Alternative titles; symbols
HGNC Approved Gene Symbol: ABCB4
SNOMEDCT: 1186865008, 715577009;
Cytogenetic location: 7q21.12 Genomic coordinates (GRCh38): 7:87,365,896-87,476,027 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.12 | Cholestasis, intrahepatic, of pregnancy, 3 | 614972 | Autosomal dominant; Autosomal recessive | 3 |
| Cholestasis, progressive familial intrahepatic 3 | 602347 | Autosomal recessive | 3 | |
| Gallbladder disease 1 | 600803 | Autosomal dominant; Autosomal recessive | 3 |
P-glycoproteins were discovered as large cell membrane proteins overproduced in cancer cells resistant to a diverse set of hydrophobic drugs, so-called multidrug-resistant (MDR) cells (Juliano and Ling, 1976). P-glycoproteins were initially thought to affect the permeability of cells to drugs, but they were later found to act as pumps able to extrude drugs from cells at the cost of ATP hydrolysis. P-glycoproteins belong to a class of vectorial transport proteins known as the ATP-binding cassette transporter proteins. The cystic fibrosis transmembrane conductance regulator (CFTR; 602421) is a member of the family but functions as a chloride channel and has no known active transport function. Defense against xenobiotics may be a major natural function of these P-glycoproteins. The P-glycoproteins have 2 homologous halves, each with 6 hydrophobic segments adjacent to a consensus sequence for nucleotide binding. The hydrophobic segments may form a membrane channel, whereas the nucleotide binding site may be involved in energization of drug transport.
In liver cDNA banks, Van der Bliek et al. (1987) found a cDNA corresponding to a novel human P-glycoprotein gene. The sequence of the 3-prime part of the cDNA displays a domain organization of the derived protein similar to that of the known P-glycoproteins and an 80% amino acid homology with the product of the human MDR1 gene (PGY1; 171050). The gene was designated MDR3 since it appears to correspond to the third of the P-glycoprotein genes mapped in the hamster. Transcription studies indicated that the MDR3 transcript is 400 nucleotides shorter than the MDR1 transcript as a result of a shorter 3-prime untranslated region of the MDR3 mRNA. Van der Bliek et al. (1987) found evidence for alternative splicing of MDR3 pre-mRNAs. One alternative had an insert of 7 amino acids between the major blocks of the nucleotide binding site and another had a deletion of 43 or 47 amino acids covering a putative transmembrane segment. These alternatives may explain the large variation in cross-resistance patterns observed in cell lines selected for multidrug resistance with different cytostatic drugs.
Lincke et al. (1991) found that 4 alternatively spliced transcripts of the MDR3 gene arise from alternative splicing of exons 23 and 26.
Weber et al. (2019) noted that human ABCB4 produces 3 isoforms: isoform A, isoform B, which contains a 7-amino acid insertion near nucleotide-binding domain-2, and isoform C, which has a 47-amino acid deletion that includes transmembrane domain-11. Immunofluorescence and confocal microscopy showed that isoform A localized to the cell membrane of transfected HuH-7 human hepatic cells, whereas isoforms B and C were expressed only in the cytoplasm.
Roninson et al. (1986) referred to MDR3 as MDR2. The mouse homolog of MDR3 is mdr2.
Lincke et al. (1991) determined that the MDR3 gene contains 28 exons and spans 74 kb.
By pulsed-field gradient gel electrophoresis, Van der Bliek et al. (1987) determined that the MDR3 gene lies within 500 kb of MDR1, which maps to 7q21.1. Lincke et al. (1991) determined that the MDR3 gene is separated from the MDR1 gene by 34 kb. In contrast to the mouse mdr genes, both human genes are transcribed in the same direction, MDR3 being located downstream from MDR1.
Ruetz and Gros (1994) tested the capacity of the murine mdr2 and mdr3 genes to function as a lipid translocase or flippase by expressing these genes in yeast secretory vesicles. By use of a fluorescently tagged phosphatidylcholine (PC) analog, they demonstrated that mdr2 expression (human homolog MDR3) caused a time- and temperature-dependent enhancement of PC translocation to the inner leaflet of the membrane. This increased translocation was strictly ATP and magnesium ion dependent, was inhibited by the ATPase antagonist vanadate and the P-gp modulator verapamil, and was insensitive to the multidrug resistance drugs colchicine and vinblastine. Mdr3 expression did not affect the membrane distribution of phosphatidylcholine.
