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HFE
homeostatic iron regulator
The HFE gene provides instructions for a protein critical in regulating iron absorption and distribution within the body, primarily affecting cellular iron sensing and hepcidin production. The HFE gene encodes a protein that plays a key role in maintaining iron homeostasis by interacting with other proteins on cell surfaces, particularly in liver and intestinal cells.
HFE is located on the short (p) arm of chromosome 6, at band 6p22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The HFE gene, or homeostatic iron regulator, is central to the body's management of iron levels. It provides the genetic blueprint for a protein predominantly located on the surface of liver and intestinal cells, although it is also present on some immune system cells. This protein acts as a crucial sensor, helping the body detect and respond to the amount of iron present. When functioning correctly, the HFE protein ensures that iron absorption from the diet is tightly controlled, preventing both deficiency and overload.
Dysfunction of the HFE protein, often due to specific genetic variants, can disrupt this delicate balance. One of the most well-known consequences of HFE gene variants is hereditary haemochromatosis, a condition characterised by excessive iron absorption and subsequent iron accumulation in various organs. This accumulation can lead to significant organ damage if left untreated. Research into the HFE gene continues to enhance our understanding of iron metabolism and its associated disorders.
What the gene does
The HFE gene produces a protein vital for iron homeostasis, the process by which the body maintains appropriate iron levels. This HFE protein is found on cell surfaces, particularly in liver and intestinal cells, where it plays a regulatory role in iron absorption. It achieves this by interacting with other proteins involved in iron sensing and transport.
One key interaction involves transferrin receptor 1. When the HFE protein binds to transferrin receptor 1, it reduces the ability of transferrin - an iron-carrying protein - to bind to the receptor. Transferrin binding to its receptor is a crucial step for iron entry into liver cells. Therefore, the HFE protein likely regulates iron levels in liver cells by limiting this interaction. This mechanism helps to control the amount of iron entering the liver, a primary site for iron storage and metabolism.
Furthermore, the HFE protein influences the production of hepcidin, a hormone produced by the liver that serves as the master regulator of iron. Hepcidin controls how much iron is absorbed from the diet and released from the body's storage sites. When the HFE protein is not bound to transferrin receptor 1, it associates with a different group of proteins, including hepcidin. This interaction triggers hepcidin production. Conversely, when HFE is bound to transferrin receptor 1, hepcidin production is typically suppressed. This intricate interplay ensures that hepcidin levels are adjusted according to the body's iron needs, thereby modulating dietary iron absorption and release from stores.
Under normal circumstances, this regulatory system ensures that approximately 10% of dietary iron is absorbed, preventing both iron deficiency and harmful iron overload. Variants in the HFE gene can disrupt these interactions, leading to impaired hepcidin regulation and subsequent iron dysregulation.
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Chromosome location
The HFE gene is situated on chromosome 6, specifically at band 6p22.2. This location refers to the short (p) arm of chromosome 6, within region 22, band 2. The human genome comprises 23 pairs of chromosomes, and chromosome 6 is one of the larger autosomes. The HFE gene spans a considerable stretch of DNA at this chromosomal position. The protein encoded by the HFE gene consists of 348 amino acids.
Protein structure
The HFE protein is composed of several distinct regions and domains crucial for its function in iron regulation. These structural elements enable its interactions with other proteins on the cell surface. The protein includes an Alpha-1 region, spanning amino acids 23-114, which contributes to its overall folded structure. Following this is the Alpha-2 region, located between amino acids 115-205. The Alpha-3 region, encompassing amino acids 206-297, is also a significant component. Within the Alpha-3 region, an Ig-like C1-type domain is present, spanning amino acids 207-298. This immunoglobulin-like domain is often involved in protein-protein interactions. Finally, a connecting peptide region is found between amino acids 298-306, linking different parts of the protein.
Key variants
The HFE gene can exhibit a range of genetic variants, some of which are commonly associated with altered iron metabolism. These variants can include single nucleotide changes, insertions, or deletions within the gene's DNA sequence. Such changes can affect the structure and function of the HFE protein, thereby impacting its ability to regulate iron absorption and hepcidin production. While some variants may have minimal or no clinical effect, others are recognised as risk factors for conditions involving iron overload. The specific impact of an HFE variant often depends on its location within the gene and how it alters the resultant protein.
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.1006+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Alzheimer disease type 1 |
c.1022_1034del | p.His341fs | Pathogenic | ★★☆☆ | Hemochromatosis type 1 |
c.211C>T | p.Arg71Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary hemochromatosis |
c.279del | p.Trp94fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary hemochromatosis |
c.546_547del | p.Leu183fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary hemochromatosis |
c.548T>C | p.Leu183Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary hemochromatosis |
c.616+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hemochromatosis type 1 |
c.616+1G>T | - | Pathogenic | ★★☆☆ | Hemochromatosis type 1 |
c.760A>T | p.Lys254Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hemochromatosis type 1 |
c.845G>A | p.Cys282Tyr | Pathogenic/Pathogenic, low penetrance; risk factor | ★★☆☆ | Alzheimer disease type 1 |
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 HFE gene are primarily associated with conditions affecting iron metabolism. The most prominent condition linked to HFE is hereditary haemochromatosis (HFE), an autosomal recessive disorder leading to excessive iron accumulation in the body. Furthermore, some HFE variants may increase the risk or severity of other conditions, such as porphyria cutanea tarda, a disorder affecting haem production. While HFE variants can increase susceptibility, the development and severity of these conditions can also be influenced by other genetic factors and environmental elements.
