Reduced folate carrier gene

Rothem, L., Stark, M., Kaufman, Y., Mayo, L., and Assaraf, Y.G. (2004) 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. Journal of Biological Chemistry. 279, 374-384. 

Whetstine, J.R., Witt, T.L., and Matherly, L.H. (2002) The human reduced folate carrier gene is regulated by the AP2 and spl transcription factor families and a functional 61-base pair polymorphism. Journal of Biological Chemistry. 277, 43873-43880. 

Rady PL, Szucs S, Matalon RK et al. Genetic polymorphism (G80A) of reduced folate carrier gene in ethnic populations. Mol Genet Metab 2001 73 285-286. 

Laverdiere C, Chiasson S, Costea 1 et al. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. B/oorf 2002 100 3832-3834. 

Rothem L, Ifergan I, Kaufman Y, Priest DG, Jansen G, Assaraf YG. Resistance to multiple novel antifolates is mediated via defective drug transport resulting from clustered mutations in the reduced folate carrier gene in human leukaemia cell lines. Biochem J 2002 367 741-50. 

Chango, A., Emery-Fillon, N., de Courcy, G.P., Lambert, D., Pfister, M., Rosenblatt, D.S., and Nicolas, J.P., 2000. A polymorphism (80G- > A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Molecular Genetics and Metabolism. 70 310-315. 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Thymidylate Synthase Gene Reduced Folate Carrier (RFC) Gene Discussion References... 

The reduced folate carrier is the major transporter of methotrexate into cells. The RFC gene is comprised of 40,719 base pairs, has 12 exons, and is located on 21q22.3. The primary polymorphisms studied to date is the RFCl G80A variant, which is associated with a decrease in MTX transport into cells. Rady et al. noted similar rates of variation in several ethnic groups variant homozygosity rates were 28.7% in individuals of Ashkenazi-Jewish decent, 20.8% in African-American, 29% in Caucasians, and 26% in Hispanics (23). 

Folates are transported from the extracellular milieu to the inside of cells by either receptor-mediated (FRa) or carrier-mediated uptake (RFC). Because folates are essential for proper cellular function and necessary for neural tube closure, it is easy to envision how mutations in these receptor genes could lead to reduced levels of intracellular folates and thereby NTDs. Thus, several groups have searched for... 

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