Alternative titles; symbols
HGNC Approved Gene Symbol: SLC10A1
Cytogenetic location: 14q24.1 Genomic coordinates (GRCh38): 14:69,775,416-69,797,241 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.1 | Hypercholanemia, familial 2 | 619256 | Autosomal recessive | 3 |
The SLC10A1 gene encodes a transporter of conjugated bile salts from the plasma compartment into the hepatocyte. It is localized to the basolateral cell membrane and operates as a symporter, cotransporting 2 Na+ ions per bile salt molecule. The reuptake of bile salts by the SLC10A1 transporter concludes the enterohepatic cycle of bile salt circulation (summary by Vaz et al., 2015).
Sodium/bile acid cotransporters are integral membrane glycoproteins that participate in the enterohepatic circulation of bile acids. Two homologous transporters are involved in the reabsorption of bile acids, one absorbing from the intestinal lumen, the bile duct, and the kidney with an apical localization (SLC10A2; 601295), and the other being found in the basolateral membranes of hepatocytes (SLC10A1) (summary by Hallen et al., 2002).
Hagenbuch and Meier (1994) used a cDNA probe from a cloned rat liver Na+/taurocholate cotransporting polypeptide to screen a human liver cDNA library. A 1,599-bp cDNA clone that encodes the human equivalent NTCP was isolated. The deduced protein consists of 349 amino acids with a calculated molecular mass of 38 kD and exhibits 77% amino acid homology with the rat polypeptide. In vitro translation experiments indicated that the protein is glycosylated and has a molecular mass similar to that in the rat.
Hagenbuch and Meier (1994) found that injection of in vitro transcribed NTCP cRNA into Xenopus oocytes resulted in the expression of Na(+)-dependent taurocholate uptake. NTCP-mediated taurocholate uptake in oocytes was inhibited by all major bile acid derivatives and by bromosulfophthalein.
Using an uptake inhibition assay, Yan et al. (2014) showed that binding of the pre-S1 domain of hepatitis B virus (HBV) large envelope protein to NTCP interfered with bile acid transport by NTCP in HepG2 cells, and that this effect was conserved in human, mouse, and monkey. Furthermore, substrates of NTCP, such as bile salts, inhibited binding of the pre-S1 domain to NTCP, and thus viral infection by HBV and hepatitis D virus (HDV), through direct interference. Mutation of the predicted bile salt-binding sites on human NTCP reduced viral infection by HDV and HBV. Likewise, mutation of the Na(+)-binding sites of human NTCP interfered with HBV and HDV infection. However, unlike the bile acid-binding sites that were indispensable for viral infection, the Na(+)-binding sites only contributed to pre-S1 binding and viral infection. Further analysis demonstrated that an extracellular Na+ concentration close to the intracellular level was sufficient for NTCP binding to pre-S1 and HBV and HDV infection in HepG2 cells, indicating that an inward flow of Na+ current across cell membranes was likely not required for viral entry mediated by NTCP.
Studies by Peng et al. (2015) also showed that SLC10A1 is a cellular receptor for HBV.
Hallen et al. (2002) analyzed the structure and the structure-function relationship of SLC10A1 by topographic analysis, alanine insertion to disrupt predicted well-ordered structural elements, and glycosylation-site mutagenesis. They found that, like other sodium/bile acid transporters, SLC10A1 contains an exoplasmic N terminus, an odd number of transmembrane regions, and a cytoplasmic C terminus. Alanine insertion experiments confirmed that 7 of the 9 hydrophobic stretches are membrane-integrated, with secondary structures and transport activity sensitive to positional displacement. Two amphipathic sequences are critical for intramolecular interactions and for proper trafficking of SLC10A1 to the plasma membrane. Hallen et al. (2002) also determined that only 2 of the 5 potential N-linked glycosylation sites are utilized, and 1 of these is required for proper trafficking.
Shiao et al. (2000) determined that the SLC10A1 gene contains 5 exons and spans about 23 kb. In contrast to the rat promoter, the human promoter has no consensus TATA or CAAT box sequences. The authors identified a number of putative DNA-binding sites for the liver-enriched binding factors HNF3 (see 602294), HNF6 (604164), and CEBP (see CEBPA; 116897), as well as binding sites for numerous ubiquitous transcription factors. The promoter also contains potential sites for STAT proteins (see STAT1; 600555). Cotransfection of CEBP, but not other putative liver-enriched binding factors, increased SLC10A1 promoter activity. Electrophoretic mobility shift assays demonstrated specific protein-DNA interactions that involved CEBPA and CEBPB (189965).
