Alternative titles; symbols
HGNC Approved Gene Symbol: ABCC1
Cytogenetic location: 16p13.11 Genomic coordinates (GRCh38): 16:15,949,143-16,143,053 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.11 | ?Deafness, autosomal dominant 77 | 618915 | Autosomal dominant | 3 |
The ABCC1 gene encodes multidrug resistance protein-1 (MRP1), which belongs to the ABC transporter family. MRP1 transports a structurally diverse range of endogenous substances, as well as xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions, and lipids. It is ubiquitously expressed in the body, particularly in cells at the interface between tissues and systemic circulation, such as the blood-brain barrier (summary by Li et al., 2019).
Cole et al. (1992) identified a transporter protein whose gene is overexpressed in a multidrug-resistant variant of the small cell lung cancer cell line NCI-H69. Unlike most tumor cell lines that are resistant to multiple chemotherapeutic agents, it did not overexpress the transmembrane transport protein P-glycoprotein (MDR1; 171050). Cole et al. (1992) isolated cDNA clones corresponding to mRNAs overexpressed in the resistant H69 cells. One cDNA hybridized to an mRNA of 7.8 to 8.2 kb that was expressed 100- to 200-fold higher in the resistant cells than in the drug-sensitive H69 cells. Overexpression was associated with amplification of the cognate gene. The cDNA contained a single open reading frame of 1,522 amino acids encoding a protein that they designated MRP, for 'multidrug resistance-associated protein.' (Cole and Deeley (1993) corrected the predicted protein sequence to 1,531 amino acids.) Database analyses demonstrated similarities in primary sequence to the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of transport systems. Included in this superfamily are the genes for MDR1 and for the cystic fibrosis transmembrane conductance regulator (CFTR; 602421). Northern blot analysis readily detected MRP transcripts in lung, testis, and peripheral blood mononuclear cells; MRP transcripts were below the level of detection in placenta, brain, kidney, salivary gland, uterus, liver, and spleen.
Li et al. (2019) found expression of the Abcc1 gene in the mouse inner ear, where it localized to the stria vascularis as well as to auditory nerves with a cytomembrane distribution. The findings suggested that the protein may function in exchanging substances in the inner ear.
Zaman et al. (1994) described experiments leading them to conclude that MRP is a plasma membrane drug-efflux pump.
Lorico et al. (2002) showed that glutathione is a cofactor in MRP-mediated resistance to heavy metal oxyanions: human fibrosarcoma cells overexpressing MRP1 together with the heavy (catalytic) subunit of gamma-glutamylcysteine synthetase (606857) showed increased resistance to sodium arsenite and antimony toxicity.
Using flow cytometric analysis, Muller et al. (2002) found that when a FLAG epitope was introduced into the extracellular loops of membrane-spanning domain-1 (MSD1) or MSD3 of MRP1, it was accessible on the cell surface upon removal of N-glycosylation sites. In contrast, FLAG epitope inserted into MSD2 was not accessible even after removal of all 3 N-glycosylation sites, indicating that MSD2 is deeply buried in the plasma membrane.
Using RT-PCR and Western blot analysis, Pascolo et al. (2003) found that MRP1 and MRP3 (ABCC3; 604323) were highly expressed in placenta, but only MRP1 was highly expressed in a trophoblastic cell line. MRP2 (ABCC2; 601107) and MRP5 (ABCC5; 605251) were only weakly expressed in placenta and the trophoblastic cell line. Third-trimester placenta expressed more MRP1 than first-trimester placenta. MRP1 expression increased markedly in the trophoblastic cell line upon polarization. Pascolo et al. (2003) concluded that MRP1 expression increases with trophoblast maturation.
In cultured mouse astrocytes, Gennuso et al. (2004) found that unconjugated bilirubin induced increased expression and transient redistribution of Mrp1 from the Golgi apparatus to the plasma membrane and throughout the cytoplasm. Blocking Mrp1 efflux pumps increased the susceptibility of the cells to the toxic effects of unconjugated bilirubin, suggesting that Mrp1 is an important protector in this scenario. The authors noted the relevance of the findings to neonatal encephalopathy caused by increased bilirubin.
