Alternative titles; symbols
HGNC Approved Gene Symbol: SLC2A10
SNOMEDCT: 458432002; ICD10CM: Q87.82;
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38) : 20:46,708,320-46,736,347 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Arterial tortuosity syndrome | 208050 | Autosomal recessive | 3 |
SLC2A10 is a member of the facilitative glucose transporter family, which plays a significant role in maintaining glucose homeostasis (McVie-Wylie et al., 2001).
By EST database searching, sequence analysis, 3-prime and 5-prime RACE, and screening of a human liver cDNA library, McVie-Wylie et al. (2001) cloned a full-length SLC2A10 cDNA encoding a 541-amino acid protein. SLC2A10 shares between approximately 28% (SLC2A3; 138170) and 34% (SLC2A8; 605245) amino acid sequence identity with other members of the facilitative glucose transporter family. SLC2A10 has 12 transmembrane domains, with a hydrophilic intracellular loop between helices 6 and 7, together with a large extracellular loop (containing a potential N-linked glycosylation site) between helices 9 and 10. Northern blot analysis of adult tissues detected a major 4.3-kb transcript with highest levels of expression in liver and pancreas and lower levels of expression in all other tissues examined.
By RT-PCR, Wood et al. (2003) detected widespread expression of mouse Glut10, including expression in white adipose tissue and stromal vasculature. GLUT10 was also expressed in human adipose tissue and in an adipocyte cell line.
Using in situ hybridization, Lee et al. (2010) found that Glut10 mRNA was highly expressed in smooth muscle layers of mouse aortic tissues.
McVie-Wylie et al. (2001) determined that the SLC2A10 gene contains 5 exons and spans at least 28 kb of genomic DNA.
By sequence analysis, McVie-Wylie et al. (2001) mapped the SLC2A10 gene to chromosome 20q12-q13.1.
Dawson et al. (2001) found that expression of human GLUT10 increased uptake of 2-deoxy-D-glucose in Xenopus oocytes. D-glucose and D-galactose competed with 2-deoxy-D-glucose, and transport was inhibited by the glucose transport inhibitor phloretin.
Lee et al. (2010) found that Glut10 localized to the Golgi apparatus under basal conditions in differentiated mouse 3T3-L1 adipocytes and relocalized to mitochondria upon insulin stimulation. In A10 rat aortic smooth muscle cells, Glut10 localized mainly to mitochondria under both basal and insulin-stimulated conditions. Overexpression of Glut10 increased mitochondrial uptake of radiolabeled L-dehydroascorbic acid (DHA), the oxidized form of vitamin C, and increased mitochondrial ascorbic acid content. DHA uptake was inhibited by D-glucose. Overexpression of Glut10 in A10 cells reduced mitochondrial production of reactive oxygen species following H2O2-dependent oxidative stress, possibly by enhancing mitochondrial reduction of DHA to ascorbic acid.
Arterial tortuosity syndrome (ATORS; 208050) 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. Coucke et al. (2006) narrowed the candidate region on 20q13.1 and found homozygous mutations in the SLC2A10 gene, encoding the facilitative glucose transporter GLUT10, in 6 affected families. The parents in all 6 families were heterozygous for the mutation. GLUT10 deficiency is associated with upregulation of the TGF-beta (see 190180) pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome (609192), 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 (125853) (Dawson et al., 2001; McVie-Wylie et al., 2001). The findings of Coucke et al. (2006) may provide new insight on the mechanisms causing microangiopathic changes associated with diabetes and suggested that therapeutic compounds intervening with TGF-beta signaling represent a new treatment strategy.
In 16 patients from 12 families with ATORS, Callewaert et al. (2008) identified 11 different mutations in the SLC2A10 gene (see, e.g., 606145.0005-606145.0006). Several mutations represented founder effects.
Pathogenic Effects of SLC2A10 Mutations
By immunohistochemical analysis, Zoppi et al. (2015) observed disarray of several structural components of the extracellular matrix in skin fibroblasts from 3 ATORS patients with different GLUT10 mutations. Expression profiling and quantitative RT-PCR of control and patient fibroblasts revealed differential expression of genes involved in TGF-beta signaling and of genes that influence lipid metabolism, intracellular redox homeostasis, and maintenance of extracellular matrix. Immunofluorescence microscopy, Western blot analysis, and flow cytometry confirmed increased synthesis of ALDH1A1 (100640) and PPAR-gamma (PPARG; 601487) and increased production of reactive oxidative species in ATORS patient fibroblasts. Patient fibroblasts also showed activation of a noncanonical alpha-V (ITGAV; 193210)/beta-3 (ITGB3; 173470) integrin-mediated TGF-beta signaling pathway. Stable expression of GLUT10 partially normalized ATORS fibroblasts.