In Drosophila, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR; 142910) activity controls germ cell attraction to the mesoderm and the recruitment of germ cells to the somatic gonad. Ricardo and Lehmann (2009) showed that Drosophila germ cell migration uses a pathway similar to the yeast sterol-6 (Ste6, a functional homolog of Mdr3) pathway, demonstrating that invertebrate germ cells, like yeast cells, are attracted to lipid-modified peptides. In flies, Ricardo and Lehmann (2009) generated a strong loss-of-function allele of Mdr49. Mdr49 mutant embryos showed defects in germ cell migration, like embryos in which the HMGCR pathway was mutant: germ cells migrated through the posterior midgut but then failed to associate with the somatic gonad, which was properly specified. This migration phenotype was observed only in Mdr49 mutants and not in mutants for other ABCB transporters. Ricardo and Lehmann (2009) found that yeast Ste6 rescued the germ cell migration phenotype observed in the Mdr49 embryos, suggesting that Mdr49 is functionally equivalent to Ste6 and acts in mesodermal cells to attract germ cells.
Progressive Familial Intrahepatic Cholestasis 3
Deleuze et al. (1996) found a lack of MDR3 mRNA in the liver of patients with progressive familial intrahepatic cholestasis (PFIC3; 602347) associated with increased serum levels of gamma-glutamyltransferase (GGT1; 612346). PFIC characterized by high serum GGT activity and liver histology shows portal inflammation and ductular proliferation in an early stage (Maggiore et al. (1987, 1991)). The histologic and biochemical characteristics of this subtype resemble those of the mdr2 -/- knockout mice very closely.
In 2 patients with PFIC3 who demonstrated negative canalicular staining for MDR3 P-glycoprotein, de Vree et al. (1998) identified 2 different homozygous mutations in the MDR3 gene (171060.0001); (171060.0002).
In a large consanguineous family with PFIC3, Jacquemin et al. (1999) identified a homozygous mutation in the ABCB4 gene (171060.0003).
Degiorgio et al. (2007) identified 29 distinct mutations in the ABCB4 gene, including 25 novel mutations (see, e.g., 171060.0009; 171060.0010), in 18 probands with PFIC3. The findings indicated high allelic variability in the disorder with a high prevalence of mutations in exon 17 of the ABCB4 gene.
Gallbladder Disease 1/Low Phospholipid-Associated Cholelithiasis
Rosmorduc et al. (2001) identified 4 different mutations in the ABCB4 gene (171060.0005-171060.0008) in 6 symptomatic adult patients with a peculiar form of gallbladder disease (GBD1; 600803) characterized by intrahepatic sludge and gallbladder cholesterol gallstones, mild chronic cholestasis, recurrence of symptoms after cholecystectomy, and prevention of recurrence by ursodeoxycholic acid (UDCA). Mutations occurred in both the homozygous and compound heterozygous state. One of the female patients presented during pregnancy, consistent with intrahepatic cholestasis of pregnancy (ICP; 614972), and another presented after taking oral contraceptives, consistent with oral contraceptive-induced cholestasis (OCIC; see 614972). Hepatic bile composition in 2 patients showed a high cholesterol/phospholipid ratio and cholesterol crystals.
Ziol et al. (2008) identified 8 different mutations in the ABCB4 gene (see, e.g., 171060.0012-171060.0013) in 11 (34%) of 32 patients with chronic unexplained anicteric cholestasis. Eight patients carried a heterozygous mutation, whereas 3 were compound heterozygous for 2 mutations.
In 16 (37%) of 43 adult patients with low phospholipid-associated cholelithiasis (LPAC; 600803), Pasmant et al. (2012) identified 32 different heterozygous loss of function mutations in the ABCB4 gene. Three (7%) of the 43 patients were found to carry partial or whole gene deletions affecting the ABCB4 gene. The patients had intrahepatic cholelithiasis despite cholecystectomy before age 40 years. The disorder was associated with cholecystitis, cholangitis, acute pancreatitis, and intrahepatic hyperechoic foci; patients showed a favorable response to UDCA therapy. Pasmant et al. (2012) emphasized the importance of ABCB4 gene dosage studies in patients with adult-onset liver disease, particularly since treatment with UDCA has been proven effective.
Intrahepatic Cholestasis of Pregnancy 3/Oral Contraceptive-Induced Cholestasis
De Vree et al. (1998) found that a heterozygous mother of a child with PFIC3 due to a homozygous ABCB4 mutation (R957X; 171060.0002) had recurrent episodes of intrahepatic cholestasis of pregnancy (ICP3; 614972).
Jacquemin et al. (1999) reported a family in which 4 women with ICP3 were heterozygous for a mutation in the ABCB4 gene (171060.0003).