Mitra et al. (2006) found that sphingosine-1-phosphate (S1P) was released from mast cells independently of degranulation. S1P secretion was dependent on ABCC1, but not on ABCB1 (171050), and inhibition of ABCC1 blocked both constitutive and antigen-stimulated S1P release. Chemotaxis assays showed that ABCC1-mediated transport of S1P influenced mast-cell migration, but not mast-cell degranulation.
The reactivation of latent human cytomegalovirus (HCMV) infection after transplantation is associated with high morbidity and mortality. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, whose establishment and/or maintenance require expression of the viral transcript UL138. Weekes et al. (2013) used stable isotope labeling by amino acids in cell culture-based mass spectrometry to identify a dramatic UL138-mediated loss of cell surface MRP1 and the reduction of substrate export by this transporter. Latency-associated loss of MRP1 and accumulation of the cytotoxic drug vincristine, an MRP1 substrate, depleted virus from naturally latent CD14+ (158120) and CD34+ (142230) progenitors, all of which are in vivo sites of latency. Weekes et al. (2013) concluded that the UL138-mediated loss of MRP1 provides a marker for detecting latent HCMV infection and a therapeutic target for eliminating latently infected cells before transplantation.
Grant et al. (1997) defined the intron/exon structure of MRP and characterized a number of splicing variants of MRP mRNA. The gene spans at least 200 kb. It contains 31 exons and a high proportion of class 0 introns, alternative splicing of which results in significant levels of variant transcripts that maintain the original open reading frame of MRP mRNA. (A class 0 splice occurs between 2 codons, e.g., ATG/ATG = Met.Met. A class 1 splice would be ATGA/TG and a class 2 splice would be ATGAT/G.) Analyses of the conservation of intron/exon organization and protein primary structure suggested that the MRP-related transporters evolved from a common ancestor shared with CFTR by fusion with 1 or more genes encoding polytopic membrane proteins.
By isotopic in situ hybridization, Cole et al. (1992) mapped the MRP1 gene to chromosome 16p13.1. Grant et al. (1997) located the MRP1 gene close to the short arm breakpoint of the pericentric inversion associated with the M4Eo subclass of acute myeloid leukemia and on the telomeric side of the MYH11 gene (160745).
Using PCR-SSCP analysis, Conrad et al. (2001) screened 36 Caucasian volunteers for mutations in the coding exons of the MRP1 gene, including the adjacent intron sequences. Among several changes found, 2 were predicted to cause amino acid substitutions. One of these mutations, G671V, was of special interest because it is located near the first nucleotide-binding domain. To determine whether this mutation caused a change in the MRP1 phenotype, a mutant MRP1 expression vector was constructed and transfected into SV40-transformed human embryonic kidney cells and the transport properties of the mutant protein were examined. With the substrates studied, the mutant showed no differences in organic anion transport activities compared to wildtype MRP1.
Wang et al. (2005) scanned for genomic signatures of recent positive selection in MRP1 in approximately 480 individuals sampled from the Chinese, Malay, Indian, European American, and African American populations. The genetic profile of SNPs at this locus revealed high haplotype diversity and weak linkage disequilibrium (LD). Despite this weak LD, the G allele of the -260G-C SNP (rs4148330) in the promoter region of the MRP1 gene, which was contained within a high-frequency haplotype, exhibited extended haplotype homozygosity across 135 kb in European Americans. Long-range haplotype and F(st) statistic tests showed evidence of positive selection for the G allele in the European American population. An MRP1 promoter-reporter assay showed significantly lower activity for the G allele-containing promoter when compared with the C allele-containing promoter in all 4 cell lines tested (P = less than 0.01). Wang et al. (2005) suggested that rs4148330 may account, in part, for interindividual variations and population differences in drug response.
Autosomal Dominant Deafness 77
In 10 affected members of a multigenerational Han Chinese family (family HN-SD01) with autosomal dominant deafness-77 (DFNA77; 618915), Li et al. (2019) identified a heterozygous missense mutation in the ABCC1 gene (N590S; 158343.0001). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. In vitro functional expression studies of patient-derived lymphoblastoid cells showed transiently decreased efflux capacity of an ABCC1 substrate compared to controls; however, by 6 hours, the efflux was the same between patient cells and controls. Screening of ABCC1 in an additional 217 patients with hearing loss identified candidate heterozygous pathogenic variants in 2 patients (G231D and E296V). Both variants were absent in the ExAC and gnomAD databases. However, familial segregation for these patients was not possible, and functional studies of these variants were not performed. Li et al. (2019) postulated that ABCC1 may exhibit a protective role in maintaining the homeostasis of the inner ear; decreased activity of this efflux pump may lead to impairment of inner ear function, resulting in late-onset hearing loss.
