Alternative titles; symbols
HGNC Approved Gene Symbol: ABCG2
Cytogenetic location: 4q22.1 Genomic coordinates (GRCh38): 4:88,090,264-88,231,626 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q22.1 | [Junior blood group system] | 614490 | 3 | |
| [Uric acid concentration, serum, QTL1] | 138900 | ?Autosomal dominant | 3 |
The ABCG2 gene encodes a membrane transporter belonging to the ATP-binding cassette (ABC) superfamily of membrane transporters, which are involved in the trafficking of biologic molecules across cell membranes. ABCG2 was initially found to be a xenobiotic transporter that plays a role in the multidrug resistance phenotype of a specific human breast cancer (Doyle et al., 1998) and has since been shown to confer multidrug resistance in several cancer cells by actively exporting a wide variety of drugs across the plasma membrane. The ABCG2 protein is also a high capacity transporter for uric acid excretion in the kidney, liver, and gut (summary from Matsuo et al., 2009 and Saison et al., 2012).
For general information on the ABC superfamily, see ABCA4 (601691).
Allikmets et al. (1998) characterized an ABC transporter gene, which they designated ABCP, that is highly expressed in the placenta. The ABCP gene produces 2 transcripts that differ at the 5-prime end and encode the same 655-amino acid protein. The predicted protein is closely related to the Drosophila White and the yeast ADP1 proteins.
MCF-7/AdrVp is a multidrug-resistant human breast cancer subline that displays an ATP-dependent reduction in the intracellular accumulation of anthracycline anticancer drugs in the absence of overexpression of known multidrug resistance transporters such as P-glycoprotein (PGY1; 171050). By RNA fingerprinting, Doyle et al. (1998) identified a 2.4-kb mRNA that is overexpressed in these cells of the subline relative to parental MCF-7 cells. The mRNA encodes a 665-amino acid member of the ATP-binding cassette superfamily of transporters, which Doyle et al. (1998) termed the transporter breast cancer resistance protein (BCRP).
Miyake et al. (1999) cloned 2 cDNAs for ABCG2, which they called MRX1 and MRX2, that were overexpressed in human colon carcinoma cells selected for mitoxantrone resistance. Northern blot analysis confirmed marked overexpression of mRNA between 2.89 and 3.4 kb in the resistant cells. Using porcine brain capillary endothelial cells as a model for the blood-brain barrier, Eisenblatter and Galla (2002) identified porcine ABCG2 mRNA overexpressed in hydrocortisone-treated cultures. Northern blot analysis revealed expression in brain, with predominant localization within endothelial cells isolated from porcine brain capillaries.
Doyle et al. (1998) found that enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux or rhodamine-123 in the cloned transfected cells. Thus, BCRP is a xenobiotic transporter that appears to play a major role in the multidrug resistance phenotype of a specific human breast cancer.
Ozvegy et al. (2001) expressed ABCG2 as an underglycosylated recombinant protein in Sf9 insect cells. In vitro assays of isolated membrane preparations revealed a high-capacity, vanadate-sensitive ATPase activity associated with ABCG2 expression that was stimulated by compounds known to be transported by this protein. Ozvegy et al. (2001) concluded that ABCG2 is likely functioning as a homodimer or homooligomer in this expression system since it is unlikely that putative Sf9 transport partners would be overexpressed at similarly high levels.
Ozvegy et al. (2002) expressed wildtype human ABCG2, ABCG2 with mutations identified in drug-selected tumor cells (arg482 to gly (R482G) or arg482 to thr (R482T)), and ABCG2 with a catalytic center mutation (K86M) in Sf9 insect cells. The K86M mutant had no transport or ATP hydrolytic activity, although its ability to bind ATP was retained. Wildtype ABCG2 and the R482G and R482T mutants showed characteristically different drug and dye transport activities, but transport in each was blocked by the specific inhibitor fumitremorgin C. All variants showed high basal ATPase activity and vanadate-dependent adenine nucleotide trapping under nonhydrolytic conditions. However, only the R482G and R482T mutants showed ATPase activity that was stimulated in a drug-dependent manner and nucleotide trapping that was stimulated by transported compounds.