By Southern blot analysis of genomic DNA from a panel of human/hamster somatic cell hybrids, Hagenbuch and Meier (1994) mapped the human NTCP gene to chromosome 14. Using somatic cell hybrid analysis and PCR-based screening of a YAC library, Shiao et al. (2000) refined the localization of the SLC10A1 gene to chromosome 14q24.1.
Green et al. (1998) used linkage analysis with the BSS backcross DNA panel of the Jackson Laboratory to map the mouse Slc10a1 gene to chromosome 12.
Ho et al. (2004) identified several polymorphisms in the SLC10A1 gene that had higher frequencies among certain populations. For example, a missense polymorphism (S267F; 182396.0002) was found in 7.5% of Chinese Americans, K314E was found in Hispanics, and I223T was found in Africans.
Deng et al. (2016) determined an allele frequency of the S267F variant in SLC10A1 of 4.7% among 75 healthy Chinese controls. They stated that their findings were consistent with other studies demonstrating that this polymorphism is common in East Asian countries, including China and Vietnam, but not in European, African, or Hispanic countries. Since SLC10A1 is the functional receptor of human hepatitis viruses B and D and the S267F mutation was shown to impair HBV infections in culture, Deng et al. (2016) suggested that the high allele frequency in this population may be a result of positive selection, since hepatitis B is more prevalent in those regions.
Familial Hypercholanemia 2
In a 5-year-old girl, born of consanguineous Afghan parents, with familial hypercholanemia-2 (FHCA2; 619256), Vaz et al. (2015) identified a homozygous missense mutation in the SLC10A1 gene (R252H; 182396.0001). In vitro functional expression studies in transfected HEK293 cells showed that the mutation caused a decrease in the Vmax for sodium-dependent taurocholate transport, although there was about 10% residual activity. The variant protein was not properly glycosylated and did not localize to the plasma membrane.
In a 30-month-old Chinese boy with FHCA2, Deng et al. (2016) identified a homozygous missense variant in the SLC10A1 gene (S267F; 182396.0002). The variant, which was confirmed by Sanger sequencing, segregated with the phenotype in the family. The S267F variant was considered to be a polymorphism, as it was found at an allele frequency of 4.7% in healthy Chinese controls. These findings were consistent with other studies demonstrating that this polymorphism is common in East Asian countries, including China and Vietnam, but not in European, African, or Hispanic countries. Deng et al. (2016) noted that SLC10A1 is the functional receptor of human hepatitis viruses B and D and that the S267F mutation impairs HBV infections in culture; this variant allele is associated with resistance to chronic hepatitis B in humans. The high allele frequency in this population may be a result of positive selection, since hepatitis B is more prevalent in those regions.
In 2 unrelated Chinese infants with FHCA2 and neonatal hyperbilirubinemia, Qiu et al. (2017) identified compound heterozygous variants in the SLC10A1 gene: S267F and I88T (182396.0003). The variants, which were found by Sanger sequencing, segregated with the disorder in both families. I88T was not present in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, but was found in 1 of 150 healthy Chinese controls (allele frequency of 0.67%). Functional studies of the I88T variant were not performed, but molecular modeling suggested that it may alter the conformation of the molecule.
Protection Against Hepatitis B Infection
Among 1,899 Chinese Han patients with chronic hepatitis B infection (see 610424) and 1,828 controls, Peng et al. (2015) found that the S267F variant in the SLC10A1 gene was significantly associated with resistance to chronic hepatitis B; see 182396.0002.
Mao et al. (2019) found that Slc10a1-null mice had increased serum bile acid levels that tended to decrease gradually with age. Transcriptome analysis of liver tissue derived from mutant mice showed several alterations, including inhibition of bile acid synthesis, enhancement of bile acid detoxification, altered bile acid transport, and increased expression of sulfotransferase genes, likely reflecting compensatory mechanisms.
