Alternative titles; symbols
HGNC Approved Gene Symbol: ABCB11
SNOMEDCT: 1155841005;
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:168,915,390-169,031,324 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Cholestasis, benign recurrent intrahepatic, 2 | 605479 | Autosomal recessive | 3 |
| Cholestasis, progressive familial intrahepatic 2 | 601847 | Autosomal recessive | 3 |
By positional cloning within the candidate region for progressive intrahepatic cholestasis-2 (PFIC2; 601847) on chromosome 2q24, Strautnieks et al. (1998) identified and cloned the ABCB11 gene, which they called BSEP. The deduced protein has a predicted topology similar to that of other members of the multidrug resistant (MDR) family, with 2 putative transmembrane domains, each with 6 spans, and 2 nucleotide-binding folds containing highly conserved ATP-binding cassettes (ABC). Northern blot analysis detected a 5.5-kb mRNA transcript in liver.
Gerloff et al. (1998) had identified the rat homolog, designated 'sister of P-glycoprotein' (Spgp). Rat Spgp is expressed only in the liver canalicular membrane. In vitro studies showed that rat Spgp is a functional bile acid transporter.
Gross (2016) mapped the ABCB11 gene to chromosome 2q31.1 based on an alignment of the ABCB11 sequence (GenBank AF136523) with the genomic sequence (GRCh38).
Progressive Familial Intrahepatic Cholestasis 2
In patients with progressive familial intrahepatic cholestasis-2 (PFIC2; 601847) Strautnieks et al. (1998) identified 10 different mutations in the ABCB11 gene (see, e.g., 603201.0001-603201.0004). Four mutations predicted premature termination of the protein; the remaining mutations were missense changes. Five of the missense mutations were found in consanguineous families and the affected individuals were all homozygous for the mutation. The combination of the in vitro functional studies of rat Spgp and the phenotype seen in PFIC2 patients provided evidence that ABCB11 is the major canalicular bile salt export pump in man.
Using immunohistochemistry, Jansen et al. (1999) found absence of the BSEP protein in 16 of 28 liver biopsy samples from patients with PFIC. All 10 of the BSEP-negative patients tested were found to have mutations in the ABCB11 gene (see, e.g., 603201.0007). Six patients had heterozygous mutations, and Jansen et al. (1999) suggested that the second disease-causing mutations had not yet been identified.
Knisely et al. (2006) studied 11 patients with PFIC in whom hepatocellular carcinoma was diagnosed between the ages of 13 and 52 months. Archival material was retrieved for study, and leukocytes on patients and parents were studied when available. BSEP deficiency was demonstrated by immunohistochemical analysis, and 13 different mutations in the ABCB11 gene were identified in all patients in whom leukocyte DNA could be studied; these mutations were confirmed in the parents. Knisely et al. (2006) concluded that PFIC2 caused by mutations in the ABCB11 gene increases the risk of hepatocellular carcinoma in early life.
Benign Recurrent Intrahepatic Cholestasis 2
Van Mil et al. (2004) identified 8 different mutations in the ABCB11 gene (see, e.g., 603201.0002) in 11 patients from 8 families with benign recurrent intrahepatic cholestasis-2 (BRIC2; 605479). Homozygous and compound heterozygous mutations were identified in 7 patients and 3 patients, respectively. One patient had only a heterozygous mutation.
In a patient with BRIC2, Noe et al. (2005) identified compound heterozygosity for 2 mutations in the ABCB11 gene (603201.0002; 603201.0006). In vitro functional expression studies showed that both mutant proteins retained residual transport activity, consistent with the milder phenotype. Hepatic BSEP protein expression was preserved in liver biopsy from the patient.
Wang et al. (2001) showed that knockout of the Spgp gene in mice results in intrahepatic cholestasis, but with significantly less severity than PFIC2 in humans. Some unexpected characteristics were observed. Notably, although the secretion of cholic acid in mutant mice was greatly reduced (6% of wildtype), total bile salt output in mutant mice was about 30% of wildtype. Also, secretion of an unexpectedly large amount of tetrahydroxylated bile acids (not detected in wildtype) was observed. These results suggested that hydroxylation and an alternative canalicular transport mechanism for bile acids compensate for the absence of Spgp function and protect the mutant mice from severe cholestatic damage.
In affected members of a Latin-American family segregating progressive familial intrahepatic cholestasis (PFIC2; 601847), Strautnieks et al. (1998) identified homozygosity for a 1723C-T transition in the ABCB11 gene, resulting in an arg575-to-ter (R575X) substitution. In affected members of a Belgian family with PFIC2, the mutation was heterozygous and a second ABCB11 mutation on the other allele was not identified.
Progressive Familial Intrahepatic Cholestasis 2
In affected members of 7 families segregating progressive familial intrahepatic cholestasis (PFIC2; 601847), Strautnieks et al. (1998) identified homozygosity for an 890A-G transition in the ABCB11 gene, resulting in a glu297-to-gly (E297G) substitution in the intracellular loop between transmembrane spans 4 and 5. Affected members of 6 other families had a heterozygous E297G mutation, but a second ABCB11 mutation on the other allele was not identified.
In a patient with PFIC2, Jansen et al. (1999) identified compound heterozygosity for 2 mutations in the ABCB11 gene: E297G and R1057X (603201.0007). Immunohistochemistry showed absence of the BSEP protein in liver.
Benign Recurrent Intrahepatic Cholestasis 2
Van Mil et al. (2004) identified homozygosity for the E297G mutation in 2 unrelated patients with benign recurrent intrahepatic cholestasis 2 (605479). Both patients had numerous episodes and developed permanent cholestasis later in life.
