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. Author manuscript; available in PMC: 2011 Nov 1.
Published in final edited form as: Pharmacogenet Genomics. 2010 Nov;20(11):708–715. doi: 10.1097/FPC.0b013e32833eca92

Table 1.

The functional effect of genetic variants in SLC19A1 gene identified through sequencing project in healthy subjects, in patients and in antifolate resistant cells.

Summary of SLC19A1 variants in healthy subjects (germline polymorphisms)
SNP Source Function/Effect Allele Frequency
rs1051266 (Arg27His) HapMap database and dbSNP (Build 131)c
  1. Association with plasma folate levels [3133]

  2. Association with risk of common birth defects [35, 36]

  3. Association with methotrexate transport [38]

  4. Association with methotrexate plasma level and response [4042]

  5. Association with methotrexate toxicities [57]

  6. Association with risk of cancer [4650]

G allele: 55% (European); 50% (Han Chinese); 43.2% (Japanese); 25.8% (Sub-Saharan African)
rs59638403 (Leu338Phe) PMT sequencing project in unrelated healthy individualsa, b Not characterized 0.6% in African American
rs56822323 (Gly341Asp) PMT sequencing project in unrelated healthy individualsa, b Not characterized 0.6% in African American
rs58227024 (Cys458Gly) PMT sequencing project in unrelated healthy individualsa, b Not characterized 0.6% in African American
rs58836581 (Asp522Asn) PMT sequencing project in unrelated healthy individualsa, b Not characterized 0.6% in African American
rs59841046 (Arg456Gln) PMT sequencing project in unrelated healthy individualsa, b Not characterized 1.7% in Asian American
rs7278825 (Ala469Val) PMT sequencing project in unrelated healthy individualsa, b Not characterized 1% in Mexican and 0.8% in Asian
rs56138890 (Ala324Ala) PMT sequencing project in unrelated healthy individualsa, b and in Indian population in India (dbSNP Build 131)c Not characterized 12.7% Asian American; 3% in Mexican American; 14.9% Indian
61bp insertion in -715 and -714 of SLC19A1 basal promoter (GenBank: AF046920.1) In 72 healthy subjects Increase in promoter activity [13]. 78% with this insertion. The ethnicity of the subjects was not mentioned.
Summary of SLC19A1 variants identified in tumor specimense
SNP Source Function/Effect Allele Frequency
Asp56His and Asp522Asn (rs58836581) 3 B-precursor ALL out of 203 B-precursor ALL, 32 T-lineage ALL specimens and 11 AML specimensd,e The uptake of methotrexate in blast cells from patients with Asp522Asn variant is significantly lowered compared to other samples containing reference SLC19A1 gene [28]. Asp167His: 1 patient; Asp522Asn: 1 patient
Ser46Asn, Glu21Lys, Ala7Val, Ser4Pro and Arg27His (rs1051266) 162 osteosarcoma samples The effect of these variants with methotrexate plasma level and resistance cannot be ruled out [29]. Arg27/Arg27: 30.2%; His27/His27: 22.8%; His27/Arg27: 37.6%; Ser46Asn: 4.32%; Glu21Lys: 1.85%; Ala7Val: 1.23%; Ser4Pro: 1.23%;
Summary of point mutations of SLC19A1 identified by acquired resistance to various antifolates in sublinese
SNP Source Function/Effect Allele Frequency
Ile46Phe and Trp105Gly Point mutations in L1210 mouse leukemia cells. Transfection of the SLC19A1 cDNA containing these mutants in L1210 cells conferred resistance to 5,10-dideazatetrahydrofolate compound [16, 25]. Not determined
Arg27His (rs1051266), Val29Leu, Glu45Lys and Ser46Ile, Leu143Pro, Ala147Val, Arg148Gly, Gln150Stop, Ser225Stop, Gly239Stop, Lys393Stop, Leu203Stop, Gly44Arg, Glu257Stop Point mutations in human CCRF-CEM leukemia cells. Human CCRF-CEM leukemia cells resistant to methotrexate and other anti-folates (e.g. GW1843, PT523, pemetrexed, trimetrexate, edatrexate)
  1. Glu45Lys: Folic acid influx doubled in the transfected L1210 cells with Glu45Lys. Whereas methotrexate and 5-formyltetrahydrofolate influx markedly decreased in the murine cells transfected with Glu45Lys. In addition, this study conducted in CEM cells demonstrated that E45K transfected cells have an initial rate of methotrexate influx ~ 0.5-fold that of reference cells [24, 58].

  2. Val29Leu, Glu45Lys, Ser46Ile: Transfection of the SLC19A1 cDNA containing these mutants in CEM cells conferred resistance to GW1843 [26].

  3. Gly44Arg: Transfection of this mutant into K562 and Chinese Hamster Ovary cells resulted in 12-fold increase in the transport Km for MTX [19, 59].

  4. Leu143Pro, Ala147Val, Arg148Gly, Gln150Stop: These mutations were found in CEM cells exposed to increasing PT523 concentrations. The resulted sublines displayed up to 3500 fold resistance to antifolates compounds, have decreased SLC19A1 protein levels and have impaired methotrexate transport [27].

  5. Stop condon: Ser225Stop, Gly239Stop, Lys393Stop, Leu203Stop, Glu257Stop: The SLC19A1 protein is not expressed in these nonsense mutations (stop codon). The SLC19A1 mRNA is expressed in these resistance sublines except for the sublines resistance to ZD9331 and PT523 antifolates compounds where no SLC19A1 mRNA is detected [59].

  6. Arg27His: This common SNP is also found in CEM cells exposed to methotrexate and edatrexate and it is present together with another point mutation (e.g. Glu45Lys and Ser225Stop). The functional effect is likely due to be the point mutation that occurs rather than Arg27His, since other studies have shown similar methotrexate uptake and kinetic transport between K562 cells transfected with Arg27 and His27 [38].

Not determined

Source:

Note:

d

These leukemia samples were collected during the time of diagnosis and approximately 10% of the samples were at the time of disease recurrence.

e

These variants are likely from somatic cells although the possibility that the variants are from normal cell DNA (germline DNA) that contaminated the tumor sample cannot be ruled out.