| Note | The protein product of SLC19A3 gene is often referred as thiamine transporter-2 (THTR-2). |
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| Description | A thiamine transporter protein of 496 amino acid residues, 56 kDa, containing 12 transmembrane domains, and cytosolic N- and C-terminals (Eudy et al., 2000). |
| Expression | SLC19A3 expression has been widely detetced in human tissues including brain, heart, gastrointestinal tract, lung, pancreas, muscle, ovary, testis, adrenal gland, with the highest levels observed in placenta, liver and kidney (Eudy et al., 2000). A more restricted pattern of SLC19A3 expression was found in mouse tissues, including only brain, heart, lung, kidney and small intestine. |
| Localisation | Plasma membrane. In polarized intestinal epithelial cells, THTR-2 are restrictedly localized at the apical membrane domain (Subramanian et al., 2006a). |
| Function | THTR-2 mediates the transmembrane uptake of thiamine (vitamin B1) via a proton anti-port mechanism (Rajgopal et al., 2001). This thiamine uptake process was reported to be temperature-, energy- and pH-dependent (Ashokkumar et al., 2006; Subramanian et al., 2007), and is adaptively regulated by the extracellular thiamine level through transcriptional regulation of the SLC19A3 gene (Nabokina et al., 2013). In human intestinal epithelial cells, THTR-2 interacts with the human transmembrane 4 super-family 4 (TM4SF4) and influences the intestinal thiamine uptake (Subramanian et al., 2014). |
| Homology | THTR-2 protein belongs to the SLC19 gene family (folate/thiamine transporter family) of solute carriers. Two other members of the family are SLC19A1 (a folate transporter) and SLC19A2 (a thiamine transporter, THTR-1), which share 42% and 53% amino acid sequence identities to the human THTR-2 (Ganapathy et al., 2004). The human SLC19A3 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito. |
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| Entity | Breast cancer |
| Note | SLC19A3 expression was downregulated in breast cancer tumors as compared to the normal tissues (Ng et al., 2011). Exogenous expression of SLC19A3 in breast cancer cells resulted in an increased sensitivity to doxorubicin- and radiation-induced apoptosis (Liu et al., 2003), and modulated the gene expression associated with prostaglandin metabolism (Liu et al., 2004). |
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| Entity | Gastric cancer |
| Note | Hypermethylation of SLC19A3 promoter was detected in gastric cancer cell lines and carcinoma tissues, which led to the epigenetic downregulation of SLC19A3 expression (Liu et al., 2009). The methylation status of SLC19A3 promoter was further validated in plasma samples of breast and gastric cancer patients, suggesting it as a potential blood biomarker for cancer diagnosis (Ng et al., 2011). |
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| Entity | Biotin-responsive basal ganglia disease |
| Note | Biotin-responsive basal ganglia disease (BBGD) is a recessive metabolic disorder caused by the homozygous or compound heterozygous mutations in SLC19A3 (Zeng et al., 2005; Debs et al., 2010). Functional study of SLC19A3 [p.Gly23Val and p.Thr422Ala] mutants demonstrated that these 2 mutations did not affect THTR-2 protein trafficking to the apical membrane, but resulting in impaired thiamine transport activity (Subramanian et al., 2006b). |
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| Entity | Leigh syndrome |
| Note | Mutational dysfunction of SLC19A3 has been reported to be associated with Leigh syndrome. A nonsense mutation (c.20C>A; p.Ser7*) has been detected in SLC19A3, and was described as a founder mutation in the Moroccan population (Gerards et al., 2013). |
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| Entity | Wernicke's-like encephalopathy |
| Note | Compound mutations in SLC19A3 [p.Lys44Glu and p.Glu320Gln] were reported in patients with Wernicke's-like encephalopathy. From the expression study, p.Lys44Glu mutantion resulted in impaired THTR-2 intracellular transport, whereas the p.Glu320Gln mutant showed normal cell surface localization but a significiantly decreased thiamine uptake activity (Kono et al., 2009). |
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| Entity | Apoptosis |
| Note | THTR2-transfected breast cancer cells were found an increase in sensitivity to chemotherapy agent doxorubicin and ionizing radiation, and an increase in apoptosis involving the caspase-3-dependent pathway (Liu et al., 2003). |
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| Entity | Diabetic nephropathy |
| Note | SLC19A3 expression was demonstrated to be down-regulated in kidney proximal tubular epithelium under high glucose concentration, which led to the impaired renal re-uptake of thiamine, and producing thiamine insufficiency. This implies a novel mechanism of renal thiamine mishandling linked to the development of diabetic nephropathy (Larkin et al., 2012). |
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| Entity | Biotin deficiency |
| Note | SLC19A3 expression was found to be strikingly repressed in human leukocytes upon marginal biotin deficiency, suggesting it as a potential indicator of biotin status (Vlasova et al., 2005). |
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| Thiamin uptake by the human-derived renal epithelial (HEK-293) cells: cellular and molecular mechanisms. |
