Alternative titles; symbols
HGNC Approved Gene Symbol: SLCO1B1
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38) : 12:21,131,194-21,239,796 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.1 | Hyperbilirubinemia, Rotor type, digenic | 237450 | Digenic recessive | 3 |
By searching an EST database for organic anion transporter (OATP, or SLC21A3; 602883)- and prostaglandin transporter (SLC21A2; 601460)-related sequences, Abe et al. (1999) identified ESTs encoding SLC21A6, which they called LST1. The SLC21A6 gene encodes a deduced 691-amino acid protein containing 12 transmembrane domains, 7 putative N-glycosylation sites in the extracellular loops, and 2 potential phosphorylation sites. Northern blot analysis detected major 3.0- and minor 4.8-kb SLC21A6 transcripts exclusively in liver, in contrast to the more widely expressed SLC21A3.
By searching an EST database using the OATP sequence as the probe, Konig et al. (2000) identified an EST encoding SLC21A6, which they called OATP2. The authors indicated that the SLC21A6 protein contains 6 putative N-glycosylation sites in the extracellular loops. Northern blot analysis detected a 2.8-kb SLC21A6 transcript, likely to correspond to the fully spliced mRNA, and a 4.5-kb SLC21A6 transcript, likely to correspond to a partially or unspliced mRNA; both transcripts were detected only in liver. Western blot analysis detected an SLC21A6 protein of 84 kD that was reduced to 58 kD by deglycosylation. Confocal immunofluorescence analyses revealed expression of SLC21A6 on the basolateral membranes but not the canalicular domain of hepatocytes.
By radiation hybrid analysis, Tamai et al. (2000) mapped the SLCO1B1 gene to chromosome 12, between markers D12S358 and D12S1596.
Abe et al. (1999) found that SLC21A6 transported eicosanoids, thyroid hormones, and conjugated steroids, particularly 17-beta-glucuronosyl estradiol, in a sodium-independent manner.
Tamai et al. (2000) overexpressed OATPC in HEK293 cells and found that it mediated transport of estrone-3-sulfate, estradiol-17 beta-glucuronide, benzylpenicillin, and, more weakly, prostaglandin E2.
Wang et al. (2003) found that HeLa and HEK293 cells transfected with human SLC21A6 acquired the ability to transport the synthetic organic anionic dye sulfobromophthalein, but not the natural pigment bilirubin.
In a series of mouse knockout studies, van de Steeg et al. (2012) demonstrated that the human SLCO1B1 and SLCO1B3 (605495) genes encode proteins expressed at the hepatic sinusoidal membrane that effectively reabsorb bilirubin glucuronides from plasma into the liver. The studies suggested that ABCC3 (604323), SLCO1B1, and SLCO1B3 may form a liver-blood shuttling loop for bilirubin glucuronide, in which ABCC3 secretes conjugated bilirubin back into the blood, and the SLC proteins reabsorb it in downstream hepatocytes, thus facilitating efficient detoxification.
Rotor-Type Hyperbilirubinemia, Digenic
In affected members of 8 families with Rotor-type hyperbilirubinemia (HBLRR; 237450), van de Steeg et al. (2012) identified 2 different homozygous mutations in 2 different genes: the SLCO1B1 gene (604843.0001-604843.0003) and the SLCO1B3 gene (605495.0001-605495.0003). Three of the families, who were Saudi Arabian, were homozygous for a 405-kb deletion on chromosome 12 encompassing exons 3 to 15 of SLCO1B3 (605495) and the whole of SLCO1B1, as well as homozygous for a splice site mutation in SLCO1B1 (604843.0002). Segregation patterns in the families indicated that the disorder can only be caused by complete and simultaneous deficiencies of these 2 genes, which mediate uptake and clearance of conjugated bilirubin across the hepatic sinusoidal membranes into bile. Affected individuals showed conjugated hyperbilirubinemia, delayed plasma clearance of an anionic diagnostic dye (bromsulfthalein), and increased urinary excretion of coproporphyrin I. Van de Steeg et al. (2012) suggested that individuals with Rotor syndrome may also be at increased risk for drug toxicity, since these proteins are involved in the clearance of drug conjugates.
