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ABCB4
ATP binding cassette subfamily B member 4
The ABCB4 gene provides instructions for a protein critical in moving phospholipids into bile, a digestive fluid, and is associated with various cholestatic liver conditions. The ABCB4 gene, also known as MDR3, encodes a protein that functions as a floppase, transporting phospholipids across cell membranes in the liver.
ABCB4 is located on the long (q) arm of chromosome 7, at band 7q21.12. Arm ratio per GRCh38 - banding schematic.
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Overview
The ABCB4 gene, fully named ATP binding cassette subfamily B member 4, is integral to liver function. It encodes a protein that plays a key role in the secretion of phospholipids into bile, a digestive fluid produced by the liver. Proper functioning of the ABCB4 protein is essential for maintaining the solubility of cholesterol in bile and protecting liver cells from potential damage by bile acids.
Disruptions in ABCB4 function can lead to impaired bile flow and various liver conditions, particularly those characterised by cholestasis.
What the gene does
The ABCB4 gene directs the synthesis of a protein belonging to the ATP-binding cassette (ABC) transporter family, specifically categorised as a floppase. This protein's primary function is to transport phosphatidylcholine, a type of phospholipid, from the inner leaflet to the outer leaflet of hepatocyte canalicular membranes. Once outside the cell, these phospholipids are incorporated into bile.
In bile, phospholipids bind to bile acids, reducing their toxicity to liver cells and helping to keep cholesterol dissolved, thus preventing the formation of gallstones. When the ABCB4 protein is dysfunctional, insufficient phospholipids are secreted into bile, leading to an imbalance that can cause liver damage and impaired bile flow.
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Chromosome location
The ABCB4 gene is situated on chromosome 7, specifically at position 7q21.12. This genomic location defines where the gene resides within the human genome, influencing its inheritance and potential associations with genetic conditions.
Protein structure
The ABCB4 protein is composed of 1286 amino acids and exhibits a complex domain architecture characteristic of ABC transporters. It features two ABC transmembrane type-1 domains, specifically ABC transmembrane type-1 1 (amino acids 57-359) and ABC transmembrane type-1 2 (amino acids 711-999). Additionally, it contains two ABC transporter domains, ABC transporter 1 (amino acids 394-630) and ABC transporter 2 (amino acids 1034-1279). A specific region for interaction with HAX1 has been identified between amino acids 625-647.
Key variants
Variants within the ABCB4 gene can impact the structure and function of the encoded protein, affecting its ability to transport phospholipids effectively. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their pathogenicity depends on the specific alteration and its effect on protein activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1006-2A>C | - | Pathogenic | ★★☆☆ | not provided |
c.100del | p.Thr34fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial intrahepatic cholestasis |
c.1015del | p.Ser339fs | Pathogenic | ★★☆☆ | not provided |
c.1216C>T | p.Arg406Ter | Pathogenic | ★★☆☆ | not provided |
c.1318C>T | p.Gln440Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Low phospholipid associated cholelithiasis |
c.1371del | p.Gln458fs | Pathogenic | ★★☆☆ | Low phospholipid associated cholelithiasis |
c.139C>T | p.Arg47Ter | Pathogenic | ★★☆☆ | not provided |
c.1436C>T | p.Pro479Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive familial intrahepatic cholestasis type 3 |
c.153G>A | p.Trp51Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive familial intrahepatic cholestasis type 3 |
c.1553del | p.Leu518fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ABCB4 gene are associated with several liver disorders, primarily those involving impaired bile flow. These include progressive familial intrahepatic cholestasis type 3 (PFIC3), a severe form of liver disease that often manifests in early childhood. Other conditions linked to ABCB4 variants include intrahepatic cholestasis of pregnancy (ICP) and low phospholipid-associated cholelithiasis (LPAC).
- Progressive familial intrahepatic cholestasis type 3 Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ABCB4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ABCB4 gene is included in several UK NHS national genomic test directories, reflecting its clinical significance. It is listed on panels for Cholestasis (R171), Likely inborn error of metabolism (R98), Neonatal cholestasis, and Undiagnosed metabolic disorders, indicating its role in diagnosing and managing these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ABCB4 gene?
The ABCB4 gene provides instructions for making a protein that transports phospholipids into bile, which is crucial for solubilising cholesterol and protecting liver cells from bile acid toxicity.
Which conditions are associated with variants in the ABCB4 gene?
Variants in the ABCB4 gene are associated with several liver conditions, including progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, and low phospholipid-associated cholelithiasis.
How is ABCB4 relevant to carrier screening?
ABCB4 is classified for autosomal recessive carrier screening because individuals carrying one pathogenic variant typically do not show symptoms, but if both parents are carriers, there is a risk of their child inheriting two pathogenic variants and developing a related condition.
References
- Davit-Spraul A, Gonzales E, Baussan C. Progressive familial intrahepatic cholestasis. Orphanet journal of rare diseases. 2009. PMID: 19133130
- Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World journal of gastroenterology. 2009. PMID: 19418576
- Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet journal of rare diseases. 2007. PMID: 17562004
- Degiorgio D, Colombo C, Seia M. Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3). European journal of human genetics : EJHG. 2007. PMID: 17726488
- Pauli-Magnus C, Stieger B, Meier Y. Enterohepatic transport of bile salts and genetics of cholestasis. Journal of hepatology. 2005. PMID: 15975683
- Dixon PH, Weerasekera N, Linton KJ. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Human molecular genetics. 2000. PMID: 10767346