Rosmorduc et al. (2001) reported a woman with ICP who was heterozygous for a mutation in the ABCB4 gene (1327insA; 171060.0008). Her son, who also carried the mutation, developed cholangitis and cholesterol gallstones in his twenties. Another unrelated woman with oral contraceptive-induced cholestasis (OCIC; see 614972) carried a homozygous mutation in the ABCB4 gene (S320F; 171060.0005).
Bacq et al. (2009) identified homozygous or heterozygous mutations in the ABCB4 gene (see, e.g., S320F, 171060.0005; R144X, 171060.0011; and R590Q, 171060.0012) in 8 (16%) of 50 French Caucasian women with ICP. There was no phenotypic difference between patients with or without ABCB4 mutations.
Pasmant et al. (2012) identified ABCB4 mutations in 16 (27%) of 59 patients with ICP or oral contraceptive-induced cholestasis. One (2%) of the 59 patients carried a 5-Mb deletion of chromosome 7q including the ABCB4 gene. Pasmant et al. (2012) emphasized the importance of ABCB4 gene dosage studies in patients with adult-onset liver disease, particularly since treatment with UDCA has been proven effective.
To obtain information on the function of the mdr2-type P-glycoprotein, Smit et al. (1993) disrupted the mdr2 gene in mouse embryonic stem (ES) cells and generated mice homozygous for this disruption. The tissue distribution of the gene product of the human MDR3 and the mouse mdr2 genes (bile canalicular membrane of hepatocytes, B cells, heart, and muscle) suggested a specialized metabolic function. The homozygous mdr2-disrupted mice developed a liver disease that appeared to be caused by the complete inability of the liver to secrete phospholipid into the bile. Heterozygous mice showed no detectable liver pathology, but had half the level of phospholipid in bile. Smit et al. (1993) suggested that mdr2 P-glycoprotein has an essential role in the secretion of phosphatidylcholine into bile and hypothesized that it may be a phospholipid transport protein or phospholipid flippase. They hypothesized further that the animal model might cast light on the pathogenesis and management of cholestatic liver disease. By trapping endogenously synthesized bile salts in the gut and supplying exogenous hydrophilic bile salts, the damage to bile canaliculi and ducts from bile salt uncomplexed to phospholipid might be reduced. Specifically, Offerhaus (1994) suggested that Byler disease (e.g., PFIC1) might be a human spontaneous counterpart of the transgenic model.
To test the hypothesis that activation of NFKB, which is frequently detected in tumors, may constitute a missing link between inflammation and cancer, Pikarsky et al. (2004) studied the Mdr2 (171060) knockout mouse, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. Pikarsky et al. (2004) monitored hepatitis and cancer progression in Mdr2 knockout mice and showed that the inflammatory process triggers hepatocyte Nfkb through upregulation of TNF-alpha in adjacent endothelial and inflammatory cells. Switching off Nfkb in mice from birth to 7 months of age, using a hepatocyte-specific inducible I-kappa-B superrepressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing Nfkb inhibition through anti-TNF-alpha treatment or induction of I-kappa-B superrepressor in later stages of tumor development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Pikarsky et al. (2004) concluded that NFKB is essential for promoting inflammation-associated cancer and is therefore a potential target for cancer prevention in chronic inflammatory diseases.
Weber et al. (2019) found that transgenic expression of human ABCB4 isoform A had therapeutic effects on PFIC3 in 2- or 5-week old Abcb4 -/- mice.
In a Turkish boy, born of healthy consanguineous parents, who was affected with the form of progressive familial intrahepatic cholestasis associated with elevated serum gamma-glutamyltransferase activity (PFIC3; 602347), de Vree et al. (1998) used reverse transcription-coupled PCR sequencing to demonstrate a homozygous 7-bp deletion (TATATAC), starting at codon 132 of the MDR3 gene and resulting in a frameshift with introduction of a stop codon 29 codons downstream (fs161ter).
In a North African boy with progressive familial intrahepatic cholestasis (PFIC3; 602347), born of first-cousin parents, de Vree et al. (1998) identified a homozygous C-to-T transition in the ABCB4 gene, resulting in an arg957-to-ter (R957X) substitution. The heterozygous mother of the affected child experienced recurrent episodes of intrahepatic cholestasis of pregnancy-3 (ICP3; 614972).
In a patient with severe progressive familial intrahepatic cholestasis (PFIC3; 602347) requiring liver transplantation at the age of 6 years, Jacquemin et al. (1999) identified a homozygous 1-bp deletion (1712delT) in the ABCB4 gene, resulting in a frameshift and premature stop codon 15 codons downstream of codon 571. The mutation resulted in an inactive truncated protein. Four women in the family with intrahepatic cholestasis of pregnancy (614972) were heterozygous for the mutation. The family was consanguineous.