Associations Pending Confirmation
By Western blot analysis of 81 human liver samples, Michalski et al. (2002) identified 1 with a reduced amount of SLC21A6 protein. The SLC21A6 cDNA from this sample contained 5 basepair changes in 1 allele, and 3 of the mutations resulted in amino acid substitutions. Two of the amino acid changes, asn130 to asp (N130D) and pro155 to thr (P155T), were polymorphisms, but the third, a leu193-to-arg (L193R) substitution, appeared to be a rare mutation. When transfected into MDCK canine kidney cells, SLC21A6 with either N130D or P155T showed altered substrate specificity compared with wildtype SLC21A6. In contrast, SLC21A6 with L193R was more weakly expressed at the protein level and showed altered cellular distribution. Wildtype SLC21A6 was expressed at the basolateral membrane of normal human liver and in transfected MDCK cells, but both SLC21A6 with the mutant haplotype and SLC21A6 with only L193R were retained intracellularly, although their corresponding mRNA levels appeared unchanged. In transfected MDCK cells, neither SLC21A6 with the mutant haplotype nor SLC21A6 with L193R showed transport activity.
Takane et al. (2006) genotyped 33 hypercholesterolemic patients for variants in the SLCO1B1 gene and analyzed their response to the cholesterol-lowering drug pravastatin. Patients who were carriers of the so-called *15 allele had significantly smaller reductions in total and LDL cholesterol than noncarriers at 8 weeks, although there were no significant differences at 1 year posttreatment. Takane et al. (2006) suggested that the SLCO1B1*15 allele is associated with a slow response to pravastatin.
The SEARCH Collaborative Group (2008) identified a significant association between common variants in the SLCO1B1 gene and statin-induced myopathy. A genomewide scan among 85 individuals with myopathy identified a noncoding SNP in intron 11 of the SLCO1B1 gene (rs4363657). Further analysis found a significant association between myopathy and a nonsynonymous SNP in exon 6 (rs4149056). The odds ratio for myopathy was 4.5 per copy of the C allele and 16.9 among CC homozygotes as compared with TT homozygotes (p = 2 x 10(-9)). Replication was achieved in a group of 16,664 individuals, although the odds ratio decreased to 2.6 per C allele. However, the study also indicated that the risk of myopathy may be substantially increased in patients who take 80 mg of simvastatin daily, as well as in those who are also receiving certain other drugs.
Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked variation of rifampin concentration occurs among individuals, and decreased response to therapy has been observed among patients at African sites compared with non-African sites. Weiner et al. (2010) evaluated rifampin pharmacokinetics in 72 adult patients with tuberculosis (TB; see 607948) from Africa, North America, and Spain and in 16 healthy controls from North America. They found that rifampin pharmacokinetics were similar between TB patients and controls. However, in multivariable analyses, the plasma area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) for rifampin was significantly affected by rifampin dosage, the presence of TB by geographic region, and a SNP in the SLCO1B1 gene, C to A at cDNA position 463 (463C-A; rs11045849), which results in a P155T substitution. The adjusted AUC(0-24) was lowest in the 37 TB patients from Africa compared with 33 non-African TB patients and the controls (P = 0.02, ANCOVA). Furthermore, the adjusted AUC(0-24) was 36% lower in 15 participants heterozygous for the SLCO1B1 SNP, i.e., genotype 463CA, compared with 71 people with genotype 463CC (P = 0.001, ANCOVA). The 463CA genotype was more frequent among Africans and individuals of African descent than non-Africans (24% vs 10%, respectively; P = 0.09, chi-square test). SNPs in another organic ion transporter peptide, SLCO1B3 (605495), and in P-glycoprotein (ABCB1; 171050), both of which, like SLCO1B1, are induced by chronic rifampin use via activation of NR1I2 (603065), were not associated with rifampin concentration. Weiner et al. (2010) concluded that the 463C-A SNP in the SLCO1B1 gene is a significant factor affecting the rifampin concentration achieved in TB patients.
For discussion of a possible association between variation in the SLCO1B1 gene and serum bilirubin level, see 601816.
