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Gene Review

SLC19A1  -  solute carrier family 19 (folate...

Homo sapiens

Synonyms: CHMD, FLOT1, FOLT, Folate transporter 1, IFC-1, ...
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Disease relevance of SLC19A1


High impact information on SLC19A1


Chemical compound and disease context of SLC19A1


Biological context of SLC19A1

  • In this segment, each family displayed one of two different missense mutations that altered the coding sequence of SLC19A3, the gene for a transporter related to the reduced-folate (encoded by SLC19A1) and thiamin (encoded by SLC19A2) transporters [15].
  • Recently, our laboratory reported an intricate regulation of the human reduced folate carrier (hRFC) gene, involving multiple promoters and noncoding exons [16].
  • A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC-1 AA + ATIC 347GG + TSER *2/*2) carried by the patients [17].
  • Moreover, they document a functionally novel polymorphism that increases promoter activity and may contribute to interpatient variations in hRFC expression and effects on tissue folate homeostasis and antitumor response to antifolates [16].
  • We have shown recently that decreased cAMP-responsive element (CRE)-dependent transcription contributes to the loss of hRFC gene expression in multiple antifolate-resistant cell lines [18].

Anatomical context of SLC19A1

  • Consistently, introduction into MTX transport null cells of a homologous D88H mutation in the hRFC did not result in restoration of MTX transport activity, thereby suggesting that D88 is an essential residue for MTX transport activity [19].
  • Restoration of transport activity by co-expression of human reduced folate carrier half-molecules in transport-impaired K562 cells: localization of a substrate binding domain to transmembrane domains 7-12 [20].
  • This is the first report that transcriptional silencing of the hRFC gene in multiple tumor cell lines with resistance to various novel antifolates is a result of a simultaneous loss of function of multiple transcription factors but not promoter methylation [21].
  • There was little protection by thymidine of RFC-null HeLa cells under the latter conditions [22].
  • We isolated a cDNA for the reduced folate carrier (RFC-1) from human skin fibroblasts [23].

