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ABCB4
ATP binding cassette subfamily B member 4
The ABCB4 gene provides instructions for a protein that plays a crucial role in transporting phospholipids into bile, essential for liver function and digestion. The ABCB4 gene, also known as MDR3, encodes a protein responsible for moving specific fat molecules called phospholipids across liver cell membranes.
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 (ATP binding cassette subfamily B member 4), also known as MDR3, provides genetic instructions for producing a protein involved in the transport of phospholipids. This protein is primarily active in liver cells, where it facilitates the movement of these fatty molecules into bile. Proper ABCB4 function is essential for maintaining bile composition and protecting the liver from potentially harmful bile acids.
Disruptions in the ABCB4 gene's function can lead to various liver conditions, particularly those characterised by cholestasis, a reduction or stoppage of bile flow. These conditions range from disorders affecting pregnant individuals to more severe progressive liver diseases in children.
What the gene does
The ABCB4 gene encodes an ATP-binding cassette (ABC) transporter protein, specifically a 'floppase'. This protein's primary function is to transport phospholipids from the inner to the outer leaflet of liver cell membranes, ultimately releasing them into the bile. Phospholipids perform two key roles in bile: they help to keep cholesterol dissolved, preventing the formation of gallstones, and they bind to bile acids, reducing their toxicity to liver cells.
The ABCB4 protein contributes to the proper composition of bile, ensuring efficient fat digestion and protecting liver cells from damage. The protein's transport activity, powered by ATP hydrolysis, is critical for this process. Without sufficient functional ABCB4 protein, phospholipid levels in bile can drop, leading to an imbalance that can damage liver cells and impair bile flow.
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Chromosome location
The ABCB4 gene is located on chromosome 7, specifically at position 7q21.12. This genomic location refers to the long (q) arm of chromosome 7, within region 21, band 12. The precise placement of the gene ensures its stable inheritance and expression.
Protein structure
The ABCB4 protein is composed of 1286 amino acids and features several distinct functional domains. It includes two ABC transmembrane type-1 domains, with the first located between amino acids 57-359 and the second between amino acids 711-999. There are also two ABC transporter domains, the first spanning amino acids 394-630 and the second from amino acids 1034-1279. Additionally, a specific region between amino acids 625-647 has been identified for its interaction with HAX1.
Key variants
Genetic variations within the ABCB4 gene can impact the structure and function of the encoded protein. Pathogenic variants, which are changes that impair the protein's normal activity, can disrupt phospholipid transport. These alterations can lead to a range of clinical presentations, depending on the specific variant and its effect on protein function.
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.1356+2T>C | - | 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 |
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 conditions primarily affecting the liver and bile ducts. These include Progressive familial intrahepatic cholestasis type 3, a severe inherited liver disorder that often manifests in early childhood and can lead to liver failure. Other conditions linked to ABCB4 variants include intrahepatic cholestasis of pregnancy and low phospholipid-associated cholelithiasis, which involves the formation of gallstones.
- 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
In the UK, the ABCB4 gene is included on several NHS Genomic Medicine Service national test panels due to its clinical significance. It is listed as 'green' on panels for Cholestasis, Likely inborn error of metabolism, Neonatal cholestasis, and Undiagnosed metabolic disorders, indicating that there is strong evidence for its association with these conditions and it is routinely tested.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ABCB4 gene?
The ABCB4 gene provides instructions for making a protein that transports phospholipids into bile, which is crucial for fat digestion and protecting the liver from harmful bile acids.
What happens if the ABCB4 gene doesn't work correctly?
If the ABCB4 gene doesn't function properly, it can lead to reduced phospholipid levels in bile, causing conditions like cholestasis, where bile flow is impaired, and increasing the risk of liver damage or gallstone formation.
Is ABCB4 associated with inherited conditions?
Yes, pathogenic variants in the ABCB4 gene are linked to inherited conditions such as Progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, and low phospholipid-associated cholelithiasis.
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