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HGNC Approved Gene Symbol: SLCO1B3
Cytogenetic location: 12p12.2 Genomic coordinates (GRCh38) : 12:20,810,705-20,916,911 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.2 | Hyperbilirubinemia, Rotor type, digenic | 237450 | Digenic recessive | 3 |
SLCO1B3 belongs to the organic anion transporter (OATP) family. OATPs are involved in the membrane transport of bile acids, conjugated steroids, thyroid hormone, eicosanoids, peptides, and numerous drugs in many tissues (Mikkaichi et al., 2004).
An SLCO1B3-SLCO1B7 (619875) spliced read-through transcript also appears to produce a functional OATP (Malagnino et al., 2018).
Based on sequence homology to human organic anion transporter-2 (OATP2) (SLCO1B1; 604843), Konig et al. (2000) cloned SLCO1B3, which they termed OATP8 (SLC21A8). The deduced 702-amino acid OATP8 protein shares 80% sequence identity with OATP2, a hepatic basolateral uptake transporter. Northern blot analysis revealed a liver-specific expression pattern similar to that of OATP2. An antibody raised against the C terminus localized OATP8 to the basolateral membrane of human hepatocytes and the recombinant glycoprotein, expressed in MDCKII cells, to the lateral membrane.
SLCO1B3-SLCO1B7 Read-Through Transcript
Malagnino et al. (2018) identified a human SLCO1B3-SLCO1B7 spliced read-through transcript, which they called LST-3TM12, in which the 5-prime part originated from SLCO1B3 and the remainder originated from SLCO1B7. The read-through transcript encodes an OATP with 12 transmembrane domains and a large fifth extracellular loop. RT-PCR analysis showed that SLCO1B3-SLCO1B7 was expressed in human liver and originated from hepatocytes. Immunostaining revealed that SLCO1B3-SLCO1B7 localized to multiple vesicular intracellular structures representing the endoplasmic reticulum (ER). Heterologous expression in HeLa cells confirmed ER localization and also showed localization in the plasma membrane.
By Western blot analysis, Malagnino et al. (2019) showed that the SLCO1B3-SLCO1B7 protein, which they called OATP1B3-1B7, was expressed in microsomes of human liver and small intestine and localized to smooth ER (SER).
Konig et al. (2000) determined that the SLCO1B3 gene contains 14 exons, similar to the SLCO1A2 (602883) and SLCO1B1 genes. SLCO1B3 has 13 and 9 exons identical in length with those of SLCO1B1 and SLCO1A2, respectively.
Konig et al. (2000) mapped the SLCO1B3 gene to chromosome 12p12 by identification of its sequence within a cosmid clone.
Meyer zu Schwabedissen et al. (2020) stated that the SLCO1B3 gene maps to chromosome 12p12.2, upstream of the SLCO1B7 gene.
Konig et al. (2000) found that OATP8 is also an uptake transporter of organic anions including sulfobromophthalein and 17-beta-glucuronosyl estradiol. They also found that OATP8 did not transport several bile salts that are transported by OATP2.
In a series of mouse knockout studies, van de Steeg et al. (2012) demonstrated that the human SLCO1B1 (604843) and SLCO1B3 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.
SLCO1B3-SLCO1B7 Read-Through Transcript
Malagnino et al. (2018) showed that overexpression of SLCO1B3-SLCO1B7 significantly enhanced uptake of dehdroepiandrosterone sulfate (DHEAS) and estradiol 17-beta-D-glucuronide in transfected HeLa cells. SLCO1B3-SLCO1B7 was enriched on microsomes and likely accumulated the substrates in liver microsomes.
Using a drug screening test in HeLa cells, Malagnino et al. (2019) identified ezetimibe as an inhibitor of OATP1B3-1B7-mediated transport of DHEAS. Ezetimibe was not only an OATP1B3-1B7 inhibitor, but also a substrate of OATP1B3-1B7. Ezetimibe glucuronidation rates were decreased by BSP, another OATP1B3-1B7 inhibitor, suggesting that OATP1B3-1B7 may function as an SER gateway for ezetimibe.
