willaert
Andy
A
Wessels
Marja W
MW
Callewaert
Bert
B
Zoppi
Nicoletta
N
De Backer
Julie
J
Fox
Joyce E
JE
Mancini
Grazia M S
GM
Kambouris
Marios
M
Gardella
Rita
R
Facchetti
Fabio
F
Willems
Patrick J
PJ
Forsyth
Ramses
R
Dietz
Harry C
HC
Barlati
Sergio
S
Colombi
Marina
M
Loeys
Bart
B
De Paepe
Anne
A
D000595:Amino Acid Sequence; D001158:Arteries / Q000473:pathology*; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20; D005260:Female; D051246:Glucose Transport Proteins, Facilitative / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D014652:Vascular Diseases / Q000235:genetics*
D051246:Glucose Transport Proteins, Facilitative; C430746:SLC2A10 protein, human