ABCB4
protein-codingATP binding cassette subfamily B member 4, the group of ATP binding cassette subfamily B
Gene summary
The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]
- PGY3
- MDR3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~78.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011214
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0013995
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0004982
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0010939
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011214
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011214
Submitter: ClinGen
The *ABCB4* gene was first reported in relation to progressive familial intrahepatic cholestasis, an autosomal recessive condition, with the 1998 publication of affected patients harboring variants in the homozygous state (PMID: 9419367). Affected individuals harboring homozygous or compound heterozygous variants are typically diagnosed with progressive familial intrahepatic cholestasis type 3, and generally present between infancy and late adolescence with jaundice, pruritus, bile duct proliferation, cholestasis, hepatosplenomegaly, elevated serum gamma-glutamyltransferase, and/or increased serum bile acids. The disease progresses in many cases to develop portal hypertension, fibrosis, cirrhosis, and eventually liver failure and transplantation, although some cases respond positively to ursodeoxycholate treatment (PMID: 17726488). Neoplasm of the liver can develop in some cases as well. Heterozygous *ABCB4* variants have also been reported in association with cholestasis, typically with a diagnosis of either intrahepatic cholestasis of pregnancy 3 or gallbladder disease 1. Although these presentations can occur in carriers in families with recessive progressive familial intrahepatic cholestasis, their adult onset, low penetrance and monoallelic state constitute a different disease. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism of loss of function has been found to be consistent between cases harboring biallelic and monoallelic variants in *ABCB4*. However, the dramatic difference in phenotypic severity between the biallelic and monoallelic cases distinguishes them as two different conditions rather than a single broad spectrum disease. Therefore, cases caused by biallelic *ABCB4* variants have been separately curated here for progressive familial intrahepatic cholestasis type 3 (MONDO:0011214, MIM #614972). Twelve suspected pathogenic variants have been scored as part of this curation (six missense, two nonsense, three frameshift, and one disrupting a canonical splice site). These have been collectively reported in ten probands in four publications (PMID: 9419367, PMID: 26474921, PMID: 32793533, PMID: 11313315). The mechanism of pathogenicity appears to be biallelic loss of *ABCB4* function conferred by null and/or hypomorphic variants. Eight out of ten probands were homozygous for their respective variants, while two probands were compound heterozygous. Segregation evidence has not contributed to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature but was not included in this curation as the maximum score for this category of evidence had already been reached. This gene-disease association is also supported by experimental evidence that the expression pattern of *ABCB4* across human tissues is highly restricted to the liver (PMID: 23715323). Biochemical studies indicate that *ABCB4* encodes a transporter of the ATP-binding cassette family that localizes to the canalicular membrane of hepatocytes, consistent with a role in transporting phospholipid into bile secretions that form at this site (PMID: 7734012). Reduced expression of *ABCB4* has been detected in a subset of progressive familial intrahepatic cholestasis cases characterized by elevated serum levels of gamma-glutamyltransferase activity (PMID: 8666348). Homozygous disruption of the mouse ortholog of *ABCB4* recapitulates human patient features such as the absence of phospholipids from bile, hyperbilirubinemia, nonsuppurative inflammatory cholangitis, bile duct proliferation, portal inflammation, neoplasm of the liver, hepatocyte degeneration, portal fibrosis, and widening and tortuosity of the bile canaliculi (PMID: 7977654). Some of these phenotypes can be rescued by injection of lipid nanoparticles delivering wild-type *ABCB4* mRNA (PMID: 33340584). In summary, *ABCB4* is definitively associated with progressive familial intrahepatic cholestasis type 3, an autosomal recessive condition. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Gene Curation Expert Panel on November 23rd, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0011214
Submitter: PanelApp Australia
Inheritance Pattern: SD
Disease ID:MONDO:0010939
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0010939
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010939
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal
Intervention: Gastrointestinal; Obstetric; Pharmacogenomic
Rationale: Medical treatment (eg, with ursodeoxycholine) may be beneficial, though in some forms, liver transplantation has been described as necessary; Medications (eg, OCPs) may lead to adverse reactions; In pregnancy, the condition can cause severe sequelae (including death) in the fetus, as well as adverse maternal health outcomes, and precautions, including early delivery, may be beneficial