Robbiani et al. (2000) showed that migration of dendritic cells (DCs) from skin to lymph nodes utilizes the leukotriene C4 (LTC4; see 246530) transporter MRP1. DC mobilization from the epidermis and trafficking into lymphatic vessels was greatly reduced in Mrp1 -/- mice, but migration was restored by exogenous cysteinyl leukotrienes LTC4 or LTD4. In vitro, these cysteinyl leukotrienes promoted optimal chemotaxis to the chemokine CCL19 (SCYA19; 602227) but not to other related chemokines. Antagonism of CCL19 in vivo prevented DC migration out of the epidermis. Thus, the authors concluded that MRP1 regulates DC migration to lymph nodes, apparently by transporting LTC4, which in turn promotes chemotaxis to CCL19 and mobilization of DCs from the epidermis.
Schultz et al. (2001) showed that Mrp1-deficient mice had diminished outgrowth of Streptococcus pneumoniae and strongly reduced mortality compared with wildtype mice after intranasal infection. This advantage could be abrogated by treatment with a 5-lipoxygenase inhibitor. Mutant mice had low levels of LTC4 in lung because of accumulation of intracellular LTC4 and inhibition of LTC4 synthase. On the other hand, they had a reduced inflammatory response and high levels of LTB4 (see LTB4R2; 605773), which was associated with increased LTA4 hydrolase (151570) activity and was required for the protective effect. Schultz et al. (2001) suggested that MRP1 may be a novel target for adjunctive therapy in pneumonia.
Lorico et al. (2002) found resistance to heavy metal oxyanion toxicity in cell cultures overexpressing MRP1, but no increase in sensitivity to sodium arsenite and antimony in Mrp1 -/- knockout mice. The authors stated that the redundancy of transmembrane export pumps suggests that other pump(s) may effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.
In 10 affected members of a multigenerational Han Chinese family (family HN-SD01) with autosomal dominant deafness-77 (DFNA77; 618915), Li et al. (2019) identified a heterozygous c.1769A-G transition (c.1769A-G, NM_004996.3) in the ABCC1 gene, resulting in an asn590-to-ser (N590S) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Three unaffected or possibly affected members of the youngest generation also carried the mutation, suggesting age-dependent penetrance of the phenotype. The variant was found at low frequencies (less than 0.0001) in various populations in the gnomAD database; it was not found in 564 ethnically matched chromosomes from controls with normal hearing. Molecular modeling suggested that the mutation may affect the substrate-binding pocket. Analysis of patient cells and HEK cells transfected with the mutation showed that the mutant mRNA was less stable than wildtype, and that the mutant protein showed both normal membrane and abnormal cytoplasmic localization. In vitro functional expression studies of patient-derived lymphoblastoid cells showed transiently decreased efflux capacity of an ABCC1 substrate compared to controls; however, by 6 hours, the efflux was the same between patient cells and controls.
Cole, S. P. C., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., Stewart, A. J., Kurz, E. U., Duncan, A. M. V., Deeley, R. G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258: 1650-1654, 1992. Note: Erratum: Science 260: 879 only, 1993. [PubMed: 1360704] [Full Text: https://doi.org/10.1126/science.1360704]
Cole, S. P. C., Deeley, R. G. Multidrug resistance-associated protein: sequence correction. (Letter) Science 260: 879 only, 1993. [PubMed: 8098549] [Full Text: https://doi.org/10.1126/science.8098549]
Conrad, S., Kauffmann, H.-M., Ito, K., Deeley, R. G., Cole, S. P. C., Schrenk, D. Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution. J. Hum. Genet. 46: 656-663, 2001. [PubMed: 11721885] [Full Text: https://doi.org/10.1007/s100380170017]
Gennuso, F., Fernetti, C., Tirolo, C., Testa, N., L'Episcopo, F., Caniglia, S., Morale, M. C., Ostrow, J. D., Pascolo, L., Tiribelli, C., Marchetti, B. Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1). Proc. Nat. Acad. Sci. 101: 2470-2475, 2004. [PubMed: 14983033] [Full Text: https://doi.org/10.1073/pnas.0308452100]
Grant, C. E., Kurz, E. U., Cole, S. P. C., Deeley, R. G. Analysis of the intron-exon organization of the human multidrug-resistance protein gene (MRP) and alternative splicing of its mRNA. Genomics 45: 368-378, 1997. [PubMed: 9344662] [Full Text: https://doi.org/10.1006/geno.1997.4950]
Li, M., Mei, L., He, C., Chen, H., Cai, X., Liu, Y., Tian, R., Tian, Q., Song, J., Jian, L., Liu, C. Wu, H., and 11 others. Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepside genetic analysis. Genet. Med. 21: 2744-2754, 2019. [PubMed: 31273342] [Full Text: https://doi.org/10.1038/s41436-019-0594-y]
Lorico, A., Bertola, A., Baum, C., Fodstad, O., Rappa, G. Role of multidrug resistance protein 1 in protection from heavy metal oxyanions: investigations in vitro and in Mrp1-deficient mice. Biochem. Biophys. Res. Commun. 291: 617-622, 2002. [PubMed: 11855834] [Full Text: https://doi.org/10.1006/bbrc.2002.6489]
Mitra, P., Oskeritzian, C. A., Payne, S. G., Beaven, M. A., Milstien, S., Spiegel, S. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc. Nat. Acad. Sci. 103: 16394-16399, 2006. [PubMed: 17050692] [Full Text: https://doi.org/10.1073/pnas.0603734103]
Muller, M., Yong, M., Peng, X.-H., Petre, B., Arora, S., Ambudkar, S. V. Evidence for the role of glycosylation in accessibility of the extracellular domains of human MRP1 (ABCC1). Biochemistry 41: 10123-10132, 2002. [PubMed: 12146977] [Full Text: https://doi.org/10.1021/bi026075s]
Pascolo, L., Fernetti, C., Pirulli, D., Crovella, S., Amoroso, A., Tiribelli, C. Effects of maturation on RNA transcription and protein expression of four MRP genes in human placenta and in BeWo cells. Biochem. Biophys. Res. Commun. 303: 259-265, 2003. [PubMed: 12646196] [Full Text: https://doi.org/10.1016/s0006-291x(03)00327-9]
Robbiani, D. F., Finch, R. A., Jager, D., Muller, W. A., Sartorelli, A. C., Randolph, G. J. The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3-beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103: 757-768, 2000. [PubMed: 11114332] [Full Text: https://doi.org/10.1016/s0092-8674(00)00179-3]
Schultz, M. J., Wijnholds, J., Peppelenbosch, M. P., Vervoordeldonk, M. J. B. M., Speelman, P., van Deventer, S. J. H., Borst, P., van der Poll, T. Mice lacking the multidrug resistance protein 1 are resistant to Streptococcus pneumoniae-induced pneumonia. J. Immun. 166: 4059-4064, 2001. [PubMed: 11238654] [Full Text: https://doi.org/10.4049/jimmunol.166.6.4059]
Wang, Z., Wang, B., Tang, K., Lee, E. J. D., Chong, S. S., Lee, C. G. L. A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection. Hum. Molec. Genet. 14: 2075-2087, 2005. [PubMed: 15944197] [Full Text: https://doi.org/10.1093/hmg/ddi212]
Weekes, M. P., Tan, S. Y. L., Poole, E., Talbot, S., Antrobus, R., Smith, D. L., Montag, C., Gygi, S. P., Sinclair, J. H., Lehner, P. J. Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science 340: 199-202, 2013. [PubMed: 23580527] [Full Text: https://doi.org/10.1126/science.1235047]
Zaman, G. J. R., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., Pinedo, H. M., Scheper, R. J., Baas, F., Broxterman, H. J., Borst, P. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc. Nat. Acad. Sci. 91: 8822-8826, 1994. [PubMed: 7916458] [Full Text: https://doi.org/10.1073/pnas.91.19.8822]