By 5-prime RACE analysis, Malagnino et al. (2019) showed that transcription of OATP1B3-1B7, as well as both SLCO1B3 and SLCO1B7, was regulated by the SLCO1B3 promoter. Consequently, knockdown of SLCO1B3 in Huh-7 cells reduced SLCO1B3 and SLCO1B7 expression. Treatment of Huh-7 and HepaRG cells with activators of FXR (NR1H4; 603826), a regulator of SLCO1B3, increased both SLCO1B3 and OATP1B3-1B7 transcripts and influenced cellular accumulation of an OATP1B3-1B7 substrate. Bile acids interacted with OATP1B3-1B7, and their transport into human liver microsomes was significantly reduced in the presence of BSP, an OATP1B3-1B7 inhibitor, indicating that OATP1B3-1B7 is also a bile acid transporter.
Meyer zu Schwabedissen et al. (2020) identified SLCO1B7 coding polymorphisms that influenced the in vitro transport function of OATP1B3-1B7 without altering its expression.
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 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
For discussion of a possible association between variation in the SLCO1B3 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 7.2-kb deletion within the SLCO1B3 gene, removing exon 12 and introducing a frameshift and a premature termination codon, thus removing the 3 C-terminal transmembrane domains, and the other was a homozygous mutation in the SLCOB1 gene (R580X; 604843.0001).
In a Filipino patient with Rotor-type hyperbilirubinemia (237450), van de Steeg et al. (2012) identified 2 different homozygous mutations affecting 2 different genes. One was a homozygous G-to-A transition in intron 13 of the SLCO1B3 gene (1747+1G-A), predicted to result either in an aberrant transcript or in a truncated protein, and the other was a homozygous truncating mutation in the SLCO1B1 gene (R253X; 604843.0003).
Konig, J., Cui, Y., Nies, A. T., Keppler, D. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J. Biol. Chem. 275: 23161-23168, 2000. [PubMed: 10779507] [Full Text: https://doi.org/10.1074/jbc.M001448200]
Malagnino, V., Duthaler, U., Seibert, I., Krahenbuhl, S., Meyer zu Schwabedissen, H. E. OATP1B3-1B7 (LST-3TM12) is a drug transporter that affects endoplasmic reticulum access and the metabolism of ezetimibe. Molec. Pharm. 96: 128-137, 2019. [PubMed: 31127008] [Full Text: https://doi.org/10.1124/mol.118.114934]
Malagnino, V., Hussner, J., Issa, A., Midzic, A., Meyer zu Schwabedissen, H. E. OATP1B3-1B7, a novel organic anion transporting polypeptide, is modulated by FXR ligands and transports bile acids. Am. J. Physiol. Gastrointest. Liver Physiol. 317: G751-G762, 2019. [PubMed: 31509437] [Full Text: https://doi.org/10.1152/ajpgi.00330.2018]
Malagnino, V., Hussner, J., Seibert, I., Stolzenburg, A., Sager, C. P., Meyer zu Schwabedissen, H. E. LST-3TM12 is a member of the OATP1B family and a functional transporter. Biochem. Pharm. 148: 75-87, 2018. [PubMed: 29248594] [Full Text: https://doi.org/10.1016/j.bcp.2017.12.012]
Meyer zu Schwabedissen, H. E., Seibert, I., Grube, M., Alter, C. L., Siegmund, W., Hussner, J. Genetic variants of SLCO1B7 are of relevance for the transport function of OATP1B3-1B7. Pharm. Res. 161: 105155, 2020. [PubMed: 32818652] [Full Text: https://doi.org/10.1016/j.phrs.2020.105155]
Mikkaichi, T., Suzuki, T., Onogawa, T., Tanemoto, M., Mizutamari, H., Okada, M., Chaki, T., Masuda, S., Tokui, T., Eto, N., Abe, M., Satoh, F., Unno, M., Hishinuma, T., Inui, K., Ito, S., Goto, J., Abe, T. Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc. Nat. Acad. Sci. 101: 3569-3574, 2004. [PubMed: 14993604] [Full Text: https://doi.org/10.1073/pnas.0304987101]
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]