In a 16-year-old boy with benign recurrent intrahepatic cholestasis 2, Noe et al. (2005) identified compound heterozygosity for 2 mutations in the ABCB11 gene: E297G and R432T (603201.0006). In vitro functional expression studies showed that the E297G and R432T mutant proteins had 20% and 13% transport activity, respectively, compared to wildtype.
In affected members of a Polish family segregating progressive familial intrahepatic cholestasis (PFIC2; 601847), Strautnieks et al. (1998) identified a heterozygous 1-bp deletion (908delG) in the ABCB11 gene, resulting in a change of amino acid 303 and the introduction of 17 novel amino acids followed by termination of the protein.
In affected members of a family segregating progressive familial intrahepatic cholestasis (PFIC2; 601847), Strautnieks et al. (1998) identified a homozygous 1-bp insertion (3767insC) in the ABCB11 gene, resulting in a change in amino acid 1256 with the introduction of 39 novel amino acids followed by termination of the protein.
In a patient with progressive familial intrahepatic cholestasis (PFIC2; 601847), Noe et al. (2005) identified compound heterozygosity for 2 mutations in the ABCB11 gene: an A-to-C transversion in intron 4, resulting in a splice site mutation, and a 5-bp insertion in exon 21, resulting in a frameshift and premature termination of the protein (R930X; 603201.0008). Each unaffected parent was heterozygous for 1 of the mutations. Immunohistochemical staining revealed complete absence of hepatic BSEP expression in the patient.
In a 16-year-old boy with benign recurrent intrahepatic cholestasis-2 (605479), Noe et al. (2005) identified compound heterozygosity for 2 mutations in the ABCB11 gene: a 1296G-C transversion in exon 12, resulting in an arg432-to-thr (R432T) substitution, and E297G (603201.0002). Each unaffected parent was heterozygous for 1 of the mutations. The patient presented with a history of intermittent episodes of pruritus and steatorrhea for several years. Cholestatic episodes were reportedly triggered by infections or intake of certain medications. Liver biopsy showed mild hepatocellular and canalicular cholestasis without portal fibrosis. In vitro functional expression studies showed that the E297G and R432T mutant proteins had 20% and 13% transport activity, respectively, compared to wildtype.
In a patient with progressive familial intrahepatic cholestasis (PFIC2; 601847), Jansen et al. (1999) identified compound heterozygosity for 2 mutations in the ABCB11 gene: arg1057-to-ter (R1057X) and E297G (603201.0002). Immunohistochemistry showed absence of the BSEP protein in liver.
For discussion of the 5-bp insertion in exon 21 of the ABCB11 gene that was identified in compound heterozygous state in a patient with progressive familial intrahepatic cholestasis-2 (PFIC2; 601847) by Noe et al. (2005), see 603201.0005.
Gerloff, T., Stieger, B., Hagenbuch, B., Madon, J., Landmann, L., Roth, J., Hofmann, A. F., Meier, P. J. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273: 10046-10050, 1998. [PubMed: 9545351] [Full Text: https://doi.org/10.1074/jbc.273.16.10046]
Gross, M. B. Personal Communication. Baltimore, Md. 11/30/2016.
Jansen, P. L. M., Strautnieks, S. S., Jacquemin, E., Hadchouel, M., Sokal, E. M., Hooiveld, G. J. E. J., Koning, J. H., De Jager-Krikken, A., Kuipers, F., Stellaard, F., Bijleveld, C. M. A., Gouw, A., Van Goor, H., Thompson, R. J., Muller, M. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 117: 1370-1379, 1999. [PubMed: 10579978] [Full Text: https://doi.org/10.1016/s0016-5085(99)70287-8]
Knisely, A. S., Strautnieks, S. S., Meier, Y., Stieger, B., Byrne, J. A., Portmann, B. C., Bull, L. N., Pawlikowska, L., Bilezikci, B., Ozcay, F., Laszlo, A., Tiszlavicz, L., and 14 others. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44: 478-486, 2006. [PubMed: 16871584] [Full Text: https://doi.org/10.1002/hep.21287]
Noe, J., Kullak-Ublick, G. A., Jochum, W., Stieger, B., Kerb, R., Haberl, M., Mullhaupt, B., Meier, P. J., Pauli-Magnus, C. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J. Hepatol. 43: 536-543, 2005. [PubMed: 16039748] [Full Text: https://doi.org/10.1016/j.jhep.2005.05.020]
Sandor, T., Surinya, M., Monus, Z. Familial occurrence of giant cell hepatitis in infancy. Acta Hepatogastroent. (Stuttg.) 23: 101-104, 1976.
Strautnieks, S. S., Bull, L. N., Knisely, A. S., Kocoshis, S. A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M. S., Kagalwalla, A. F., Nemeth, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N. B., Gardiner, R. M., Thompson, R. J. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genet. 20: 233-238, 1998. [PubMed: 9806540] [Full Text: https://doi.org/10.1038/3034]
van Mil, S. W. C., van der Woerd, W. L., van der Brugge, G., Sturm, E., Jansen, P. L. M., Bull, L. N., van den Berg, I. E. T., Berger, R., Houwen, R. H. J., Klomp, L. W. J. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 127: 379-384, 2004. [PubMed: 15300568] [Full Text: https://doi.org/10.1053/j.gastro.2004.04.065]
Wang, R., Salem, M., Yousef, I. M., Tuchweber, B., Lam, P., Childs, S. J., Helgason, C. D., Ackerley, C., Phillips, M. J., Ling, V. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc. Nat. Acad. Sci. 98: 2011-2016, 2001. [PubMed: 11172067] [Full Text: https://doi.org/10.1073/pnas.98.4.2011]