Comments: Heterozygous variants reported in Cholestasis, progressive familial intrahepatic 3 are associated with other related conditions such as Intrahepatic cholestasis of pregnancy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ABCB4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000443.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 17 | 284 | 3 | 304 | ||
| missense | 7 | 73 | 643 | 14 | 737 | |
| nonsense | 42 | 29 | 2 | 73 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 62 | 38 | 2 | 102 | ||
| splice donor/acceptor (+/-2bp) | 26 | 34 | 2 | 62 | ||
| Total | 139 | 175 | 666 | 298 | 3 | 1281 |
Highest pathogenic variant AF is 0.0011865061
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000434.1 | 27 | MANE Select | |
| Ensembl | ENSP00000496956.2 | 27 | MANE Select | |
| RefSeq | NP_061337.1 | 27 | Standard | |
| RefSeq | NP_061338.1 | 26 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| abcb4 | Danio rerio | Structure: efflux transmembrane transporter activity Quality: decreased process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Bile secretion - Homo sapiens (human)
- ABC transporters - Homo sapiens (human)
- Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
- Farnesoid X Receptor Pathway
- Nuclear Receptors Meta-Pathway
Biological Process
- lipid metabolic process
- regulation of lipid metabolic process
- positive regulation of cholesterol transport
- bile acid secretion
- response to drug
Molecular Function
- protein binding
- ATP binding
- phospholipid transporter activity
- phosphatidylcholine transporter activity
- ATPase activity, coupled to transmembrane movement of substances
Cellular Component
- nucleoplasm
- cytoplasm
- cytosol
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265723
- Coding exons
- 27
- Length
- 78739
- Individuals with no LoFs
- 125690
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 58
- Defined
- 125748
- p
- 0.000231
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.97 | 539 | 684 | 0.788 | 0.0000365 | 8409 |
| Missense (PolyPhen) | 131 | 222.79 | 0.588 | 2707 | ||
| Synonymous | 0.828 | 243 | 260 | 0.935 | 0.0000150 | 2536 |
| Loss of Function | 4.82 | 24 | 66.4 | 0.361 | 0.00000370 | 785 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00050 | 0.00049 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts (PubMed:7957936, PubMed:8898203, PubMed:9366571, PubMed:17523162, PubMed:23468132, PubMed:24806754, PubMed:24723470, PubMed:24594635, PubMed:21820390). Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to fu rther enrichment of SM and cholesterol in raft membranes in hepatocytes (PubMed:23468132). Required for proper phospholipid bile formation (By similarity). Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP- dependent manner (PubMed:24045840). Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane (PubMed:9366571, PubMed:28012258). In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts (PubMed:21820390). Does not confer multidrug resistance (By similarity). {ECO:0000250|UniProtKB:P21440, ECO:0000269|PubMed:17523162, ECO:0000269|PubMed:21820390, ECO:0000269|PubMed:23468132, ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24594635, ECO:0000269|PubMed:24723470, ECO:0000269|PubMed:24806754, ECO:0000269|PubMed:28012258, ECO:0000269|PubMed:7957936, ECO:0000269|PubMed:8898203, ECO:0000269|PubMed:9366571}.;
- Disease
- DISEASE: Cholestasis, progressive familial intrahepatic, 3 (PFIC3) [MIM:602347]: A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. {ECO:0000269|PubMed:11313315, ECO:0000269|PubMed:12671900, ECO:0000269|PubMed:17726488, ECO:0000269|PubMed:21119540, ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24594635, ECO:0000269|PubMed:24806754, ECO:0000269|PubMed:28012258, ECO:0000269|PubMed:9419367}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cholestasis of pregnancy, intrahepatic 3 (ICP3) [MIM:614972]: A liver disorder of pregnancy. It presents during the second or, more commonly, the third trimester of pregnancy with intense pruritus which becomes more severe with advancing gestation and cholestasis. It causes fetal distress, spontaneous premature delivery and intrauterine death. Patients have spontaneous and progressive disappearance of cholestasis after delivery. Cholestasis results from abnormal biliary transport from the liver into the small intestine. {ECO:0000269|PubMed:10767346, ECO:0000269|PubMed:12746424, ECO:0000269|PubMed:15077010}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gallbladder disease 1 (GBD1) [MIM:600803]: One of the major digestive diseases. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations in western countries. Most people with gallstones, however, remain asymptomatic through their lifetimes. {ECO:0000269|PubMed:11313316, ECO:0000269|PubMed:12891548, ECO:0000269|PubMed:22331132, ECO:0000269|PubMed:23533021, ECO:0000269|PubMed:24723470, ECO:0000269|PubMed:28012258, ECO:0000269|Ref.2}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.407
Intolerance Scores
- LoFtool
- 0.0172
- RVIS EVS
- -0.55
- RVIS percentile EVS
- 20.02
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.135
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |