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

Abstract

Arterial tortuosity syndrome (ATS) is an autosomal recessive\ud disorder characterized by tortuosity, elongation, stenosis and\ud aneurysm formation in the major arteries owing to disruption\ud of elastic fibers in the medial layer of the arterial wall1.\ud Previously, we used homozygosity mapping to map a candidate\ud locus in a 4.1-Mb region on chromosome 20q13.1 (ref. 2).\ud Here, we narrowed the candidate region to 1.2 Mb containing\ud seven genes. Mutations in one of these genes, SLC2A10,\ud encoding the facilitative glucose transporter GLUT10, were\ud identified in six ATS families. GLUT10 deficiency is associated\ud with upregulation of the TGFb pathway in the arterial wall, a\ud finding also observed in Loeys-Dietz syndrome, in which aortic\ud aneurysms associate with arterial tortuosity3. The identification\ud of a glucose transporter gene responsible for altered arterial\ud morphogenesis is notable in light of the previously suggested\ud link between GLUT10 and type 2 diabetes4,5. Our data\ud could provide new insight on the mechanisms causing\ud microangiopathic changes associated with diabetes and\ud suggest that therapeutic compounds intervening with\ud TGFb signaling represent a new treatment strategy

Clinical utility gene card for: Arterial tortuosity syndrome

“…Inguinal hernias are frequent, but diaphragmatic hernias rarely occur. 1,6 Infants with ATS may develop dyspnoea revealing pulmonary hypertension, due to stenoses of the pulmonary arteries or branches, which can be confirmed by cardiovascular imaging (ultrasound, catheterisation, angioCT or angioMRI) showing truncal or branch stenosis of the pulmonary arteries followed by a dilated segment.…”

“…[3][4][5] Differential diagnosis between those two conditions can be considered on the basis of slight dysmorphic differences of the face, a tendency to more generalised and severe cutis laxa in ARCL1b patients. 4 In cases when the ATS is revealed by late childhood or adulthood cardiovascular complications, the differential diagnosis includes connective tissue disorders affecting the arterial system as Loeys-Dietz syndromes (LDS), 6 and Ehlers-Danlos syndromes (EDS), particularly the vascular form. All differential diagnoses of ATS are available for diagnostic testing and should be explored in case of negativity of SLC2A10 screening (see 2.3).…”

Evaluation of the adolescent or adult with some features of Marfan syndrome

“…Mutations in a nuclear glucose transporter encoded by the SLC2A10 gene have been found. 20 Monitoring guidelines are the same as those described above for LDS.…”

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome

“…1,2 During the last decade, it has become increasingly clear that dysregulated transforming growth factor beta (TGFb) signaling is having a major role in the pathogenesis of MFS, LDS, and related disorders involving thoracic aortic aneurysms. [3][4][5][6][7][8][9] Because of the overlap with MFS and LDS and because several lines of evidence have confirmed a key role of TGFb signaling in the pathogenesis of MFS and LDS, it was hypothesized that altered TGFb signaling also underlies the SGS pathogenesis. Indeed, de novo, heterozygous mutations in SKI (Sloan-Kettering Institute), encoding a known repressor of TGFb signaling, were identified in 10 SGS patients.…”