On this page
ATP7B
ATPase copper transporting beta
The ATP7B gene provides instructions for making a protein crucial for transporting copper, playing a key role in maintaining proper copper balance within the body. ATP7B encodes a copper-transporting ATPase protein, primarily active in the liver, which regulates copper levels.
ATP7B is located on the long (q) arm of chromosome 13, at band 13q14.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 13 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The ATP7B gene, also known as ATPase copper transporting beta, provides the genetic blueprint for a protein called copper-transporting ATPase 2. This protein is a member of the P-type ATPase protein family, which harnesses ATP's chemical energy to drive metal ion movement through cellular membranes [PMID:1650772].
Copper is vital for many enzymatic functions, yet its excessive accumulation can be toxic. The ATP7B protein is predominantly found in liver cells, with smaller quantities present in the kidneys and brain. Its primary roles involve transporting copper from the liver to other bodily tissues and facilitating the elimination of surplus copper, thereby maintaining cellular copper homeostasis [PMID:29396347].
What the gene does
The ATP7B protein, copper-transporting ATPase 2, is integral to the cellular management of copper. As a P-type ATPase, it uses the energy from ATP hydrolysis to actively move copper ions across biological membranes. Its activity is particularly critical in the liver, which is the main organ for processing and distributing copper throughout the body.
Within liver cells, the ATP7B protein typically resides in the Golgi apparatus, an organelle responsible for modifying and packaging proteins. In this location, the protein incorporates copper into ceruloplasmin molecules, enabling systemic copper distribution through circulation [PMID:1650772]. This process ensures copper is delivered efficiently to cells where it is needed for essential enzyme function.
Furthermore, the ATP7B protein is essential for detoxifying excess copper. If copper levels within the liver become too high, ATP7B relocates from the Golgi apparatus. Under high-copper conditions, ATP7B redirects copper into vesicular compartments that ultimately merge with the biliary system, allowing hepatic copper excretion. Bile, a substance produced by the liver, then carries the excess copper out of the body through the digestive system, preventing harmful accumulation.
More than 250 ATP7B gene mutations are known to cause Wilson disease. Approximately half of these mutations result in changes to individual amino acids that comprise the copper-transporting ATPase 2 protein. Such amino acid substitutions can disrupt the protein's normal three-dimensional structure or reduce its stability, consequently impairing its ability to transport copper effectively [PMID:29396347].
Video: Genetics 101
Chromosome location
The ATP7B gene is situated on chromosome 13, specifically at location 13q14.3. This position refers to the long arm (q) of chromosome 13, within region 14 and sub-band 3. The precise genomic location of a gene helps scientists understand its neighbourhood on the chromosome and how it might be inherited or interact with other genes.
Protein structure
The ATP7B protein, comprising 1465 amino acids, is characterised by several key functional domains. The N-terminal region contains six heavy metal associated (HMA) domains, which are crucial for copper binding. Specifically, these include HMA 1 (amino acids 58-124), HMA 2 (amino acids 143-209), HMA 3 (amino acids 257-323), HMA 4 (amino acids 359-425), HMA 5 (amino acids 488-554), and HMA 6 (amino acids 564-630). Interspersed with some of these HMA domains are two disordered regions (amino acids 230-249 and 322-355), which may play a role in protein flexibility or interactions. These HMA domains are vital for the protein's ability to bind copper ions, an essential step in their subsequent transport.
Key variants
Genetic variants within the ATP7B gene can lead to a range of impacts on protein function, from minor alterations to complete loss of function. These variations include single nucleotide changes, insertions, and deletions that can modify the amino acid sequence, affect protein folding, or lead to premature termination of protein synthesis. Such changes can impair the copper-transporting ATPase 2 protein's ability to bind, transport, or excrete copper, leading to its accumulation in various tissues. Research has identified numerous pathogenic variants associated with inherited conditions.
