Annotated PGx Gene Information for SLC19A1
Submitted by: Ilaria Badagnani (PMT)
Reviewed by: Reviewed
Submitted date: July 11, 2006
| Gene HGNC Name: | SLC19A1 |
|---|---|
| Gene Common Name: | RFC1 |
| Introductory Information: | Transport of folates and antifolates into mammalian cells can occur via receptor-mediated or carrier-mediated mechanisms, and a functional coordination between these transport mechanisms has been proposed to be responsible for folate uptake in certain cell types. The reduced folate carrier (RFC1 or SLC19A1) plays a role in maintaining intracellular concentrations of folate, and also actively transports antifolate chemotherapeutic agents, such as methotrexate (MTX), into cells [PMID: 7826387, 9041240, 7615551, 7852378, 8276792, 9111015]. Several groups of investigators have independently cloned cDNAs (approximately 2.7 kb in length) encoding the 591-amino acid human RFC1 from lymphoblast, placenta, and small intestine cDNA libraries [PMID: 7826387, 9041240, 7615551, 7852378]. It has been shown that expressing human RFC1 in transport-deficient Chinese hamster ovary cells results in restoration of MTX transport and MTX sensitivity in these cells [PMID: 7615551]. Several point mutations have been identified in RFC1 and downregulation of RFC1 mRNA has also been reported [PMID: 9748272, 9028333, 9605439, 10187828]. These constitute important factors in the development of resistance to anti-folate chemotherapeutic agents. The RFC1 gene from human lymphoblasts was shown to contain five exons (exon 2 to exon 6), which code for RFC1 protein [PMID: 10226652, 9602167, 12228234]. There are at least four 5-prime alternative exons, which are used in the production of RFC1 mRNA transcript in lymphoblast cells. These are spliced in a mutually exclusive manner to exon 2, which was reported to contain the translational start site for the RFC1 protein. Using semi-quantitative PCR it was determined that exon 1 is preferentially incorporated in the transcript. In a separate study, RFC1 was shown to exhibit alternative splicing [PMID: 12144527]. Specifically, three splice variants of RFC1 were identified from a human liver genomic library, and resulted from the incorporation of three alternatives of exon 1 and different 3' sequences. Functional deletion analysis of the region upstream of the transcriptional start site of the RFC1 gene led to the identification of two TATA-less promoters, each of which showed significant differences in the efficiency of transcription. Several cellular and clinical studies have investigated the functional role of genetic variation in RFC1. In one study, L1210 mouse leukemia cells were selected for resistance to the anti-folate (6R)-5,10-dideazatetrahydrofolate [PMID: 9748272]. The resistant cells were shown to have two point mutations in RFC1, I48F and W105G, which contributed to the drug-resistant phenotype. Since these mutations dramatically altered the kinetics of folate transport, they were reported as participating in substrate interaction and likely constitute the substrate recognition domain of RFC1. Since the L1210/D3 resistant cells were shown to express the mutant transporter but the wild-type allele was still present in the genomic DNA, it was concluded that the wild-type allele was silenced during the development of resistance. A case-control interview study was performed to investigate whether there was an interaction between periconceptional folate supplementation in mothers and the development of spina bifida in infants carrying a naturally occurring polymorphism in RFC1, A80G (subsequent studies have determined that the G allele is more common, but in this paper, the polymorphism is referred to as A80G [PMID: 11857541]). Although the findings did not reach statistical significance, it was determined that in comparison to the AA genotype, infants with the GG genotype had decreased risk (OR = 0.5) of spina bifida if their mothers used folate supplementation, but had increased risk (OR = 2.4) of spina bifida if their mothers did not use folate supplementation. Another clinical study investigated whether the G80A polymorphism influenced the risk of congenital defects in infants depending upon whether their mothers used periconceptional folate supplementation [PMID: 16019224]. It was shown that mothers who did not use folate supplementation were more likely to have infants with congenital heart disease (CHD) compared with mothers who took folate (OR = 2.94). In addition, this study showed that among mothers who did not use folate, CHD risk was significantly higher for infants with the GG (OR = 4.03) and GA (OR = 4.14) genotypes compared to infants with the AA genotype. It was also determined that infants with the G allele at nucleotide position 80 in RFC1 were at increased risk for CHD but not cleft palate (Z = 2.140, p < .05). Another clinical study investigated whether the G80A polymorphism influenced the risk for thrombosis by affecting the disposition of homocysteine [PMID: 15964598]. It was determined that presence of the A allele in RFC1 significantly reduces the risk of thrombosis (OR = 0.56). Although the G80A polymorphism did not significantly alter plasma homocysteine levels, it resulted in an increase in the ratio of extracellular to intracellular folate levels, which is consistent with the physiological role of RFC1 in maintaining cellular folate homeostasis. Another clinical study examined whether the G80A polymorphism was associated with outcome in pediatric patients with acute lymphoblastic leukemia [PMID: 12411325]. It was shown that patients with the AA genotype had increased risk of having an event compared to patients with the AA genotype (OR = 3.0). In addition, patients with the AA genotype had worse outcomes and had significantly higher plasma levels of MTX than compared to patients with the GG genotype. |
| Key PubMed IDs: | 7826387, 9041240, 7615551, 7852378, 8276792, 9111015, 9748272, 9028333, 9605439, 10187828, 10226652, 9602167, 12228234, 12144527, 11857541, 16019224, 15964598, 12411325 |
| Key Pathways: | Methotrexate Pathway |
| Drugs/Substrates: | Methotrexate [PMID: 10598550], leucovorin [PMID: 16115875], pemetrexed [PMID: 12571805], Tomudex [PMID: 11705857], 5,10-dideazatetrahydrofolate [PMID:11705857], GW1843U89 [PMID: 11705857], and 10-ethyl-10-deazaaminopterin [PMID: 11705857] |
| Phenotypes/Diseases: | Congenital heart disease [PMID: 16019224], thrombosis [PMID: 15964598], MTX plasma levels [PMID:12411325] |
| Important Variants: | SLC19A1:Arg27His, SLC19A1:upstream inserted repeat |