Jonker et al. (2002) showed that mice lacking Abcg2 became extremely sensitive to the dietary chlorophyll-breakdown product pheophorbide-a, resulting in severe, sometimes lethal phototoxic lesions on light-exposed skin. Abcg2 transports pheophorbide-a, which occurs in various plant-derived foods and food supplements and is highly efficient in limiting its uptake from ingested food. Homozygous deficient mice also displayed a novel type of protoporphyria (see 177000). Erythrocyte levels of the heme precursor and phototoxin protoporphyrin IX, which is structurally related to pheophorbide-a, were increased 10-fold. Transplantation with wildtype bone marrow cured the protoporphyria and reduced the phototoxin sensitivity of Abcg2 -/- mice. These results indicated that humans or animals with low or absent ABCG2 activity may be at increased risk for developing protoporphyria and diet-dependent phototoxicity and illustrated the importance of drug transporters in protection from toxicity of normal food constituents.
Accumulation of heme can lead to production of cell-damaging reactive oxygen species, and accumulation of heme/porphyrin can lead to collapse of mitochondrial function. Thus, regulation of intracellular porphyrin levels is fundamental to cell survival, particularly under conditions of low oxygen, when the cellular concentration of heme may increase. Krishnamurthy et al. (2004) showed that hematopoietic cells from Bcrp-null mice had increased sensitivity to hypoxia and accumulated heme. The hypoxia sensitivity of these cells was rescued by inhibition of heme biosynthesis. Krishnamurthy et al. (2004) found that Bcrp bound heme and that the presence of heme modified Bcrp-mediated transport. Bcrp expression was upregulated by hypoxia, and this upregulation involved the hypoxia-inducible transcription factor complex Hif1 (see 603348). Krishnamurthy et al. (2004) concluded that cells can, upon hypoxic demand, use BCRP to reduce heme or porphyrin accumulation.
Jonker et al. (2005) found high alveolar expression of ABCG2 in lactating but not virgin or nonlactating mammary glands of mice, cows, and humans. Clinically and toxicologically important substrates such as the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the anticancer drug topotecan, and the antiulcer drug cimetidine were highly concentrated in the milk of wildtype mice, but active secretion of these compounds was abolished in Abcg2 -/- mice. Jonker et al. (2005) concluded that ABCG2 is a major factor in the concentrative transfer of drugs, carcinogens, and dietary toxins to the milk of mice, cows, and humans.
Sims-Mourtada et al. (2007) showed that inhibition of Sonic hedgehog (SHH; 600725) signaling increased the response of human cancer cell lines to multiple structurally unrelated chemotherapies. SHH activation induced chemoresistance in part by increasing drug efflux in an ABC transporter-dependent manner. SHH signaling regulated expression of ABCB1 (171050) and ABCG2, and targeted knockdown of ABCB1 and ABCG2 expression by small interfering RNA partially reversed SHH-induced chemoresistance.
In Xenopus oocytes, Woodward et al. (2009) demonstrated that the human ABCG2 gene encodes a uric acid efflux transporter. In mammals, the proximal renal tubule is the major site of renal urate handling. ABCG2 was also found to be expressed at the apical brush border membrane in polarized renal epithelial cells, indicating that it is a secretory urate transporter in the proximal tubule. Thus, mutations in the ABCG2 gene that increase serum urate concentrations must be loss-of-function mutations.
In HEK293 cells, Matsuo et al. (2009) demonstrated that ABCG2 is a high-capacity, low-affinity exporter of uric acid.
Wang et al. (2010) identified ABCG2 as a target of microRNA-520H (MIR520H; 614755). Expression of an MIR520H mimic in PANC-1 human pancreatic cancer cells reduced ABCG2 mRNA and protein expression.