Associations of SLC19A1 with chemical compounds


Physical interactions of SLC19A1


Other interactions of SLC19A1


Analytical, diagnostic and therapeutic context of SLC19A1


  1. Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Shen, M., Rothman, N., Berndt, S.I., He, X., Yeager, M., Welch, R., Chanock, S., Caporaso, N., Lan, Q. Lung Cancer (2005) [Pubmed]
  2. Folate-related genes and omphalocele. Mills, J.L., Druschel, C.M., Pangilinan, F., Pass, K., Cox, C., Seltzer, R.R., Conley, M.R., Brody, L.C. Am. J. Med. Genet. A (2005) [Pubmed]
  3. Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Ulrich, C.M., Curtin, K., Potter, J.D., Bigler, J., Caan, B., Slattery, M.L. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  4. Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Lightfoot, T.J., Skibola, C.F., Willett, E.V., Skibola, D.R., Allan, J.M., Coppede, F., Adamson, P.J., Morgan, G.J., Roman, E., Smith, M.T. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  5. Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Morin, I., Devlin, A.M., Leclerc, D., Sabbaghian, N., Halsted, C.H., Finnell, R., Rozen, R. Mol. Genet. Metab. (2003) [Pubmed]
  6. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Qiu, A., Jansen, M., Sakaris, A., Min, S.H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M.H., Goldman, I.D. Cell (2006) [Pubmed]
  7. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Diaz, G.A., Banikazemi, M., Oishi, K., Desnick, R.J., Gelb, B.D. Nat. Genet. (1999) [Pubmed]
  8. Human intestinal folate transport: cloning, expression, and distribution of complementary RNA. Nguyen, T.T., Dyer, D.L., Dunning, D.D., Rubin, S.A., Grant, K.E., Said, H.M. Gastroenterology (1997) [Pubmed]
  9. Endocytosis of GPI-linked membrane folate receptor-alpha. Rijnboutt, S., Jansen, G., Posthuma, G., Hynes, J.B., Schornagel, J.H., Strous, G.J. J. Cell Biol. (1996) [Pubmed]
  10. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. Kishi, S., Griener, J., Cheng, C., Das, S., Cook, E.H., Pei, D., Hudson, M., Rubnitz, J., Sandlund, J.T., Pui, C.H., Relling, M.V. J. Clin. Oncol. (2003) [Pubmed]
  11. Transcriptional regulation of the human reduced folate carrier in childhood acute lymphoblastic leukemia cells. Liu, M., Ge, Y., Payton, S.G., Aboukameel, A., Buck, S., Flatley, R.M., Haska, C., Mohammad, R., Taub, J.W., Matherly, L.H. Clin. Cancer Res. (2006) [Pubmed]
  12. Down syndrome, drug metabolism and chromosome 21. Taub, J.W., Ge, Y. Pediatric blood & cancer. (2005) [Pubmed]
  13. Role of the E45K-reduced folate carrier gene mutation in methotrexate resistance in human leukemia cells. Gifford, A.J., Haber, M., Witt, T.L., Whetstine, J.R., Taub, J.W., Matherly, L.H., Norris, M.D. Leukemia (2002) [Pubmed]
  14. G80A reduced folate carrier SNP modulates cellular uptake of folate and affords protection against thrombosis via a non homocysteine related mechanism. Yates, Z., Lucock, M. Life Sci. (2005) [Pubmed]
  15. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Zeng, W.Q., Al-Yamani, E., Acierno, J.S., Slaugenhaupt, S., Gillis, T., MacDonald, M.E., Ozand, P.T., Gusella, J.F. Am. J. Hum. Genet. (2005) [Pubmed]
  16. The human reduced folate carrier gene is regulated by the AP2 and sp1 transcription factor families and a functional 61-base pair polymorphism. Whetstine, J.R., Witt, T.L., Matherly, L.H. J. Biol. Chem. (2002) [Pubmed]
  17. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Dervieux, T., Furst, D., Lein, D.O., Capps, R., Smith, K., Walsh, M., Kremer, J. Arthritis Rheum. (2004) [Pubmed]
  18. Impaired CREB-1 phosphorylation in antifolate-resistant cell lines with down-regulation of the reduced folate carrier gene. Rothem, L., Stark, M., Assaraf, Y.G. Mol. Pharmacol. (2004) [Pubmed]
  19. Disruption of transport activity in a D93H mutant thiamine transporter 1, from a Rogers Syndrome family. Baron, D., Assaraf, Y.G., Drori, S., Aronheim, A. Eur. J. Biochem. (2003) [Pubmed]
  20. Restoration of transport activity by co-expression of human reduced folate carrier half-molecules in transport-impaired K562 cells: localization of a substrate binding domain to transmembrane domains 7-12. Witt, T.L., Stapels, S.E., Matherly, L.H. J. Biol. Chem. (2004) [Pubmed]
  21. Reduced folate carrier gene silencing in multiple antifolate-resistant tumor cell lines is due to a simultaneous loss of function of multiple transcription factors but not promoter methylation. Rothem, L., Stark, M., Kaufman, Y., Mayo, L., Assaraf, Y.G. J. Biol. Chem. (2004) [Pubmed]
  22. Loss of reduced folate carrier function and folate depletion result in enhanced pemetrexed inhibition of purine synthesis. Zhao, R., Zhang, S., Hanscom, M., Chattopadhyay, S., Goldman, I.D. Clin. Cancer Res. (2005) [Pubmed]
  23. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Chango, A., Emery-Fillon, N., de Courcy, G.P., Lambert, D., Pfister, M., Rosenblatt, D.S., Nicolas, J.P. Mol. Genet. Metab. (2000) [Pubmed]
  24. SLC19A3 encodes a second thiamine transporter ThTr2. Rajgopal, A., Edmondnson, A., Goldman, I.D., Zhao, R. Biochim. Biophys. Acta (2001) [Pubmed]
  25. Cytotoxic effects of pemetrexed in gastric cancer cells. Kim, J.H., Lee, K.W., Jung, Y., Kim, T.Y., Ham, H.S., Jong, H.S., Jung, K.H., Im, S.A., Kim, T.Y., Kim, N.K., Bang, Y.J. Cancer Sci. (2005) [Pubmed]
  26. Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells. Rothem, L., Aronheim, A., Assaraf, Y.G. J. Biol. Chem. (2003) [Pubmed]
  27. PT523 and other aminopterin analogs with a hemiphthaloyl-L-ornithine side chain: exceptionally tight-binding inhibitors of dihydrofolate reductase which are transported by the reduced folate carrier but cannot form polyglutamates. Rosowsky, A. Current medicinal chemistry. (1999) [Pubmed]
  28. Effect of glutamate carboxypeptidase II and reduced folate carrier polymorphisms on folate and total homocysteine concentrations in dialysis patients. Födinger, M., Dierkes, J., Skoupy, S., Röhrer, C., Hagen, W., Puttinger, H., Hauser, A.C., Vychytil, A., Sunder-Plassmann, G. J. Am. Soc. Nephrol. (2003) [Pubmed]
  29. Transcriptional regulation of the human reduced folate carrier A1/A2 promoter: Identification of critical roles for the USF and GATA families of transcription factors. Payton, S.G., Liu, M., Ge, Y., Matherly, L.H. Biochim. Biophys. Acta (2005) [Pubmed]
  30. The influence of drug-exposure conditions on the development of resistance to methotrexate or ZD1694 in cultured human leukaemia cells. Takemura, Y., Kobayashi, H., Gibson, W., Kimbell, R., Miyachi, H., Jackman, A.L. Int. J. Cancer (1996) [Pubmed]
  31. XRCC1 R399Q polymorphism is associated with response to platinum-based neoadjuvant chemotherapy in bulky cervical cancer. Chung, H.H., Kim, M.K., Kim, J.W., Park, N.H., Song, Y.S., Kang, S.B., Lee, H.P. Gynecol. Oncol. (2006) [Pubmed]
  32. Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients. Winkelmayer, W.C., Eberle, C., Sunder-Plassmann, G., Födinger, M. Kidney Int. (2003) [Pubmed]
  33. Thymidylate synthase inhibitors. Touroutoglou, N., Pazdur, R. Clin. Cancer Res. (1996) [Pubmed]
  34. Clustering of mutations in the first transmembrane domain of the human reduced folate carrier in GW1843U89-resistant leukemia cells with impaired antifolate transport and augmented folate uptake. Drori, S., Jansen, G., Mauritz, R., Peters, G.J., Assaraf, Y.G. J. Biol. Chem. (2000) [Pubmed]
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