Alternative titles; symbols
HGNC Approved Gene Symbol: ATP8B1
SNOMEDCT: 1155913007;
Cytogenetic location: 18q21.31 Genomic coordinates (GRCh38) : 18:57,646,426-57,803,315 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.31 | Cholestasis, benign recurrent intrahepatic | 243300 | Autosomal recessive | 3 |
| Cholestasis, intrahepatic, of pregnancy, 1 | 147480 | Autosomal dominant | 3 | |
| Cholestasis, progressive familial intrahepatic 1 | 211600 | Autosomal recessive | 3 |
ATP8B1 is a type-4 P-type ATPase that maintains lipid balance by translocating phospholipids, such as phosphatidylserine, from the outer to the inner leaflets of membrane bilayers. ATP8B1 also transports cardiolipin, a mitochondrial membrane phospholipid (Ray et al., 2010).
Bull et al. (1998) described positional cloning of a gene, which they termed FIC1, within the candidate region for 2 clinically distinct forms of familial cholestasis that had been mapped to chromosome 18q21: benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300) and progressive familial intrahepatic cholestasis type 1 (PFIC1; 211600). A cDNA corresponding to the FIC1 gene was isolated from a human intestinal cDNA library. The deduced 1,251-residue protein contains 10 transmembrane domains and signature motifs that characterize non-heavy metal-binding P-type ATPases. The ATP8B1 gene belongs to the P-type ATPase subfamily IV (Pawlikowska et al., 2004); ATP-dependent amino phospholipid transport was a previously described function of members of this family. Northern blot analysis detected a 7-kb mRNA transcript. Bull et al. (1998) found that FIC1 is expressed in several epithelial tissues, the pancreas, and more strongly in small intestine than in liver. The authors determined that the protein product is likely to play an essential role in enterohepatic circulation of bile acids.
Using immunoblot analysis, Eppens et al. (2001) determined that the FIC1 protein has a molecular mass of 140 kD.
Pawlikowska et al. (2004) isolated the murine Atp8b1 gene and found that the deduced protein shares 98% sequence identity with human ATP8B1.
Klomp et al. (2004) determined that the ATP8B1 gene contains 28 exons and spans at least 77 kb.
By genomic sequence analysis, Bull et al. (1998) mapped the ATP8B1 gene to chromosome 18q21.
Eppens et al. (2001) found that the FIC1 protein was present at the canalicular membrane in rat, mouse, and human liver sections; no protein was identified in liver from a patient with PFIC1. Studies in mouse liver showed colocalization of the FIC1 protein within cholangiocytes. Eppens et al. (2001) concluded that the FIC1 protein directly or indirectly plays a role in bile formation.
Ray et al. (2010) found that critically ill patients with bacterial pneumonia had significantly higher amounts of cardiolipin in tracheal aspirates compared with critically ill patients with nonpulmonary diagnoses or congestive heart failure. Cardiolipin levels were also elevated in bronchoalveolar lavage fluid from mice infected with Haemophilus influenzae or Escherichia coli. Cardiolipin in lung fluid adversely affected mouse lung mechanics by impairing surfactant activity, and it altered expression of cytokines and was associated with altered lung structure and decreased cell viability. Studies with cultured primary mouse type II lung epithelia cells showed that elevated extracellular cardiolipin was due to reduced cardiolipin uptake. Overexpression of Atp8b1 in cultured mouse lung type II cells resulted in elevated cardiolipin uptake. Gene delivery of Atp8b1 to mice prior to E. coli infection lowered cardiolipin levels and reversed E. coli-induced impairment of lung mechanics. Mutation analysis identified a 40-residue cardiolipin-binding motif near the C terminus of ATP8B1.
Progressive Familial Intrahepatic Cholestasis 1 And Benign Recurrent Intrahepatic Cholestasis 1
In patients with progressive familial intrahepatic cholestasis-1 (PFIC1; 211600), Bull et al. (1998) identified homozygous or compound heterozygous mutations in the ATP8B1 gene (602397.0001-602397.0005). Mutations were also identified in the ATP8B1 gene (602397.0006-602397.0007) in patients with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), confirming that these disorders are allelic.
Klomp et al. (2004) identified 36 distinct mutations in the ATP8B1 gene in 39 (30%) of 130 PFIC families. Twenty-five of the mutations were detected only in 1 family. The authors also identified 16 distinct mutations in the ATP8B1 gene in 20 (40%) of 50 BRIC families. Fourteen of the BRIC families were homozygous or heterozygous for the common I661T mutation (602397.0006).