Bailey-Dell et al. (2001) determined that the ABCG2 gene contains 16 exons and spans over 66 kb. Sequence analysis indicated that the promoter region has a CCAAT box but no TATA box, a potential CpG island, and putative binding sites for SP1 (189906), AP1 (see 165160), and AP2 (TFAP2A; 107580). The promoter does not have a serum response element, suggesting that ABCG2 is not a lipid transporter. Assays of reporter gene activity with truncation mutants in the ABCG2 promoter suggested the presence of positive and negative regulatory elements.
Cryoelectron Microscopy
Taylor et al. (2017) presented the structure of human ABCG2 determined by cryoelectron microscopy, providing the first high-resolution insight into a human multidrug transporter. ABCG2 was visualized in complex with 2 antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. Taylor et al. (2017) observed 2 cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, Taylor et al. (2017) concluded that their results suggested a multidrug recognition and transport mechanism of ABCG2, rationalized disease-causing SNPs and the allosteric inhibition by the 5D3 antibody, and provided the structural basis of cholesterol recognition by other G-subfamily ABC transporters.
Manolaridis et al. (2018) presented high-resolution cryoelectron microscopy structures of human ABCG2 in a substrate-bound pretranslocation state and an ATP-bound posttranslocation state. For both structures, Manolaridis et al. (2018) used a mutant containing a glutamine replacing the catalytic glutamate, which resulted in reduced ATPase and transport rates and facilitated conformational trapping for structural studies. In the substrate-bound state, a single molecule of estrone-3-sulfate is bound in a central, hydrophobic, and cytoplasm-facing cavity about halfway across the membrane. Only 1 molecule of estrone-3-sulfate can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains, and a change in the relative orientation of the nucleotide-binding domain subdomains. Mutagenesis and in vitro characterization of transport and ATPase activities demonstrated the roles of specific residues in substrate recognition, including a leucine residue that forms a plug between the 2 cavities. Manolaridis et al. (2018) concluded that their results showed how ABCG2 harnesses the energy of ATP binding to extrude estrone-3-sulfate and other substrates, and suggested that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors.
By radiation hybrid analysis, Allikmets et al. (1998) mapped the ABCG2 gene to human chromosome 4q22, between markers D4S2462 and D4S1557. By the same method, they mapped the mouse Abcg2 gene to chromosome 6, 28 to 29 cM from the centromere.
Association with Increased Uric Acid Levels
Among 90 Japanese patients with increased serum uric acid levels (UAQTL1; 138900), Matsuo et al. (2009) identified 6 nonsynonymous changes in the ABCG2 gene. Three variants occurred at high frequencies and were studied in more detail: Q126X (603756.0002), Q141K (603756.0007), and V12M (603756.0003). In vitro cellular studies showed that ATP-dependent urate transport was reduced by 46.7% in cells expressing a Q141K mutation and was nearly eliminated in cells expressing a Q126X mutation, consistent with a loss of function. Both of these variants showed a significant association with hyperuricemia and with gout in a larger cohort of 228 Japanese men and 871 controls. These 2 variants were assigned to different risk haplotypes, and combinations of these haplotypes conferred different disease risks (up to an odds ratio of 25.8). The V12M substitution appeared to offer a protective effect and was found on a nonrisk haplotype.
Junior (Jr) Blood Group Antigen
By SNP haplotype analysis of 4 probands with Jr(a) antibodies to red blood cells, indicating that their red blood cells were of the Jr(a-) phenotype (614490), Zelinski et al. (2012) identified a shared homozygous region on chromosome 4q22 including the ABCG2 gene. Analysis of coding exons identified 4 different mutations in the ABCG2 gene (603756.0001-603756.0004) in the homozygous or compound heterozygous state. Three of the mutations caused null alleles, and erythrocytes from all individuals did not display the Jr antigen. One woman and her blood-group compatible sister were Caucasian, another woman and her blood-group compatible brother were Asian, and 2 further unrelated individuals were Asian. The findings indicated that the Jr(a-) blood group phenotype is defined by ABCG2 null alleles.
