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ABCC2
ATP binding cassette subfamily C member 2
The ABCC2 gene encodes the multidrug resistance protein 2 (MRP2), a transporter critical for moving various substances, including drug metabolites and bilirubin, out of cells. The ABCC2 gene is responsible for producing the MRP2 protein, an important transporter located primarily in the liver.
ABCC2 is located on the long (q) arm of chromosome 10, at band 10q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The ABCC2 gene provides the blueprint for a protein known as multidrug resistance protein 2 (MRP2). This protein is a member of the ATP-binding cassette (ABC) transporter family, which is involved in moving a wide range of molecules across cell membranes.
MRP2 is predominantly found in the outer membranes of liver cells, with smaller quantities present in the kidneys, intestines, and placenta. Its function is crucial for drug metabolism and the removal of various endogenous substances from the body.
What the gene does
The MRP2 protein, encoded by the ABCC2 gene, functions as an efflux transporter, meaning it actively moves substances out of cells. It is particularly important in the liver, where it clears certain drugs and their metabolites from organs and tissues. This process is part of drug metabolism, enabling drugs to be processed and eventually eliminated from the body.
Beyond drug compounds, MRP2 also facilitates the transport of bilirubin out of liver cells and into bile. Bilirubin is a yellow-orange pigment generated during the natural breakdown of old red blood cells. The protein's role in bilirubin transport is essential for preventing its accumulation, which can lead to jaundice. Given its broad transport capabilities, MRP2 is involved in maintaining cellular homeostasis and protecting against potentially toxic compounds.
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Chromosome location
The ABCC2 gene is situated on chromosome 10, specifically at position 10q24.2. This genomic location dictates where the gene resides within the human genome, providing its precise address.
Protein structure
The MRP2 protein is composed of 1545 amino acids and features several distinct functional regions. It contains two ABC transmembrane type-1 domains, located at amino acids 322-605 and 979-1264, which are involved in membrane insertion and substrate binding. Additionally, there are two ABC transporter domains, at amino acids 637-861 and 1300-1534, which likely contribute to ATP binding and hydrolysis to drive transport. A Disordered region is also noted between amino acids 253-284.
Key variants
Variants within the ABCC2 gene can impact the structure and function of the MRP2 protein. These genetic changes can affect the protein's ability to efficiently transport its various substrates, leading to an accumulation of certain compounds within cells or tissues. The consequences of such variants depend on the specific alteration and its impact 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.1031+4A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | ABCC2-related disorder |
c.1177C>T | p.Arg393Trp | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1291del | p.Leu431fs | Pathogenic | ★★☆☆ | not provided |
c.1621C>T | p.Gln541Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dubin-Johnson syndrome |
c.1882C>T | p.Arg628Ter | Pathogenic | ★★☆☆ | Dubin-Johnson syndrome |
c.1967+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1968-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1998dup | p.Val667fs | Pathogenic/Likely pathogenic | ★★☆☆ | Dubin-Johnson syndrome |
c.2077G>A | p.Gly693Arg | Pathogenic | ★★☆☆ | not provided |
c.2153del | p.Asn718fs | Pathogenic/Likely pathogenic | ★★☆☆ | Dubin-Johnson syndrome |
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
Variants in the ABCC2 gene are associated with inherited conditions, most notably Dubin-Johnson syndrome. This condition is characterised by impaired bilirubin transport, leading to a buildup of bilirubin and resulting jaundice. More than 40 genetic changes in ABCC2 have been identified as causative for Dubin-Johnson syndrome, many of which are single amino acid alterations affecting MRP2 function. Dubin-Johnson syndrome typically presents with jaundice during adolescence or early adulthood.
UK clinical status
In the UK, the ABCC2 gene is included on NHS Genomic Medicine Service national test directories. It is listed with a 'green' status for the Cholestasis (R171) and Neonatal cholestasis panels, indicating that there is strong evidence for its association with these conditions and it is routinely assessed in relevant clinical contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ABCC2 gene do?
The ABCC2 gene provides instructions for making the MRP2 protein, which is primarily found in the liver. This protein acts as a transporter, moving substances like drug metabolites and bilirubin out of cells and into bile for elimination from the body.
What is Dubin-Johnson syndrome?
Dubin-Johnson syndrome is an inherited condition caused by variants in the ABCC2 gene. It leads to impaired transport of bilirubin, a substance produced from red blood cell breakdown, causing it to build up in the body and resulting in jaundice (yellowing of the skin and eyes).
Where is the ABCC2 gene located?
The ABCC2 gene is located on chromosome 10, specifically at band 10q24.2. This location refers to its precise position within the human genome.
References
- van der Schoor LW, Verkade HJ, Kuipers F. New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition. Expert opinion on drug metabolism & toxicology. 2015. PMID: 25380746
- Devgun MS, El-Nujumi AM, O'Dowd GJ. Novel mutations in the Dubin-Johnson syndrome gene ABCC2/MRP2 and associated biochemical changes. Annals of clinical biochemistry. 2012. PMID: 23065530
- Jedlitschky G, Hoffmann U, Kroemer HK. Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert opinion on drug metabolism & toxicology. 2006. PMID: 16863439
- Machida I, Wakusawa S, Sanae F. Mutational analysis of the MRP2 gene and long-term follow-up of Dubin-Johnson syndrome in Japan. Journal of gastroenterology. 2005. PMID: 15870973
- Keitel V, Nies AT, Brom M. A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). American journal of physiology. Gastrointestinal and liver physiology. 2003. PMID: 12388192