In a 5-year-old girl, born of consanguineous Afghan parents, with familial hypercholanemia-2 (FHCA2; 619256), Vaz et al. (2015) identified a homozygous c.755G-A transition (c.755G-A, NM_003049.3) in the SLC10A1 gene, resulting in an arg252-to-his (R252H) substitution at a conserved residue predicted to be in transmembrane domain 9a. The mutation, which was found by direct sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. In vitro functional expression studies in transfected HEK293 cells showed that the mutation caused a decrease in the Vmax for sodium-dependent taurocholate transport, although there was about 10% residual activity. The variant protein was not properly glycosylated and did not localize to the plasma membrane. The data suggested that the mutant protein is retained in the endoplasmic reticulum (ER), and that absence of the protein at the plasma membrane causes the bile salt transport defect. The patient had high conjugated bile salt plasma levels without clear clinical symptoms, aside from mildly elongated prothrombin time and decreased bone density, presumably resulting from decreased absorption of fat-soluble vitamins A, D, and K.
Familial Hypercholanemia 2
In a 30-month-old Chinese boy with familial hypercholanemia-2 (FHCA2; 619256), Deng et al. (2016) identified a homozygous c.800C-T transition in the SLC10A1 gene, resulting in a ser267-to-phe (S267F) substitution. The variant, which was confirmed by Sanger sequencing, segregated with the phenotype in the family. The S267F variant was considered to be a polymorphism, as it was found at an allele frequency of 4.7% in healthy Chinese controls. One homozygote identified in the controls was a 30-year-old woman who was asymptomatic and had mildly elevated serum total bile acids. These findings were consistent with other studies demonstrating that this polymorphism is common in East Asian countries, including China and Vietnam, but not in European, African, or Hispanic countries. Deng et al. (2016) noted that SLC10A1 is the functional receptor of human hepatitis viruses B and D and that the S267F mutation impairs HBV infections in culture; this variant allele is associated with resistance to chronic hepatitis B in humans. The high allele frequency in this population may be a result of positive selection, since hepatitis B is more prevalent in those regions.
In 2 unrelated Chinese infants with FHCA2 and neonatal hyperbilirubinemia, Qiu et al. (2017) identified compound heterozygous variants in the SLC10A1 gene: S267F and a c.263T-C transition, resulting in an ile88-to-thr substitution (I88T; 182396.0003) at a conserved residue. The variants, which were found by Sanger sequencing, segregated with the disorder in both families. I88T was not present in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, but was found in 1 of 150 healthy Chinese controls (allele frequency of 0.67%). Functional studies of the I88T variant were not performed, but molecular modeling suggested that it may alter the conformation of the molecule.
Liu et al. (2017) identified 8 Chinese individuals with FHCA2 associated with a homozygous S267F variant in the SLC10A1 gene. Li et al. (2018) also described a Chinese boy with FHCA2 who carried the S267F variant in homozygosity.
Resistance to Hepatitis B Virus
Among 1,899 Chinese Han patients with chronic hepatitis B infection (see 610424) and 1,828 controls, Peng et al. (2015) found that the S267F variant in the SLC10A1 gene was significantly associated with resistance to chronic hepatitis B. The S267F variant was associated with healthy status irrespective of hepatitis surface B antibody status (p = 5.7 x 10(-23), odds ratio of 0.36), and was associated with lower incidence of acute liver failure (p = 0.007). Structural modeling showed that the S267F variant may interfere with ligand binding, thereby preventing HBV from cellular entry. The findings supported the role of SLC10A1 as a cellular receptor for HBV, and suggested that the S267F polymorphism confers a protective effect in HBV infection.
Variant Function
In vitro functional expression studies by Ho et al. (2004) showed that the S267F variant had a 98% reduction in taurocholate transport activity compared to wildtype, almost a complete loss of function. The variant showed normal expression at the plasma membrane and also retained transported activity for estrone sulfate. These findings pointed to S267 as a critical position for bile acid binding or recognition. The study also suggested that functionally relevant polymorphisms in SLC10A1 may have an impact on bile acid homeostasis.
For discussion of the c.263T-C transition in the SLC10A1 gene, resulting in an ile88-to-thr substitution (I88T), that was found in compound heterozygous state in 2 unrelated Chinese infants with familial hypercholanemia-2 (FHCA2; 619256) by Qiu et al. (2017), see 182396.0002.