In 18 unrelated women with the Jr(a-) blood type, Saison et al. (2012) identified 8 different null mutations in the ABCG2 gene (see, e.g., 603756.0004-603756.0006). All mutations occurred in the homozygous or compound heterozygous state, indicating autosomal recessive inheritance. All women were identified during pregnancy after having developed anti-Jr(a) antibodies. Protein blot and flow cytometric analysis confirmed absence of the ABCG2 transporter on red blood cells of Jr(a-) individuals. Six women belonging to Gypsy communities of southwestern Europe were homozygous for the same mutation (R236X; 603756.0004), consistent with a founder effect. Because of the possible role of the ABCG2 protein as a uric acid transporter, Saison et al. (2012) measured plasma samples from pregnant Jr(a-) women, but urate levels were not significantly increased compared to controls. However, plasma porphyrin was significantly decreased and red blood cell porphyrin significantly increased in pregnant Jr(a-) women, suggesting a role for ABCG2 in exporting excess porphyrin from red blood cells. These individuals showed no symptoms of porphyria, but the aberrations in porphyrin transport may place them at risk under certain conditions.
In 2 Caucasian sisters with the Jr(a-) blood group phenotype (614490), Zelinski et al. (2012) identified a homozygous 736C-T transition in exon 7 of the ABCG2 gene, resulting in an arg246-to-ter (R246X) substitution in the ATP-binding domain. One of the women had Jr(a)-specific antibodies to red blood cells.
Matsuo et al. (2009) identified a heterozygous gln126-to-ter (Q126X) substitution in exon 4 of the ABCG2 gene in 10 of 90 Japanese individuals with increased serum uric acid (UAQTL1; 138900), yielding an allele frequency of 5.56% in this group. The allele frequency in the Japanese population was estimated at either 2.8% (Maekawa et al., 2006) or 5.5%, depending on the method used. Additional genotyping of 228 Japanese men with hyperuricemia, including 161 with gout, and 871 controls showed that presence of the Q126X allele increased the risk of hyperuricemia (odds ratio (OR) of 3.61; p = 2.91 x 10(-7)) and the risk of gout (OR of 4.25, p = 3.04 x 10(-8)). In vitro functional expression studies showed that the Q126X mutation nearly eliminated ATP-dependent urate transport, and Western blot analysis showed no detectable protein on membrane vesicles, consistent with a loss of function.
In an Asian sister and brother and an unrelated Asian woman with the Jr(a-) blood group phenotype (614490), Zelinski et al. (2012) identified a homozygous 376C-T transition in exon 4 of the ABCG2 gene (rs72552713), resulting in a gln126-to-ter substitution in the ATP-binding domain. The 2 women had Jr(a)-specific antibodies to red blood cells.
Saison et al. (2012) identified homozygosity for the Q126X mutation in 3 unrelated Korean women with the Jr(a-) phenotype and Jr(a) antibodies. They stated that the allele frequency in Japan ranged between 1.6 and 2.4%.
Among 90 Japanese individuals with increased serum uric acid (138900), Matsuo et al. (2009) found that 23 and 3 individuals, respectively, carried a heterozygous or homozygous V12M substitution, yielding an allele frequency of 16.11% in this group. The allele frequency in the Japanese population was estimated at either 19.2% (Maekawa et al., 2006) or 34.7%, depending on the method used. Additional genotyping of 228 Japanese men with hyperuricemia, including 161 with gout, and 871 controls suggested that the presence of the V12M allele was associated with a decreased risk of hyperuricemia (OR of 0.67, p = 0.005) and gout (OR of 0.68; p = 0.020). However, in vitro functional expression assays demonstrated that the V12M substitution did not result in any changes in urate transport or ABCG2 protein levels compared to wildtype.
In an Asian woman with the Jr(a-) blood group phenotype (614490), Zelinski et al. (2012) identified 3 mutations in the ABCG2 gene: homozygosity for a 34G-A transition in exon 2 (rs2231137), resulting in a val12-to-met (V12M) substitution, and heterozygosity for R236X (603756.0004). She had Jr(a)-specific antibodies to red blood cells, suggesting that her erythrocytes did not display the Jr(a) antigen.