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.1017del | p.Arg339fs | Pathogenic/Likely pathogenic | ★★☆☆ | Wilson disease |
c.104_105insT | p.Lys35fs | Pathogenic/Likely pathogenic | ★★☆☆ | Wilson disease |
c.1063C>T | p.Gln355Ter | Pathogenic | ★★☆☆ | Wilson disease |
c.1073del | p.Cys358fs | Pathogenic/Likely pathogenic | ★★☆☆ | Wilson disease |
c.1107_1108dup | p.Cys370fs | Pathogenic | ★★☆☆ | Wilson disease |
c.111dup | p.Ala38fs | Pathogenic | ★★☆☆ | Wilson disease |
c.1136del | p.Gly379fs | Pathogenic | ★★☆☆ | Wilson disease |
c.1145_1151del | p.Ser382fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1147C>T | p.Gln383Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Wilson disease |
c.1807A>T | p.Lys603Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Wilson disease |
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 ATP7B gene are primarily associated with Wilson disease, an inherited disorder characterised by excessive copper accumulation in the body. This autosomal recessive condition can lead to severe damage in organs such as the liver, brain, and eyes. Understanding the genetic basis of Wilson disease through ATP7B analysis is crucial for diagnosis and management.
Inheritance pattern
Conditions caused by pathogenic ATP7B 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 ATP7B gene is well-recognised within the UK's National Health Service (NHS) genomic medicine services. It is included on several NHS England National Genomic Test Directory panels, indicating its established role in diagnosing a variety of conditions. These panels cover areas such as Brain channelopathy, Cholestasis (including Neonatal cholestasis), Dystonia (adult and childhood onset, and Early onset dystonia), Hereditary ataxia (adult onset), Iron metabolism disorders, Likely inborn error of metabolism, Neurodegenerative disorders (adult onset), Structural basal ganglia disorders, Undiagnosed metabolic disorders, and Wilson disease.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining overall health through a balanced diet and healthy lifestyle is generally recommended, particularly for individuals with a genetic predisposition to conditions affecting metabolic pathways. While no specific diet or lifestyle changes can prevent Wilson disease for individuals with ATP7B variants, general dietary advice includes limiting foods rich in copper, such as organ meats, shellfish, nuts, and chocolate, for those diagnosed with or suspected of having Wilson disease. However, any specific dietary modifications should always be discussed with a healthcare professional or a registered dietitian, as individual needs can vary considerably.
Supplement considerations
There is no conclusive evidence that dietary supplements can prevent the development of Wilson disease or mitigate its progression for individuals with ATP7B gene variants. Copper chelation therapy and zinc supplementation are established medical treatments for Wilson disease, prescribed and monitored by healthcare professionals. Individuals should not self-prescribe or take any supplements without consulting a doctor, especially if they have a diagnosed genetic condition or are concerned about their copper levels, as inappropriate supplementation can be harmful.
Frequently asked questions
What is the function of the ATP7B gene?
The ATP7B gene provides instructions for creating a protein called copper-transporting ATPase 2, which is responsible for moving copper within and out of cells, primarily in the liver, to maintain proper copper balance.
Which condition is primarily associated with ATP7B gene variants?
Variants in the ATP7B gene are primarily associated with Wilson disease, an inherited disorder characterised by the accumulation of excessive copper in various organs, leading to potential damage.
How does ATP7B contribute to copper regulation?
The ATP7B protein helps load copper onto ceruloplasmin for transport to other tissues and facilitates the removal of excess copper into bile for excretion, preventing toxic accumulation.
Is Wilson disease an inherited condition?
Yes, Wilson disease is an autosomal recessive inherited condition, meaning an individual must inherit two copies of a pathogenic ATP7B variant (one from each parent) to develop the condition.
Where is the ATP7B gene located?
The ATP7B gene is located on the long arm of chromosome 13, specifically at band 13q14.3.
Can diet or supplements prevent Wilson disease?
No, diet or supplements cannot prevent Wilson disease. While dietary modifications to limit copper intake may be part of management for affected individuals, any specific dietary or supplement changes should only be made under medical supervision.
References
- Ferenci P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Human genetics. 2006. PMID: 16791614
- Kitzberger R, Madl C, Ferenci P. Wilson disease. Metabolic brain disease. 2005. PMID: 16382340
- Cater MA, Forbes J, La Fontaine S. Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. The Biochemical journal. 2004. PMID: 14998371
- Langner C, Denk H. Wilson disease. Virchows Archiv : an international journal of pathology. 2004. PMID: 15205951
- Panagiotakaki E, Tzetis M, Manolaki N. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). American journal of medical genetics. Part A. 2004. PMID: 15523622
- Huster D, Hoppert M, Lutsenko S. Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. Gastroenterology. 2003. PMID: 12557139
- Fatemi N, Sarkar B. Molecular mechanism of copper transport in Wilson disease. Environmental health perspectives. 2002. PMID: 12426114