| Ashokkumar B, Vaziri ND, Said HM. |
| Am J Physiol Renal Physiol. 2006 Oct;291(4):F796-805. Epub 2006 May 16. |
| PMID 16705148 |
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| Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations. |
| Debs R, Depienne C, Rastetter A, Bellanger A, Degos B, Galanaud D, Keren B, Lyon-Caen O, Brice A, Sedel F. |
| Arch Neurol. 2010 Jan;67(1):126-30. doi: 10.1001/archneurol.2009.293. |
| PMID 20065143 |
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| Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. |
| Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH. |
| Mol Genet Metab. 2000 Dec;71(4):581-90. |
| PMID 11136550 |
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| SLC19: the folate/thiamine transporter family. |
| Ganapathy V, Smith SB, Prasad PD. |
| Pflugers Arch. 2004 Feb;447(5):641-6. Epub 2003 May 6. (REVIEW) |
| PMID 14770311 |
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| Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. |
| Gerards M, Kamps R, van Oevelen J, Boesten I, Jongen E, de Koning B, Scholte HR, de Angst I, Schoonderwoerd K, Sefiani A, Ratbi I, Coppieters W, Karim L, de Coo R, van den Bosch B, Smeets H. |
| Brain. 2013 Mar;136(Pt 3):882-90. doi: 10.1093/brain/awt013. Epub 2013 Feb 18. |
| PMID 23423671 |
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| Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. |
| Kevelam SH, Bugiani M, Salomons GS, Feigenbaum A, Blaser S, Prasad C, Haberle J, Baric I, Bakker IM, Postma NL, Kanhai WA, Wolf NI, Abbink TE, Waisfisz Q, Heutink P, van der Knaap MS. |
| Brain. 2013 May;136(Pt 5):1534-43. doi: 10.1093/brain/awt054. Epub 2013 Mar 12. |
| PMID 23482991 |
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| Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy. |
| Kono S, Miyajima H, Yoshida K, Togawa A, Shirakawa K, Suzuki H. |
| N Engl J Med. 2009 Apr 23;360(17):1792-4. doi: 10.1056/NEJMc0809100. |
| PMID 19387023 |
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| Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes. |
| Larkin JR, Zhang F, Godfrey L, Molostvov G, Zehnder D, Rabbani N, Thornalley PJ. |
| PLoS One. 2012;7(12):e53175. doi: 10.1371/journal.pone.0053175. Epub 2012 Dec 28. |
| PMID 23285265 |
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| Down-regulation of thiamine transporter THTR2 gene expression in breast cancer and its association with resistance to apoptosis. |
| Liu S, Huang H, Lu X, Golinski M, Comesse S, Watt D, Grossman RB, Moscow JA. |
| Mol Cancer Res. 2003 Jul;1(9):665-73. |
| PMID 12861052 |
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| Thiamine transporter gene expression and exogenous thiamine modulate the expression of genes involved in drug and prostaglandin metabolism in breast cancer cells. |
| Liu S, Stromberg A, Tai HH, Moscow JA. |
| Mol Cancer Res. 2004 Aug;2(8):477-87. |
| PMID 15328374 |
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| Promoter hypermethylation mediates downregulation of thiamine receptor SLC19A3 in gastric cancer. |
| Liu X, Lam EK, Wang X, Zhang J, Cheng YY, Lam YW, Ng EK, Yu J, Chan FK, Jin H, Sung JJ. |
| Tumour Biol. 2009;30(5-6):242-8. doi: 10.1159/000243767. Epub 2009 Oct 7. |
| PMID 19816091 |
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| Adaptive regulation of human intestinal thiamine uptake by extracellular substrate level: a role for THTR-2 transcriptional regulation. |
| Nabokina SM, Subramanian VS, Valle JE, Said HM. |
| Am J Physiol Gastrointest Liver Physiol. 2013 Oct 15;305(8):G593-9. doi: 10.1152/ajpgi.00237.2013. Epub 2013 Aug 29. |
| PMID 23989004 |
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| Quantitative analysis and diagnostic significance of methylated SLC19A3 DNA in the plasma of breast and gastric cancer patients. |
| Ng EK, Leung CP, Shin VY, Wong CL, Ma ES, Jin HC, Chu KM, Kwong A. |
| PLoS One. 2011;6(7):e22233. doi: 10.1371/journal.pone.0022233. Epub 2011 Jul 18. |
| PMID 21789241 |
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| SLC19A3 encodes a second thiamine transporter ThTr2. |
| Rajgopal A, Edmondnson A, Goldman ID, Zhao R. |
| Biochim Biophys Acta. 2001 Nov 29;1537(3):175-8. |
| PMID 11731220 |
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| Association of TM4SF4 with the human thiamine transporter-2 in intestinal epithelial cells. |
| Subramanian VS, Nabokina SM, Said HM. |
| Dig Dis Sci. 2014 Mar;59(3):583-90. doi: 10.1007/s10620-013-2952-y. Epub 2013 Nov 27. |
| PMID 24282057 |
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| Biotin deficiency reduces expression of SLC19A3, a potential biotin transporter, in leukocytes from human blood. |
| Vlasova TI, Stratton SL, Wells AM, Mock NI, Mock DM. |
| J Nutr. 2005 Jan;135(1):42-7. |
| PMID 15623830 |
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| A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations. |
| Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, Ishihara N, Yamada Y, Kuwano R, Tsuji S, Wakamatsu N. |
| BMC Med Genet. 2010 Dec 22;11:171. doi: 10.1186/1471-2350-11-171. |
| PMID 21176162 |
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| Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. |
| Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF. |
| Am J Hum Genet. 2005 Jul;77(1):16-26. Epub 2005 May 3. |
| PMID 15871139 |
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