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ABCG5
ATP binding cassette subfamily G member 5
The ABCG5 gene provides instructions for sterolin-1, a protein critical for managing the absorption of plant sterols and cholesterol in the intestines and liver. The ABCG5 gene encodes 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, or ATP Binding Cassette Subfamily G Member 5, is fundamental for controlling the body's absorption and elimination of plant sterols and cholesterol. It produces sterolin-1, a component of the sterolin transporter protein. This protein largely functions in the intestines and liver, preventing the buildup of plant sterols, which cannot be utilised by human cells, and helping to regulate cholesterol levels.
Efficient functioning of the ABCG5 gene is crucial for maintaining proper lipid balance, as impaired function can lead to the accumulation of these fatty substances in the body, resulting in various health issues.
What the gene does
The ABCG5 gene provides the genetic blueprint for sterolin-1, a crucial part of the sterolin transporter protein. This transporter, primarily located in cells of the intestines and liver, plays a key role in lipid metabolism. Its main function is to pump plant sterols, absorbed from food, back into the intestinal tract and into bile for excretion, thereby limiting their entry into the bloodstream. Typically, only about 5% of dietary plant sterols are absorbed into the bloodstream due to this mechanism. The sterolin transporter also contributes to regulating cholesterol absorption, with approximately 50% of dietary cholesterol normally being absorbed.
Through this action, ABCG5-encoded sterolin-1, in conjunction with sterolin-2 from the ABCG8 gene, is vital for preventing the accumulation of plant sterols and maintaining appropriate cholesterol levels within the body.
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Chromosome location
The ABCG5 gene is situated on the short (p) arm of chromosome 2, specifically at position 2p21. This gene contains multiple exons that are transcribed into messenger RNA, which then provides the instructions for building the sterolin-1 protein.
Protein structure
The ABCG5 protein, also known as sterolin-1, is composed of 651 amino acids. Its structural organisation includes a Disordered region at amino acids 1-32, an ABC transporter domain spanning amino acids 52-293, and an ABC transmembrane type-2 domain located from amino acids 388-645. This domain architecture is characteristic of ATP-binding cassette (ABC) transporter proteins, which are involved in moving various molecules across cell membranes.
Key variants
Genetic variations within the ABCG5 gene can impact the structure and function of the sterolin-1 protein. Such alterations may lead to reduced efficiency in the transport of plant sterols and cholesterol, potentially causing their accumulation in the body. Identifying these genetic changes is important for understanding their associated health implications.
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.436G>T | p.Glu146Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
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 linked to Sitosterolaemia. This autosomal recessive condition arises from the impaired elimination of plant sterols and, to a lesser extent, cholesterol, leading to their buildup in the body. This accumulation can result in various symptoms, including the formation of clogged blood vessels, skin xanthomas, and other tissue deposits.
- 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 Genomic Medicine Service national test panels, reflecting its clinical significance. It is listed as 'green' for panels such as Bleeding and platelet disorders, Familial hypercholesterolaemia, Inherited bleeding disorders, Likely inborn error of metabolism, Rare anaemia, Sitosterolaemia (R323), and Undiagnosed metabolic disorders.
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 protein that helps regulate the absorption of plant sterols and cholesterol in the intestines and liver, facilitating their removal from the body.
What condition is most commonly associated with ABCG5 variants?
Mutations in the ABCG5 gene are primarily associated with Sitosterolaemia, an inherited condition characterised by the accumulation of plant sterols and cholesterol in various body tissues.
Where in the body does the ABCG5 protein primarily act?
The ABCG5 protein, as part of the sterolin transporter, acts mainly in the cells of the intestines and liver to control the movement of plant sterols and cholesterol.
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