- Hereditary haemochromatosis (HFE)
- Porphyria cutanea tarda Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic HFE 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
In the UK, the HFE gene is recognised on several NHS Genomic Medicine Service (GMS) pathways, reflecting its clinical significance. It is part of the ACMG SF v3.2 - Secondary Findings list, designating it as a Tier 1 actionable gene for which secondary findings may be reported. HFE is also included in panels for 'Iron metabolism disorders - NOT common HFE mutations', indicating that broader screening beyond the most frequent variants is considered. Additionally, it is listed on panels related to 'Diabetes with additional phenotypes suggestive of a monogenic aetiology', 'Dilated Cardiomyopathy and conduction defects', 'Hypogonadotropic hypogonadism', 'Likely inborn error of metabolism', and 'Undiagnosed metabolic disorders', highlighting its diverse clinical associations within the NHS framework.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with HFE gene variants that predispose to iron overload, certain lifestyle considerations may be beneficial in managing iron levels, although these should always be discussed with a healthcare professional. Research suggests that dietary choices can influence the amount of iron absorbed from food. Reducing the intake of iron-rich foods, particularly red meat and foods fortified with iron, may help to manage iron accumulation. Cooking in iron cookware can also increase the iron content of food, so using alternative cookware materials might be considered.
Alcohol consumption may exacerbate liver damage in individuals with iron overload, particularly those with hereditary haemochromatosis; therefore, moderate or minimal alcohol intake is often advised. Some studies indicate that vitamin C can enhance iron absorption, so it may be prudent to consume vitamin C-rich foods or supplements separately from iron-rich meals. However, individuals should not make significant dietary changes without consulting their doctor or a registered dietitian, as personalised advice is essential. Regular monitoring of iron levels through blood tests is a crucial aspect of managing iron overload conditions.
Supplement considerations
For individuals with HFE gene variants and iron overload, discussions around supplements should always be held with a healthcare professional. There is no conclusive evidence that specific supplements can prevent hereditary haemochromatosis or treat iron overload. Some supplements, particularly those containing iron, should be avoided as they can worsen iron accumulation. This includes many multivitamin preparations that often contain iron.
Similarly, supplements containing high doses of vitamin C might increase dietary iron absorption, which could be counterproductive for those predisposed to iron overload. While some natural compounds are anecdotally suggested to affect iron metabolism, there is insufficient scientific evidence to recommend their use for managing HFE-related conditions. Any decision to start or stop supplements should be made in consultation with a doctor, who can provide tailored advice based on an individual's specific health status and iron levels.
Frequently asked questions
What is the primary function of the HFE gene?
The HFE gene provides instructions for a protein that regulates iron absorption and distribution in the body. It helps sense iron levels and influences the production of hepcidin, a hormone central to iron homeostasis.
What is hereditary haemochromatosis?
Hereditary haemochromatosis is a genetic condition, often linked to HFE gene variants, where the body absorbs too much iron from the diet, leading to excessive iron accumulation in organs like the liver, heart, and pancreas.
Can HFE gene variants affect conditions other than hereditary haemochromatosis?
Yes, some HFE variants may increase the risk or severity of other conditions, such as porphyria cutanea tarda, a disorder involving haem production, and can be relevant in certain metabolic and cardiac conditions.
How is iron absorption normally regulated in the body?
Normally, the HFE protein interacts with other cell surface proteins to regulate iron uptake into liver cells and control hepcidin production. Hepcidin then dictates how much iron is absorbed from the diet and released from stores, typically around 10% of dietary iron.
Are there lifestyle changes that can help manage HFE-related iron overload?
Research suggests that reducing intake of iron-rich foods and alcohol, and possibly consuming vitamin C separately from iron-rich meals, may help. However, all dietary changes should be discussed with a healthcare professional.
Should I take iron supplements if I have HFE gene variants?
No, if you have HFE gene variants, especially those predisposing to iron overload, you should generally avoid iron supplements and discuss all supplement intake with a healthcare provider, as some can worsen iron accumulation.
References
- Pantopoulos K. Inherited Disorders of Iron Overload. Frontiers in nutrition. 2018. PMID: 30420953
- Kaczorowska-Hac B, Luszczyk M, Antosiewicz J. HFE Gene Mutations and Iron Status in 100 Healthy Polish Children. Journal of pediatric hematology/oncology. 2017. PMID: 28406842
- Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene. 2015. PMID: 26456104
- Vujić M. Molecular basis of HFE-hemochromatosis. Frontiers in pharmacology. 2014. PMID: 24653703
- Fleming RE. Iron sensing as a partnership: HFE and transferrin receptor 2. Cell metabolism. 2009. PMID: 19254564
- Ganz T. Iron homeostasis: fitting the puzzle pieces together. Cell metabolism. 2008. PMID: 18396134
- Phillips JD, Bergonia HA, Reilly CA. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proceedings of the National Academy of Sciences of the United States of America. 2007. PMID: 17360334
- Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World journal of gastroenterology. 2007. PMID: 17729389
- Fleming RE, Britton RS. Iron Imports. VI. HFE and regulation of intestinal iron absorption. American journal of physiology. Gastrointestinal and liver physiology. 2006. PMID: 16537971
- Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annual review of nutrition. 2006. PMID: 16848710
- Andrews NC. Molecular control of iron metabolism. Best practice & research. Clinical haematology. 2005. PMID: 15737882
- Zaahl MG, Merryweather-Clarke AT, Kotze MJ. Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload. Human genetics. 2004. PMID: 15338274
- Egger NG, Goeger DE, Payne DA. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Digestive diseases and sciences. 2002. PMID: 11855561