Lee et al. (2010) generated a mouse model of ATORS by introducing a gly128-to-glu (G128E) mutation in Glut10. Mice homozygous for the G128E mutation showed a mild phenotype of abnormal elastogenesis with elastic fiber proliferation by 10 months of age. Aortic smooth muscle cells cultured from Glut10(G128E/G128E) mice had normal morphology, but they showed reduced mitochondrial DHA uptake and elevated cellular reactive oxygen species following oxidative stress compared with wildtype.
Willaert et al. (2012) found that knockdown of Slc2a10 in zebrafish via antisense morpholino oligonucleotides resulted in a wavy notochord and cardiovascular abnormalities, with reduced heart rate and blood flow and incomplete and irregular vascular patterning, especially in the tail. Treatment with a small molecular inhibitor of Tgf-beta receptor-1 (TGFBR1; 190181) caused a similar phenotype, but it had no effect on Slc2a10 expression. Array hybridization revealed an approximately 50% overlap in genes that showed altered expression following Slc2a10 knockdown or Tgfbr1 inhibition. Both treatments downregulated genes involved in eye, cardiovascular, and nervous system development and cartilage formation. Slc2a10 knockdown uniquely affected genes involved in energy metabolism, calcium binding and homeostasis, and contractile muscle cytoskeleton and connective tissue, as well as additional genes involved in DNA replication and repair and cell cycle progression. Mitochondria of Slc2a10-knockdown embryos appeared normal, but they showed reduced oxygen consumption and blunted mitochondrial response to a chemical uncoupler. Knockdown of Slc2a10 partially rescued the deleterious effects of reduced levels of Smad7 (602932), an endogenous inhibitor of Tgfbr1. Willaert et al. (2012) concluded that Slc2a10 is an effector of TGF-beta signaling that exerts its effect downstream of SMADs.
In 2 families originating from the same region in Morocco, Coucke et al. (2006) found that arterial tortuosity syndrome (ATORS; 208050) was caused by a homozygous nonsense mutation in the SLC2A10 gene: 510G-A (W170X).
In a family originating from Morocco, Coucke et al. (2006) found that arterial tortuosity syndrome (ATORS; 208050) was caused by a homozygous 961delG mutation in the SLC2A10 gene, resulting in a frameshift (Val321fsTer391).
In a consanguineous Italian kindred with arterial tortuosity syndrome (ATORS; 208050), the Sicilian family studied by Coucke et al. (2003) with 4 affected children in 2 sibships, Coucke et al. (2006) identified a homozygous frameshift mutation in the SLC2A10 gene, 1334delG (Gly445fsTer484), in affected individuals.
Callewaert et al. (2008) identified the 1334delG mutation in affected members of 4 European families with arterial tortuosity syndrome. Haplotype analysis suggested a founder effect. The authors noted that the mutation occurs in a highly conserved region in exon 3 and disrupts the endofacial loop between TMD10 and TMD11. In all patients, the mutation was in compound heterozygosity with another pathogenic SLC2A10 mutation (see, e.g., 606145.0005 and 606145.0006).
In 2 Middle Eastern families with arterial tortuosity syndrome (ATORS; 208050), 1 with 6 affected sibs and another with 2 affected sibs, Coucke et al. (2006) identified a homozygous mutation, 243C-G, in the SLC2A10 gene. The mutation resulted in a ser81-to-arg (S81R) amino acid substitution. Affected individuals shared a common haplotype, indicating a founder mutation in these families.
Faiyaz-Ul-Haque et al. (2008) identified a homozygous S81R mutation in affected members of 10 Qatari families with arterial tortuosity syndrome. The substitution occurs in the third transmembrane domain of the SLC2A10 protein. Eight of the families belonged to a large consanguineous kindred that was part of an extended Bedouin tribe originally reported as having a unique form of Ehlers-Danlos syndrome (Abdul Wahab et al., 2003).
In affected members of 3 families with arterial tortuosity syndrome (ATORS; 208050), Callewaert et al. (2008) identified a 1276G-T transversion in exon 2 of the SLC2A10 gene, resulting in a gly426-to-trp (G426W) substitution in TMD10. In all patients, the mutation was in compound heterozygosity with another pathogenic SLC2A10 mutation (see 606145.0003 and 606145.0006). Haplotype analysis suggested a founder effect for the G426W mutation.
In affected members of 3 families with arterial tortuosity syndrome (ATORS; 208050), Callewaert et al. (2008) identified a 394C-T transition in exon 2 of the SLC2A10 gene, resulting in an arg132-to-trp (R132W) substitution in the endofacial loop between TMD4 and TMD5. In all patients, the mutation was in compound heterozygosity with another pathogenic SLC2A10 mutation (see 606145.0003 and 606145.0005). Haplotype analysis suggested a founder effect for the R132W mutation.
