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CP
ceruloplasmin
The *CP* gene provides instructions for making ceruloplasmin, a protein vital for iron metabolism and transport throughout the body and brain. The *CP* gene encodes ceruloplasmin, an important protein that facilitates iron movement from tissues into the bloodstream.
CP is located on the long (q) arm of chromosome 3, at band 3q24-q25.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The *CP* gene is responsible for producing ceruloplasmin, a protein with ferroxidase activity essential for proper iron metabolism [PMID:33671239]. This protein plays a critical role in transporting iron from various organs and tissues into the blood. By preparing iron for its incorporation into transferrin, ceruloplasmin enables the delivery of iron to red blood cells where it is needed for haemoglobin production.
Beyond its systemic role, ceruloplasmin is also crucial for iron regulation within the brain. Disruptions in *CP* gene function can lead to an accumulation of iron in tissues, causing conditions like aceruloplasminaemia.
What the gene does
Ceruloplasmin, encoded by the *CP* gene, functions primarily as an enzyme (ferroxidase) that oxidises iron, preparing it for transport and storage [PMID:25700201]. This oxidative step is necessary for iron to bind to transferrin, the protein responsible for circulating iron in the blood. The liver is the main site for producing serum ceruloplasmin, which manages iron transport throughout most of the body.
In addition to the circulating form, a specific glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is produced by glial cells in the nervous system. This form is particularly important for iron processing and release from brain tissues, highlighting ceruloplasmin's dual role in both systemic and neurological iron homeostasis. Both forms ensure iron is properly mobilised and utilised, preventing its harmful accumulation in tissues.
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Chromosome location
The *CP* gene is located on chromosome 3, specifically within the 3q24-q25.1 region. This chromosomal location indicates where the gene resides on the long arm (q arm) of chromosome 3.
Protein structure
The ceruloplasmin protein consists of 1065 amino acids and features six distinct plastocyanin-like domains. These domains are sequentially arranged as Plastocyanin-like 1 (amino acids 20-200), Plastocyanin-like 2 (amino acids 209-357), Plastocyanin-like 3 (amino acids 370-560), Plastocyanin-like 4 (amino acids 570-718), Plastocyanin-like 5 (amino acids 730-900), and Plastocyanin-like 6 (amino acids 908-1061). These domains are critical for the protein's ferroxidase activity and its ability to bind copper ions, which are essential for its function [PMID:25700201].
Key variants
Variations within the *CP* gene can alter the function or production of the ceruloplasmin protein. These genetic changes may include substitutions of single protein building blocks, leading to unstable proteins that degrade rapidly. Other variants can result in abnormally short or non-functional versions of the protein, impairing its ability to manage iron effectively. The inheritance pattern for conditions associated with *CP* variants is varied.
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.1208+1G>A | - | Pathogenic | ★★☆☆ | Deficiency of ferroxidase |
c.1948G>A | p.Gly650Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation |
c.1991_1992del | p.Thr664fs | Pathogenic | ★★☆☆ | Deficiency of ferroxidase |
c.2066del | p.Pro689fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation |
c.2122G>A | p.Gly708Ser | Pathogenic | ★★☆☆ | Deficiency of ferroxidase |
c.2527_2528del | p.Ser843fs | Pathogenic | ★★☆☆ | Deficiency of ferroxidase |
c.2670C>G | p.Tyr890Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of ferroxidase |
c.2701C>T | p.Arg901Ter | Pathogenic | ★★☆☆ | Deficiency of ferroxidase |
c.2756T>C | p.Leu919Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation |
c.607+1del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of ferroxidase |
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 *CP* gene are primarily associated with Aceruloplasminaemia. This inherited condition is characterised by iron accumulation in various organs, including the brain, liver, and pancreas. The resulting iron overload can lead to neurological symptoms, diabetes, and organ damage.
UK clinical status
The *CP* gene is included in several expert-curated panels within the UK NHS Genomic Medicine Service's PanelApp. It is rated 'green' for conditions such as "Ataxia and cerebellar anomalies - childhood onset", "Dystonia, chorea or related movement disorder, adult onset", "Early onset dystonia", "Hereditary ataxia", "Hereditary ataxia, adult onset", "Iron metabolism disorders - NOT common HFE mutations", "Likely inborn error of metabolism", "Neurodegenerative disorders, adult onset", "Structural basal ganglia disorders", and "Undiagnosed metabolic disorders". This 'green' rating indicates there is strong evidence for the gene's association with these conditions, supporting its use in diagnostic testing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the CP gene?
The *CP* gene provides instructions for making ceruloplasmin, a protein essential for iron transport and metabolism throughout the body and within the brain. It helps prepare iron for transport in the blood.
What is aceruloplasminaemia?
Aceruloplasminaemia is an inherited condition caused by variants in the *CP* gene. It results in the accumulation of iron in various organs, including the brain, liver, and pancreas, leading to neurological issues and other health problems.
How does ceruloplasmin help with iron in the brain?
A specific form of ceruloplasmin, produced by glial cells, is crucial for processing iron and releasing it from brain tissue, helping to prevent iron accumulation in the central nervous system.
References
- Kono S, Suzuki H, Oda T. Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia. Journal of hepatology. 2007. PMID: 17637479
- Kono S, Miyajima H. Molecular and pathological basis of aceruloplasminemia. Biological research. 2006. PMID: 16629161
- Kono S, Suzuki H, Oda T. Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia. Neuromolecular medicine. 2006. PMID: 16775387
- Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. Brain research. Brain research reviews. 2005. PMID: 16269323
- Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annual review of nutrition. 2002. PMID: 12055353
- Nittis T, Gitlin JD. The copper-iron connection: hereditary aceruloplasminemia. Seminars in hematology. 2002. PMID: 12382203