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ABCC2
ATP binding cassette subfamily C member 2
The ABCC2 gene provides instructions for creating the multidrug resistance protein 2 (MRP2), a transporter protein critical for clearing various substances, including drugs and bilirubin, from cells. The ABCC2 gene encodes the MRP2 protein, which functions as an efflux transporter, moving molecules out of cells.
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, also known as ATP binding cassette subfamily C member 2, is responsible for producing the multidrug resistance protein 2 (MRP2). This protein is a key member of the ATP-binding cassette (ABC) transporter family, which facilitates the movement of various substances across cell membranes. MRP2 is particularly important in the liver, where it helps remove waste products and certain medications from the body.
Dysfunction of the ABCC2 gene can impact drug metabolism and the body's ability to excrete specific compounds, leading to conditions that affect liver function and drug responses.
What the gene does
The ABCC2 gene directs the synthesis of the multidrug resistance protein 2 (MRP2), a transporter protein found predominantly in the outer membranes of liver cells, with smaller quantities present in the kidneys, intestines, and placenta. MRP2's primary function is to actively transport a broad range of compounds out of cells, a process known as efflux. This includes various drugs, playing a crucial role in drug metabolism by facilitating their clearance from organs and tissues. Drug metabolism involves converting medications into chemical components that can exert their intended effects and eventually be eliminated from the body.
Additionally, MRP2 is vital for transporting bilirubin, a yellow pigment generated during the breakdown of old red blood cells, from liver cells into bile. Bile is a digestive fluid produced by the liver, essential for digestion and waste removal. The transport activity of MRP2 is powered by adenosine triphosphate (ATP), a molecule that provides energy for cellular processes.
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Chromosome location
The ABCC2 gene is located on chromosome 10, specifically at position 10q24.2. This indicates its presence on the long arm (q) of chromosome 10, within band 24.2.
Protein structure
The ABCC2 gene encodes a protein composed of 1545 amino acids. Its structure includes several distinct functional regions and domains. A Disordered region is identified between amino acids 253 and 284. The protein also contains two ABC transmembrane type-1 domains, with the first located from amino acids 322 to 605 and the second from amino acids 979 to 1264. Additionally, two ABC transporter domains are present: ABC transporter 1 spans amino acids 637 to 861, and ABC transporter 2 is found between amino acids 1300 and 1534. These domains are crucial for the protein's ability to transport substances across cell membranes.
Key variants
Genetic variations within the ABCC2 gene can alter the function or production of the MRP2 protein. These changes can range from single amino acid substitutions to larger deletions or insertions within the gene sequence. Such variants may affect the protein's transport efficiency, its stability, or its expression levels, potentially leading to impaired clearance of substrates like drugs and bilirubin.
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 primarily associated with inherited conditions that affect the liver's ability to process and excrete certain substances. The most notable condition linked to ABCC2 variants is Dubin-Johnson syndrome, which is inherited in an autosomal recessive manner. This syndrome typically manifests with jaundice, a yellowing of the skin and eyes, usually appearing during adolescence or early adulthood, due to impaired bilirubin excretion.
UK clinical status
The ABCC2 gene is included in several NHS Genomic Medicine Service (GMS) panels, reflecting its clinical significance within the UK healthcare system. It is listed on the Cholestasis panel (R171) and the Neonatal cholestasis panel, both with a 'green' status, indicating that there is strong evidence for a gene-disease association and that testing is clinically appropriate.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ABCC2 gene?
The ABCC2 gene provides instructions for making the MRP2 protein, which acts as a transporter to move various substances, including drugs and bilirubin, out of cells, particularly in the liver. This process is crucial for drug metabolism and the body's detoxification pathways.
How do ABCC2 variants affect health?
Variants in the ABCC2 gene can impair the function of the MRP2 protein, leading to reduced ability to transport substances out of cells. This can cause conditions like Dubin-Johnson syndrome, where bilirubin accumulates, resulting in jaundice.
What is Dubin-Johnson syndrome?
Dubin-Johnson syndrome is an inherited condition caused by variants in the ABCC2 gene. It is characterised by a mild, chronic form of jaundice that typically appears during adolescence or early adulthood, due to the liver's impaired ability to excrete conjugated bilirubin.
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