In affected members of 3 families from central Europe with Rotor-type hyperbilirubinemia (HBLRR; 237450), van de Steeg et al. (2012) identified 2 different homozygous mutations in 2 different genes. One was a homozygous 1738C-T transition in the SLCO1B1 gene, resulting in an arg580-to-ter (R580X) substitution (rs71581941) predicted to remove the C-terminal one-and-one-half transmembrane domains, and the other was a homozygous 7.2-kb deletion within the SLCO1B3 gene (605495.0001).
In affected individuals from 3 Saudi Arabian families with Rotor-type hyperbilirubinemia (HBLRR; 237450), van de Steeg et al. (2012) identified 2 different homozygous mutations in 2 different genes. One was a homozygous G-to-T transversion in intron 5 (481+1G-T) of the SLCO1B1 gene, predicted to result in a dysfunctional RNA or protein, and the other was a homozygous 405-kb deletion encompassing exons 3 to 15 of the SLCO1B3 gene (605495) and the whole of SLCO1B1. This same genotype was also found in a patient from central Europe with the condition.
In a Filipino patient with Rotor-type hyperbilirubinemia (HBLRR; 237450), van de Steeg et al. (2012) identified 2 different homozygous mutations in 2 different genes. One was a 757C-T transition in exon 8 of the SLCO1B1 gene, resulting in an arg253-to-ter (R253X) substitution and truncation of the protein before the C-terminal 7 transmembrane domains, and the other was a homozygous splice site mutation in the SLCO1B3 gene (605495.0002).
Abe, T., Kakyo, M., Tokui, T., Nakagomi, R., Nishio, T., Nakai, D., Nomura, H., Unno, M., Suzuki, M., Naitoh, T., Matsuno, S., Yawo, H. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J. Biol. Chem. 274: 17159-17163, 1999. [PubMed: 10358072] [Full Text: https://doi.org/10.1074/jbc.274.24.17159]
Konig, J., Cui, Y., Nies, A. T., Keppler, D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol. Gastrointest. Liver Physiol. 278: G156-G164, 2000. [PubMed: 10644574] [Full Text: https://doi.org/10.1152/ajpgi.2000.278.1.G156]
Michalski, C., Cui, Y., Nies, A. T., Nuessler, A. K., Neuhaus, P., Zanger, U. M., Klein, K., Eichelbaum, M., Keppler, D., Konig, J. A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J. Biol. Chem. 277: 43058-43063, 2002. [PubMed: 12196548] [Full Text: https://doi.org/10.1074/jbc.M207735200]
Takane, H., Miyata, M., Burioka, N., Shigemasa, C., Shimizu, E., Otsubo, K., Ieiri, I. Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy. J. Hum. Genet. 51: 822-826, 2006. [PubMed: 16917677] [Full Text: https://doi.org/10.1007/s10038-006-0025-1]
Tamai, I., Nezu, J., Uchino, H., Sai, Y., Oku, A., Shimane, M., Tsuji, A. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun. 273: 251-260, 2000. [PubMed: 10873595] [Full Text: https://doi.org/10.1006/bbrc.2000.2922]
The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy--a genomewide study. New Eng. J. Med. 359: 789-799, 2008. [PubMed: 18650507] [Full Text: https://doi.org/10.1056/NEJMoa0801936]
van de Steeg, E., Stranecky, V., Hartmannova, H., Noskova, L., Hrebicek, M., Wagenaar, E., van Esch, A., de Waart, D. R., Oude Elferink, R. P. J., Kenworthy, K. E., Sticova, E., Al-Edreesi, M., Knisely, A. S., Kmoch, S., Jirsa, M., Schinkel, A. H. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J. Clin. Invest. 122: 519-528, 2012. [PubMed: 22232210] [Full Text: https://doi.org/10.1172/JCI59526]
Wang, P., Kim, R. B., Chowdhury, J. R., Wolkoff, A. W. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J. Biol. Chem. 278: 20695-20699, 2003. [PubMed: 12670950] [Full Text: https://doi.org/10.1074/jbc.M301100200]
Weiner, M., Peloquin, C., Burman, W., Luo, C.-C., Engle, M., Prihoda, T. J., Mac Kenzie, W. R., Bliven-Sizemore, E., Johnson, J. L., Vernon, A. Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Antimicrob. Agents Chemother. 54: 4192-4200, 2010. [PubMed: 20660695] [Full Text: https://doi.org/10.1128/AAC.00353-10]