Deng, M., Mao, M., Guo, L., Chen, F.-P., Wen, W.-R., Song, Y.-Z. Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency. Exp. Ther. Med. 12: 3294-3300, 2016. [PubMed: 27882152] [Full Text: https://doi.org/10.3892/etm.2016.3752]
Green, R. M., Ananthanarayanan, M., Suchy, F. J., Beier, D. R. Genetic mapping of the Na(+)-taurocholate cotransporting polypeptide to mouse chromosome 12. Mammalian Genome 9: 598-600, 1998. [PubMed: 9657862] [Full Text: https://doi.org/10.1007/s003359900826]
Hagenbuch, B., Meier, P. J. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na(+)/bile acid cotransporter. J. Clin. Invest. 93: 1326-1331, 1994. [PubMed: 8132774] [Full Text: https://doi.org/10.1172/JCI117091]
Hallen, S., Mareninova, O., Branden, M., Sachs, G. Organization of the membrane domain of the human liver sodium/bile acid cotransporter. Biochemistry 41: 7253-7266, 2002. [PubMed: 12044156] [Full Text: https://doi.org/10.1021/bi012152s]
Ho, R. H., Leake, B. F., Roberts, R. L., Lee, W., Kim, R. B. Ethnicity-dependent polymorphism in Na(+)-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J. Biol. Chem. 279: 7213-7222, 2004. [PubMed: 14660639] [Full Text: https://doi.org/10.1074/jbc.M305782200]
Li, H., Qiu, J.-W., Lin, G.-Z., Deng, M., Lin, W.-X., Cheng, Y., Song, Y.-Z. [Clinical and genetic analysis of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency]. Zhongguo Dang Dai Er Ke Za Zhi. 20: 279-284, 2018. Note: Article in Chinese. [PubMed: 29658451] [Full Text: https://doi.org/10.7499/j.issn.1008-8830.2018.04.005]
Liu, R., Chen, C., Xia, X., Liao, Q., Wang, Q., Newcombe, P. J., Xu, S., Chen, M., Ding, Y., Li, X., Liao, Z., Li, F., and 15 others. Homozygous p.ser267phe in SLC10A1 is associated with a new type of hypercholanemia and implications for personalized medicine. Sci. Rep. 7: 9214, 2017. [PubMed: 28835676] [Full Text: https://doi.org/10.1038/s41598-017-07012-2]
Mao, F., Liu, T., Hou, X., Zhao, H., He, W., Li, C., Jing, Z., Sui, J., Wang, F., Liu, X., Han, J., Borchers, C. H., Wang, J.-S., Li, W. Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency. J. Biol. Chem. 294: 11853-11862, 2019. [PubMed: 31201272] [Full Text: https://doi.org/10.1074/jbc.RA118.007179]
Peng, L., Zhao, Q., Li, Q., Li, M., Li, C., Xu, T., Jing, X., Zhu, X., Wang, Y., Li, F., Liu, R., Zhong, C., and 12 others. The p.ser267phe variant in SLC10A1 is associated with resistance to chronic hepatitis B. Hepatology 61: 1251-1260, 2015. [PubMed: 25418280] [Full Text: https://doi.org/10.1002/hep.27608]
Qiu, J.-W., Deng, M., Cheng, Y., Atif, R.-M., Lin, W.-X., Guo, L., Li, H., Song, Y.-Z. Sodium taurocholate cotransporting polypeptide (NTCP) deficiency: identification of a novel SLC10A1 mutation in two unrelated infants presenting with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia. Oncotarget 8: 106598-106607, 2017. [PubMed: 29290974] [Full Text: https://doi.org/10.18632/oncotarget.22503]
Shiao, T., Iwahashi, M., Fortune, J., Quattrochi, L., Bowman, S., Wick, M., Qadri, I., Simon, F. R. Structural and functional characterization of liver cell-specific activity of the human sodium/taurocholate cotransporter. Genomics 69: 203-213, 2000. [PubMed: 11031103] [Full Text: https://doi.org/10.1006/geno.2000.6329]
Vaz, F. M., Paulusma, C. C., Huidekoper, H., de Ru, M., Lim, C., Koster, J., Ho-Mok, K., Bootsma, A. H., Groen, A. K., Schaap, F. G., Oude Elferink, R. P. J., Waterham, H. R., Wanders, R. J. A. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 61: 260-267, 2015. [PubMed: 24867799] [Full Text: https://doi.org/10.1002/hep.27240]
Yan, H., Peng, B., Liu, Y., Xu, G., He, W., Ren, B., Jing, Z., Sui, J., Li, W. Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J. Virol. 88: 3273-3284, 2014. [PubMed: 24390325] [Full Text: https://doi.org/10.1128/JVI.03478-13]