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HAMP
hepcidin antimicrobial peptide
The HAMP gene provides instructions for hepcidin, a protein primarily produced in the liver that plays a crucial role in regulating the body's iron levels. The HAMP gene is responsible for producing hepcidin, a key regulator of iron metabolism.
HAMP is located on the long (q) arm of chromosome 19, at band 19q13.12. Arm ratio per GRCh38 - banding schematic.
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Overview
The HAMP gene, also known as hepcidin antimicrobial peptide, encodes the hepcidin protein, which is vital for maintaining iron homeostasis within the body. Hepcidin's primary function is to regulate the absorption and distribution of dietary iron. This regulation is essential to prevent both iron deficiency and iron overload, which can have significant health implications.
Dysregulation of hepcidin production, often due to variants in the HAMP gene, is associated with various iron-related disorders. One notable condition is hereditary haemochromatosis, where excessive iron accumulates in tissues and organs.
What the gene does
The HAMP gene provides the blueprint for hepcidin, a peptide hormone predominantly synthesised in the liver. Hepcidin acts as the body's master regulator of iron levels. When the body's iron stores are high, liver cells increase hepcidin production.
Once synthesised, hepcidin circulates in the bloodstream and primarily interacts with proteins in the small intestine, liver, and certain white blood cells. Its main mechanism of action involves binding to ferroportin, an iron exporter protein found on the surface of these cells. This binding leads to the internalisation and degradation of ferroportin, thereby reducing iron release into the bloodstream from cells and diminishing iron absorption from the diet.
Through this process, hepcidin ensures that the body absorbs iron in accordance with its needs, preventing the accumulation of excess iron or the development of iron deficiency. This intricate regulatory pathway underscores hepcidin's critical role in systemic iron metabolism.
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Chromosome location
The HAMP gene is situated on chromosome 19, specifically at position 19q13.12. This location refers to the long arm (q) of chromosome 19, in region 1, band 3, sub-band 1, sub-band 2.
Protein structure
The HAMP gene encodes a protein composed of 84 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the HAMP gene can affect the production or function of the hepcidin protein, leading to disruptions in iron regulation. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. The impact of such variants depends on their specific nature and location within the gene, potentially altering hepcidin's ability to control iron absorption and distribution.
Sample of pathogenic variants
5 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.-25G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary hemochromatosis |
c.148_150+1del | - | Pathogenic | - | Hemochromatosis, juvenile, digenic |
c.166C>T | p.Arg56Ter | Pathogenic | - | Hemochromatosis type 2B |
c.176G>C | p.Arg59Pro | Pathogenic | - | Hemochromatosis type 2B |
c.95del | p.Gly32fs | Pathogenic | - | Hemochromatosis type 2B |
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 HAMP gene are associated with inherited conditions primarily affecting iron metabolism. Notably, at least 14 identified variants in this gene can lead to type 2 hereditary haemochromatosis. This is a form of hereditary haemochromatosis characterised by excessive iron absorption and accumulation in various organs, typically manifesting in childhood or adolescence. The resulting iron overload can cause damage to tissues and organs if not managed.
UK clinical status
The HAMP gene is included in several NHS England Genomic Medicine Service national genomic test directories. It is listed as a 'green' gene on panels for Diabetes with additional phenotypes suggestive of a monogenic aetiology, Dilated Cardiomyopathy and conduction defects, Hypogonadotropic hypogonadism, Iron metabolism disorders (specifically excluding common HFE mutations), Likely inborn error of metabolism, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the HAMP gene?
The HAMP gene provides instructions for making hepcidin, a protein primarily produced in the liver that is essential for maintaining the body's iron balance by regulating its absorption and distribution.
How does the HAMP gene relate to hereditary haemochromatosis?
Variants in the HAMP gene can lead to type 2 hereditary haemochromatosis, a condition where the body absorbs too much iron, leading to its accumulation in organs and tissues.
Where is the HAMP gene located?
The HAMP gene is found on chromosome 19, at the specific location 19q13.12.
References
- Gerhard GS, Paynton BV, DiStefano JK. Identification of Genes for Hereditary Hemochromatosis. Methods in molecular biology (Clifton, N.J.). 2018. PMID: 29423808
- Reichert CO, da Cunha J, Levy D. Hepcidin: Homeostasis and Diseases Related to Iron Metabolism. Acta haematologica. 2017. PMID: 28514781
- Rishi G, Wallace DF, Subramaniam VN. Hepcidin: regulation of the master iron regulator. Bioscience reports. 2015. PMID: 26182354
- Leong WI, Lönnerdal B. Hepcidin, the recently identified peptide that appears to regulate iron absorption. The Journal of nutrition. 2004. PMID: 14704284
- McGregor J, McKie AT, Simpson RJ. Of mice and men: genetic determinants of iron status. The Proceedings of the Nutrition Society. 2004. PMID: 15070436
- Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. The New England journal of medicine. 2004. PMID: 15175440
- Roetto A, Papanikolaou G, Politou M. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nature genetics. 2003. PMID: 12469120
- Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annual review of physiology. 2002. PMID: 11826284
- Hunter HN, Fulton DB, Ganz T. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. The Journal of biological chemistry. 2002. PMID: 12138110
- Anderson GJ, Frazer DM, Wilkins SJ. Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochemical Society transactions. 2002. PMID: 12196177
- Fleming RE, Sly WS. Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proceedings of the National Academy of Sciences of the United States of America. 2001. PMID: 11459944