Alvarez et al. (2004) noted that the phenotype of mice null for farnesoid X receptor (FXR, NR1H4; 603826), a transcription factor that controls bile acid homeostasis, is characterized by hypercholanemia, impaired secretion of bile acids, and failure to thrive. In 3 sibs with PFIC1, born of consanguineous parents, Alvarez et al. (2004) identified compound heterozygosity for mutations in the ATP8B1 gene (602397.0012-602397.0013). They found that in 1 of the sibs, in comparison to patients with other forms of liver disease and a normal control, expression of 2 main FXR isoforms was decreased in the liver, and there was a consistent and concomitant reduction in mRNA levels of FXR targets ABCB11 (603201) and SHP1 (NR0B2; 604630). Gene-profiling experiments identified 163 transcripts whose expression changed significantly in PFIC1-disease liver, including downregulation of several genes involved in synthesis, conjugation, and transport of bile acids. Alvarez et al. (2004) suggested that hepatic downregulation of FXR may contribute to the severe cholestasis of PFIC1.
Intrahepatic Cholestasis of Pregnancy 1
In 4 of 182 unrelated patients with intrahepatic cholestasis of pregnancy-1 (ICP1; 147480), Mullenbach et al. (2005) identified heterozygous mutations in the ATP8B1 gene (602397.0010; 602397.0011).
In a large screening of the ATP8B1 gene in 176 familial and sporadic patients with ICP, Painter et al. (2005) concluded that ATP8B1 is probably not a major gene contributing to the disorder.
In a large study of 180 families with PFIC or BRIC, Klomp et al. (2004) found that patients with PFIC1 tended to have mutations likely to severely alter the structure or function of the ATP8B1 protein such as frameshift, nonsense, or large genomic deletions, whereas those with BRIC1 tended to have a greater proportion of missense mutations. They identified 4 ATP8B1 mutations in both PFIC and BRIC patients, but the combinations of mutations in BRIC patients differed from those in PFIC patients; 1 of the mutations found in both disorders was the common I661T mutation.
Pawlikowska et al. (2004) found that mice homozygous for the G308V mutation (602397.0001) identified in PFIC1 patients had unimpaired bile secretion and no liver damage, but showed mild abnormalities such as depressed weight at weaning and elevated serum bile salt levels. Upon bile salt feeding, the mutant mice showed serum bile salt accumulation, hepatic injury, and expansion of the systemic bile salt pool. Upon infusion of a hydrophobic bile salt, wildtype mice developed cholestasis, while the mutant mice maintained high biliary output and more extensively rehydroxylated the infused bile salt. Despite the mild phenotype compared to humans, the findings in the mutant mice demonstrated the role of Atp8b1 in bile salt homeostasis and highlighted the importance of bile salt hydroxylation in the prevention of cholestasis. Pawlikowska et al. (2004) postulated that the more severe phenotype in humans with the G308V mutation results from the inability of humans to rehydroxylate secondary bile salts and the early onset of liver disease in humans.
In affected members of the Amish kindred in which Byler disease, or progressive familial intrahepatic cholestasis (PFIC1; 211600), was first described by Clayton et al. (1969), Bull et al. (1998) demonstrated a homozygous 923G-T transversion in the ATP8B1 gene, resulting in a gly308-to-val (G308V) substitution.
Ray et al. (2010) noted that patients with PFIC1 and mice expressing mutant Atp8b1 are prone to bacterial pneumonia. They found that bronchial lavage fluid of mice with the G308V mutation in Atp8b1 had elevated cardiolipin levels and showed a blunted response to T-helper type-1 cytokines. Primary mutant type II lung cells exhibited reduced ability to uptake cardiolipin and were prone to apoptosis.
In a patient of European descent with progressive familial intrahepatic cholestasis (PFIC1; 211600), Bull et al. (1998) identified a homozygous 2674G-A transition in the ATP8B1 gene, resulting in a gly892-to-arg (G892R) substitution. The affected residue is highly conserved and thought to be involved in ATP binding.
In a patient of Polish descent with progressive familial intrahepatic cholestasis (PFIC1; 211600), Bull et al. (1998) identified a homozygous 863T-C transition in the ATP8B1 gene, resulting in a leu288-to-ser (L288S) substitution.
In a patient with progressive familial intrahepatic cholestasis (PFIC1; 211600), Bull et al. (1998) found compound heterozygosity for 2 mutations in the ATP8B1 gene: a 1.4-kb deletion (602397.0005) and a 2097+2T-C transition in the splice site consensus sequence immediately 3-prime of the exon that encodes amino acid residues 645-699. This exon was predicted to encode part of the larger cytoplasmic domain.