In 7 unrelated women with the Jr(a-) blood group phenotype (614990), Saison et al. (2012) identified a homozygous 706C-T transition in exon 7 of the ABCG2 gene, resulting in an arg236-to-ter (R236X) substitution. Six of the 7 woman belonged to Gypsy communities in southwestern Europe and shared a common haplotype, consistent with a founder effect. However, 2 additional individuals not of Gypsy origin also carried R236X, suggesting that this mutation had arisen independently. Protein blot and flow cytometric analysis confirmed absence of the ABCG2 transporter on red blood cells of Jr(a-) individuals.
Zelinski et al. (2012) found that an Asian woman with the Jr(a-) phenotype was compound heterozygous for R236X and homozygous for another substitution in the ABCG2 gene (V12M; 603756.0003). Zelinski et al. (2012) noted that 706C-T (rs140207606) occurs in the ATP-binding domain.
In 2 unrelated women, believed to be of Turkish origin, with the Jr(a-) blood group phenotype (614490), Saison et al. (2012) identified a homozygous 2-bp deletion (791delTT) in exon 7 of the ABCG2 gene, predicted to result in a frameshift and premature termination. Both women developed anti-Jr(a) antibodies during pregnancy. Two additional patients from France were compound heterozygous for this mutation and another truncating mutation in the ABCG2 gene.
In a Pakistani woman with the Jr(a-) blood group phenotype (614490) who developed anti-Jr(a) antibodies during pregnancy, Saison et al. (2012) identified a homozygous 2-bp deletion (1111delAC) in exon 9 of the ABCG2 gene, resulting in a frameshift and premature termination.
By genomewide linkage analysis of 7,699 participants in the Framingham cohort and in 4,148 participants in a Rotterdam cohort, Dehghan et al. (2008) found a significant association between serum uric acid concentration (138900) and a G-to-T transversion in the ABCG2 gene (rs2231142), resulting in a gln141-to-lys (Q141K) substitution (p = 9.0 x 10(-20) and p = 3.3 x 10(-9), respectively). The findings were replicated in the ARIC cohort of 11,024 white and 3,843 black individuals, yielding p values of 9.7 x 10(-30) and 9.8 x 10(-4), respectively. The combined p value for white individuals from all 3 cohorts was 2.5 x 10(-60), and further analysis showed that the SNP was direction-consistent with the development of gout in white participants (OR of 1.74; p = 3.3 x 10(-15)).
Woodward et al. (2009) noted that the Q141K substitution occurs in a highly conserved residue in the intracellular nucleotide-binding domain. In vitro functional expression studies in Xenopus oocytes showed that the mutant Q141K protein caused a 54% reduction in urate transport compared to wildtype, consistent with a loss of function. Among 8,092 white individuals, the T allele was significantly associated with increased serum uric acid levels (p = 4 x 10(-27)). Among a larger cohort of 14,783 individuals including both blacks and whites, the T allele showed more significant associations with uric acid in whites (p = 10(-30)) compared to blacks (p = 10(-4)), owing to the lesser overall frequency of this allele among blacks. The effect was more pronounced in men compared to women. The frequency of Q141K is about 30% in Asian populations, 11% in white populations, and 3% in black populations.
Among 90 Japanese individuals with increased serum uric acid, Matsuo et al. (2009) found that 47 and 14 individuals, respectively, carried a heterozygous and homozygous Q141K substitution, yielding an allele frequency of 41.67% in this patient group. The frequency of Q141K in the general Japanese population was estimated to be 31.9% (Maekawa et al., 2006) or 53.6%, depending on the method used. Additional genotyping of 228 Japanese men with hyperuricemia, including 161 with gout, and 871 controls showed that the presence of the Q141K allele was associated with a significantly increased risk of hyperuricemia (OR of 2.06, p = 1.53 x 10(-11)) and gout (OR of 2.23; p = 5.54 x 10(-11)). In vitro functional expression studies showed that the Q141K mutation reduced the ATP-dependent transport of urate by 46.7%, consistent with a partial loss of function.
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