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ABCG5
ATP binding cassette subfamily G member 5
The ABCG5 gene encodes sterolin-1, a component of the sterolin transporter protein critical for regulating the absorption and excretion of plant sterols and cholesterol. The ABCG5 gene provides instructions for making sterolin-1, which, along with sterolin-2 from the ABCG8 gene, forms the sterolin protein.
ABCG5 is located on the short (p) arm of chromosome 2, at band 2p21. Arm ratio per GRCh38 - banding schematic.
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Overview
The ABCG5 gene, also known as ATP binding cassette subfamily G member 5, is fundamental for controlling how the body processes dietary fats, specifically plant sterols and cholesterol. It produces sterolin-1, a key component of a transporter protein called sterolin. This protein acts as a gatekeeper, largely preventing excessive absorption of plant sterols into the bloodstream.
Efficient functioning of the ABCG5 gene is vital for maintaining healthy lipid balance and preventing the accumulation of plant sterols in tissues, which can lead to various health issues.
What the gene does
The ABCG5 gene provides the blueprint for sterolin-1, which combines with sterolin-2 (encoded by the ABCG8 gene) to create the sterolin transporter. This transporter is a type of protein responsible for moving substances across cell membranes, predominantly in the intestines and liver. Its primary role involves pumping plant sterols, which are fatty components of plant-based foods, out of the body.
After plant sterols are absorbed from food into intestinal cells, the sterolin transporters in these cells actively pump them back into the intestinal tract. Similarly, sterolin transporters in liver cells facilitate the movement of plant sterols into bile, which is then released into the intestine for elimination. This mechanism ensures that only a small fraction (approximately 5%) of dietary plant sterols enters the bloodstream. Sterolin also contributes to regulating cholesterol levels in a similar fashion, influencing the proportion of dietary cholesterol absorbed by the body.
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Chromosome location
The ABCG5 gene is situated on chromosome 2 at position 2p21. This specific genomic location houses the genetic instructions necessary for the synthesis of the sterolin-1 protein, integral to sterol metabolism.
Protein structure
The ABCG5 protein, also known as sterolin-1, is 651 amino acids in length. It features several distinct domains crucial for its transporter function. The N-terminal region, spanning amino acids 1-32, is classified as Disordered. Following this, the ABC transporter domain is located between amino acids 52-293. Further towards the C-terminus, the ABC transmembrane type-2 domain extends from amino acids 388-645, playing a key role in membrane transport.
Key variants
Variations within the ABCG5 gene can impact the function of the sterolin transporter, potentially leading to altered processing of plant sterols and cholesterol. These genetic changes can range from single nucleotide polymorphisms to larger structural alterations, each with varying effects on protein function and subsequent metabolic pathways.
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.1166G>A | p.Arg389His | Pathogenic/Likely pathogenic | ★★☆☆ | Sitosterolemia 2 |
c.1222C>T | p.Arg408Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sitosterolemia 2 |
c.1256G>A | p.Arg419His | Pathogenic | ★★☆☆ | Sitosterolemia 2 |
c.1336C>T | p.Arg446Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sitosterolemia |
c.136del | p.Ser46fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1374C>G | p.Tyr458Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1464-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Sitosterolemia 2 |
c.1762+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.321del | p.Thr108fs | Pathogenic | ★★☆☆ | Sitosterolemia |
c.367G>T | p.Glu123Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sitosterolemia |
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 ABCG5 gene are primarily associated with Sitosterolaemia, an autosomal recessive condition. This disorder is characterised by an accumulation of plant sterols and, to a lesser extent, cholesterol within the body. The impaired function of the sterolin transporter leads to defective elimination of these fatty substances, resulting in their build-up in tissues such as arteries and skin.
- Sitosterolaemia Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ABCG5 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 ABCG5 gene is included in several NHS England Genomic Medicine Service approved panels. It is listed as 'green' for conditions such as Sitosterolaemia (R323), Bleeding and platelet disorders (R90), Familial hypercholesterolaemia, Inherited bleeding disorders, Likely inborn error of metabolism (R98), Rare anaemia (R92), and Undiagnosed metabolic disorders. This indicates that variants in this gene are considered clinically actionable for these specific conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ABCG5 gene?
The ABCG5 gene provides instructions for sterolin-1, a component of the sterolin transporter protein. This protein is essential for regulating the absorption and excretion of plant sterols and cholesterol, preventing their excessive accumulation in the body.
What condition is most commonly associated with variants in ABCG5?
Variants in the ABCG5 gene are primarily associated with Sitosterolaemia. This is an inherited condition where plant sterols and cholesterol build up in the body due to impaired function of the sterolin transporter.
How does the ABCG5 gene help manage dietary fats?
The ABCG5 gene, through the sterolin protein it helps form, pumps plant sterols from intestinal cells back into the digestive tract for excretion and moves them into bile in the liver. This process significantly limits the amount of plant sterols absorbed into the bloodstream.
References
- Chan J, Vandeberg JL. Hepatobiliary transport in health and disease. Clinical lipidology. 2012. PMID: 22859919
- Kerr ID, Haider AJ, Gelissen IC. The ABCG family of membrane-associated transporters: you don't have to be big to be mighty. British journal of pharmacology. 2011. PMID: 21175590
- Stender S, Frikke-Schmidt R, Nordestgaard BG. Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population. Hepatology (Baltimore, Md.). 2011. PMID: 21274884
- Calandra S, Tarugi P, Speedy HE. Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. Journal of lipid research. 2011. PMID: 21862702
- Fitzgerald ML, Mujawar Z, Tamehiro N. ABC transporters, atherosclerosis and inflammation. Atherosclerosis. 2010. PMID: 20138281
- Niu DM, Chong KW, Hsu JH. Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. Journal of inherited metabolic disease. 2010. PMID: 20521169
- Sabeva NS, Liu J, Graf GA. The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease. Current opinion in endocrinology, diabetes, and obesity. 2009. PMID: 19306529
- Kuo KK, Shin SJ, Chen ZC. Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease. The British journal of surgery. 2008. PMID: 18457353
- Rudkowska I, Jones PJ. Polymorphisms in ABCG5/G8 transporters linked to hypercholesterolemia and gallstone disease. Nutrition reviews. 2008. PMID: 18522623
- Kidambi S, Patel SB. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica; the fate of foreign compounds in biological systems. 2008. PMID: 18668442
- Adam MP, Bick S, Mirzaa GM. Sitosterolemia. 1993. PMID: 23556150