For discussion of the 1.4-kb deletion in the ATP8B1 gene that was found in compound heterozygous state in a patient with progressive familial intrahepatic cholestasis (PFIC1; 211600) by Bull et al. (1998), see 602397.0004.
In a patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), Bull et al. (1998) identified a 1982T-C transition in the ATP8B1 gene, resulting in an ile661-to-thr (I661T) amino acid substitution. The nonconservative mutation was at a site at which all members of the subfamily of P-type ATPases to which ATP8B1 belongs have a leucine or isoleucine residue. The mutation was present on the most common conserved haplotype in BRIC patients of western European descent. It was present in homozygous form in patients from 13 families and in heterozygous form in patients from 6 additional families, and was not found on 84 control chromosomes.
Tygstrup et al. (1999) identified homozygosity for the I661T mutation in 5 males with BRIC from the Faroe Islands who were originally reported by Tygstrup and Jensen (1969). Haplotype analysis suggested a founder effect.
Klomp et al. (2004) identified the I661T mutation in 14 BRIC families; 3 families were homozygous, 8 were compound heterozygous with another ATP8B1 mutation, and in 3 families a second mutation was not identified. Two families with progressive familial intrahepatic cholestasis (PFIC; 211600) were compound heterozygous for the I661T mutation and another ATP8B1 mutation. In 1 family with BRIC, 4 individuals who were homozygous for the I661T mutation were symptom-free their entire lives, suggesting reduced penetrance.
Bull et al. (1998) found that a Dutch patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300) was homozygous for a 9-bp deletion in the ATP8B1 gene. The deletion began with 2384G and resulted in deletion of amino acids gly-asn-arg (795-797). This mutation occurred in a region of the gene that demonstrates little conservation, except between ATP8B1 and its porcine homolog, in which the 3 amino acids are identical. The patient also showed a homozygous sequence alteration in the intronic sequence that preceded the exon containing the deletion.
In Inuit patients from Greenland and Canada with progressive familial intrahepatic cholestasis-1 (PFIC1; 211600), so-called Greenland familial cholestasis, Klomp et al. (2000) identified homozygosity for a 1660G-A transition in the ATP8B1 gene, resulting in an asp554-to-asn (D554N) substitution.
Ray et al. (2010) found that the D554N substitution lies within a 40-residue cardiolipin-binding motif.
In 6 affected members of a family with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), first reported by Houwen et al. (1994), Klomp et al. (2004) identified a homozygous C-to-A transversion in intron 23 of the ATP8B1 gene, resulting in the skipping of exon 24. The corresponding transcript is predicted to encode a protein lacking the complete sixth transmembrane domain and 7 flanking amino acids. In 2 patients, the disease became progressive, representing a form intermediate in severity between BRIC and PFIC.
In 3 unrelated patients with intrahepatic cholestasis of pregnancy-1 (ICP1; 147480), Mullenbach et al. (2005) identified a heterozygous 208G-A transition in exon 2 of the ATP8B1 gene, resulting in an asp70-to-asn (D70N) substitution. The D70N mutation was not identified in 120 healthy pregnant women.
Klomp et al. (2004) identified the D70N substitution in 0.5% of control chromosomes.
In a patient with intrahepatic cholestasis of pregnancy-1 (ICP1; 147480), Mullenbach et al. (2005) identified a heterozygous 2599C-T transition in exon 21 of the ATP8B1 gene, resulting in an arg867-to-cys (R867C) substitution.
In 3 Spanish Gypsy sibs with progressive familial intrahepatic cholestasis (PFIC1; 211600), born of consanguineous parents, Alvarez et al. (2004) identified compound heterozygosity for a 1367C-T transition in exon 12 and an 1804C-T transition in exon 15 of the ATP8B1 gene, resulting in thr456-to-met (T356M) and arg602-to-ter (R602X; 602397.0013) substitutions, respectively. The missense mutation was paternally transmitted, and the nonsense mutation was maternally transmitted. Neither mutation was detected in 94 unrelated control chromosomes.
For discussion of the arg602-to-ter (R602X) mutation in the ATP8B1 gene that was found in compound heterozygous state in patients with progressive familial intrahepatic cholestasis (PFIC1; 211600) by Alvarez et al. (2004), see 602397.0012.