In 1 of 8 patients with intrahepatic cholestasis of pregnancy (ICP3; 614972), Dixon et al. (2000) identified a heterozygous C-to-A transversion in exon 14 of the ABCB4 gene, resulting in an ala546-to-asp (A546D) substitution. Functional studies of the A546D mutation introduced into MDR1 (171050), a closely related homolog of MDR3, revealed disruption of protein trafficking with a subsequent lack of functional protein at the cell surface.
In a woman with gallbladder disease-1 (GBD1; 600803) presenting as chronic low phospholipid-associated cholelithiasis (LPAC), which worsened during pregnancy, Rosmorduc et al. (2001) identified a homozygous 959C-T transition in exon 9 of the ABCB4 gene, resulting in a ser320-to-phe (S320F) substitution. An unrelated woman with oral contraceptive-induced cholelithiasis (OCIC; see 614972) was also found to carry a homozygous S320F substitution. Unaffected family members in both families were heterozygous for the mutation.
Bacq et al. (2009) identified a heterozygous S320F mutation in 1 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972). The mutation was not found in 214 control chromosomes. The S320F mutation occurred in transmembrane domain-5.
In a woman with gallbladder disease-1 (GBD1; 600803), Rosmorduc et al. (2001) identified a heterozygous 523A-G transition in exon 6 of the ABCB4 gene, resulting in a thr175-to-val (T175V) substitution.
In a man with cholelithiasis (GBD1; 600803), Rosmorduc et al. (2001) identified a homozygous 3481C-T transition in exon 26 of the ABCB4 gene, resulting in a pro1161-to-ser (P1161S) substitution.
In a mother with intrahepatic cholestasis of pregnancy (ICP3; 614972) and her son who developed cholelithiasis (GBD1; 600803), Rosmorduc et al. (2001) identified a heterozygous 1-bp insertion (1327insA) in exon 12 of the ABCB4 gene. The mutation resulted in a frameshift at codon 443 and an early stop codon predicting a truncated protein of 446 amino acids.
In affected members of a family with progressive familial intrahepatic cholestasis (PFIC3; 602347), Degiorgio et al. (2007) identified a homozygous 1-bp insertion (2169insG) in exon 17 of the ABCB4 gene, resulting in a frameshift and premature termination, eliminating the C-terminal TM domains and cytoplasmic nucleotide-binding domain. The proband had jaundice and increased serum GGT at presentation.
In affected members of a family with progressive familial intrahepatic cholestasis (PFIC3; 602347), Degiorgio et al. (2007) identified a homozygous 1207T-C transition in exon 11 of the ABCB4 gene, resulting in a tyr403-to-his (Y403H) substitution in a highly conserved residue in the N-terminal nucleotide-binding domain. Y403 forms the A-loop and represents the aromatic residue interacting with the adenine ring of ATP. The proband had symptomatic cholestasis with pruritus and increased serum ALT and GGT at presentation.
In 1 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972), Bacq et al. (2009) identified a heterozygous 462C-T transition in exon 6 of the ABCB4 gene, resulting in an arg144-to-ter (R144X) substitution in the intracytoplasmic first loop of the protein. The mutation was not found in 214 control chromosomes.
In 2 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972), Bacq et al. (2009) identified a homozygous 1769G-A transition in exon 15 of the ABCB4 gene, resulting in an arg590-to-gln (R590Q) substitution in the nucleotide-binding domain. Three additional women with ICP were heterozygous for the R590Q mutation, as was 1 of 214 control chromosomes. The allelic frequency was significantly different between ICP patients and controls (7% vs 0.5%, respectively), yielding an odds ratio of 16.03. Haplotype analysis indicated a founder effect.
Ziol et al. (2008) identified a heterozygous R590Q substitution in 3 unrelated women with anicteric cholestasis. Two had cholelithiasis at ages 18 and 51 years, respectively. One developed symptoms after taking oral contraceptives (OCIC; see 614972) and the other had recurrence of symptoms after cholecystectomy (GBD1; 600803). A third woman with the mutation was asymptomatic, but was studied because of increased liver enzymes. Ziol et al. (2008) noted that the R590Q substitution was also found in 4 controls (3%), raising questions about its pathogenicity.
In a woman who developed cholelithiasis (GBD1; 600803) at age 32 years, Ziol et al. (2008) identified a heterozygous 1633C-G transition in exon 14 of the ABCB4 gene, resulting in an arg545-to-gly (R545G) substitution. She had recurrence of symptoms after cholecystectomy and intrahepatic sludge and microlithiasis.
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