Abdul Wahab, A., Janahi, I. A., Eltohami, A., Zeid, A., Ul Haque, M. F., Teebi, A. S. A new type of Ehlers-Danlos syndrome associated with tortuous systemic arteries in a large kindred from Qatar. Acta Paediat. 92: 456-462, 2003. Note: Erratum: Acta Paediat. 99: 1112 only, 2010. [PubMed: 12801113] [Full Text: https://doi.org/10.1111/j.1651-2227.2003.tb00578.x]
Callewaert, B. L., Willaert, A., Kerstjens-Frederikse, W. S., De Backer, J., Devriendt, K., Albrecht, B., Ramos-Arroyo, M. A., Doco-Fenzy, M., Hennekam, R. C. M., Pyeritz, R. E., Krogmann, O. N., Gillessen-Kaesbach, G., and 10 others. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum. Mutat. 29: 150-158, 2008. [PubMed: 17935213] [Full Text: https://doi.org/10.1002/humu.20623]
Coucke, P. J., Wessels, M. W., Van Acker, P., Gardella, R., Barlati, S., Willems, P. J., Colombi, M., De Paepe, A. Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13. J. Med. Genet. 40: 747-751, 2003. [PubMed: 14569121] [Full Text: https://doi.org/10.1136/jmg.40.10.747]
Coucke, P. J., Willaert, A., Wessels, M. W., Callewaert, B., Zoppi, N., De Backer, J., Fox, J. E., Mancini, G. M. S., Kambouris, M., Gardella, R., Facchetti, F., Willems, P. J., Forsyth, R., Dietz, H. C., Barlati, S., Colombi, M., Loeys, B., De Paepe, A. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nature Genet. 38: 452-457, 2006. [PubMed: 16550171] [Full Text: https://doi.org/10.1038/ng1764]
Dawson, P. A., Mychaleckyj, J. C., Fossey, S. C., Mihic, S. J., Craddock, A. L., Bowden, D. W. Sequence and functional analysis of GLUT10: a glucose transporter in the type 2 diabetes-linked region of chromosome 20q12-13.1. Molec. Genet. Metab. 74: 186-199, 2001. [PubMed: 11592815] [Full Text: https://doi.org/10.1006/mgme.2001.3212]
Faiyaz-Ul-Haque, M., Zaidi, S. H. E., Wahab, A. A., Eltohami, A., Al-Mureikhi, M. S., Al-Thani, G., Peltekova, V. D., Tsui, L.-C., Teebi, A. S. Identification of a pSer81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome patients from 10 Qatari families. (Letter) Clin. Genet. 74: 189-193, 2008. [PubMed: 18565096] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01049.x]
Lee, Y.-C., Huang, H.-Y., Chang, C.-J., Cheng, C.-H., Chen, Y.-T. Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: mechanistic insight into arterial tortuosity syndrome. Hum. Molec. Genet. 19: 3721-3733, 2010. [PubMed: 20639396] [Full Text: https://doi.org/10.1093/hmg/ddq286]
McVie-Wylie, A. J., Lamson, D. R., Chen, Y. T. Molecular cloning of a novel member of the GLUT family of transporters, SLC2A10 (GLUT10), localized on chromosome 20q13.1: a candidate gene for NIDDM susceptibility. Genomics 72: 113-117, 2001. [PubMed: 11247674] [Full Text: https://doi.org/10.1006/geno.2000.6457]
Willaert, A., Khatri, S., Callewaert, B. L., Coucke, P. J., Crosby, S. D., Lee, J. G. H., Davis, E. C., Shiva, S., Tsang, M., De Paepe, A., Urban, Z. GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGF-beta signaling. Hum. Molec. Genet. 21: 1248-1259, 2012. [PubMed: 22116938] [Full Text: https://doi.org/10.1093/hmg/ddr555]
Wood, I. S., Hunter, L., Trayhurn, P. Expression of class III facilitative glucose transporter genes (GLUT-10 and GLUT-12) in mouse and human adipose tissues. Biochem. Biophys. Res. Commun. 308: 43-49, 2003. [PubMed: 12890477] [Full Text: https://doi.org/10.1016/s0006-291x(03)01322-6]
Zoppi, N., Chiarelli, N., Cinquina, V., Ritelli, M., Colombi, M. GLUT10 deficiency leads to oxidative stress and non-canonical alpha-V/beta-3 integrin-mediated TGF-beta signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Hum. Molec. Genet. 24: 6769-6787, 2015. [PubMed: 26376865] [Full Text: https://doi.org/10.1093/hmg/ddv382]