Alvarez, L., Jara, P., Sanchez-Sabate, E., Hierro, L., Larrauri, J., Diaz, M. C., Camarena, C., De la Vega, A., Frauca, E., Lopez-Callazo, E., Lapunzina, P. Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum. Molec. Genet. 13: 2451-2460, 2004. [PubMed: 15317749] [Full Text: https://doi.org/10.1093/hmg/ddh261]
Bull, L. N., van Eijk, M. J. T., Pawlikowska, L., DeYoung, J. A., Juijn, J. A., Liao, M., Klomp, L. W. J., Lomri, N., Berger, R., Scharschmidt, B. F., Knisely, A. S., Houwen, R. H. J., Freimer, N. B. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nature Genet. 18: 219-224, 1998. [PubMed: 9500542] [Full Text: https://doi.org/10.1038/ng0398-219]
Clayton, R. J., Iber, F. L., Ruebner, B. H., McKusick, V. A. Byler disease: fatal familial intrahepatic cholestasis in an Amish kindred. Am. J. Dis. Child. 117: 112-124, 1969. [PubMed: 5762004]
Eppens, E. F., van Mil, S. W. C., de Vree, J. M. L., Mok, K. S., Juijn, J. A., Oude Elferink, R. P. J., Berger, R., Houwen, R. H. J., Klomp, L. W. J. FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. J. Hepatol. 35: 436-443, 2001. [PubMed: 11682026] [Full Text: https://doi.org/10.1016/s0168-8278(01)00158-1]
Houwen, R. H. J., Baharloo, S., Blankenship, K., Raeymaekers, P., Juyn, J., Sandkuijl, L. A., Freimer, N. B. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nature Genet. 8: 380-386, 1994. [PubMed: 7894490] [Full Text: https://doi.org/10.1038/ng1294-380]
Klomp, L. W. J., Bull, L. N., Knisely, A. S., van der Doelen, M. A. M., Juijn, J. A., Berger, R., Forget, S., Nielsen, I.-M., Eiberg, H., Houwen, R. H. J. A missense mutation in FIC1 is associated with Greenland familial cholestasis. Hepatology 32: 1337-1341, 2000. [PubMed: 11093741] [Full Text: https://doi.org/10.1053/jhep.2000.20520]
Klomp, L. W. J., Vargas, J. C., van Mil, S. W. C., Pawlikowska, L., Strautnieks, S. S., van Eijk, M. J. T., Juijn, J. A., Pabon-Pena, C., Smith, L. B., DeYoung, J. A., Byrne, J. A., Gombert, J., van der Brugge, G., Berger, R., Jankowska, I., Pawlowska, J., Villa, E., Knisely, A. S., Thompson, R. J., Freimer, N. B., Houwen, R. H. J., Bull, L. N. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 40: 27-38, 2004. [PubMed: 15239083] [Full Text: https://doi.org/10.1002/hep.20285]
Mullenbach, R., Bennett, A., Tetlow, N., Patel, N., Hamilton, G., Cheng, F., Chambers, J., Howard, R., Taylor-Robinson, S. D., Williamson, C. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut 54: 829-834, 2005. [PubMed: 15888793] [Full Text: https://doi.org/10.1136/gut.2004.058115]
Painter, J. N., Savander, M., Ropponen, A., Nupponen, N., Riikonen, S., Ylikorkala, O., Lehesjoki, A.-E., Aittomaki, K. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy. Europ. J. Hum. Genet. 13: 435-439, 2005. [PubMed: 15657619] [Full Text: https://doi.org/10.1038/sj.ejhg.5201355]
Pawlikowska, L., Groen, A., Eppens, E. F., Kunne, C., Ottenhoff, R., Looije, N., Knisely, A. S., Killeen, N. P., Bull, L. N., Oude Elferink, R. P. J., Freimer, N. B. A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile salt secretion. Hum. Molec. Genet. 13: 881-892, 2004. [PubMed: 14976163] [Full Text: https://doi.org/10.1093/hmg/ddh100]
Ray, N. B., Durairaj, L., Chen, B. B., McVerry, B. J., Ryan, A. J., Donahoe, M., Waltenbaugh, A. K., O'Donnell, C. P., Henderson, F. C., Etscheidt, C. A., McCoy, D. M., Agassandian, M., and 10 others. Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. Nature Med. 16: 1120-1127, 2010. [PubMed: 20852622] [Full Text: https://doi.org/10.1038/nm.2213]
Tygstrup, N., Jensen, B. Intermittent intrahepatic cholestasis of unknown etiology in five young males from the Faroe Islands. Acta Med. Scand. 185: 523-530, 1969. [PubMed: 5807632] [Full Text: https://doi.org/10.1111/j.0954-6820.1969.tb07378.x]
Tygstrup, N., Steig, B. A., Juijn, J. A., Bull, L. N., Houwen, R. H. J. Recurrent familial intrahepatic cholestasis in the Faeroe Islands: phenotypic heterogeneity but genetic homogeneity. Hepatology 29: 506-508, 1999. [PubMed: 9918928] [Full Text: https://doi.org/10.1002/hep.510290214]