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 | 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)
|
Not determined |
Source:
Note:
These leukemia samples were collected during the time of diagnosis and approximately 10% of the samples were at the time of disease recurrence.
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.