Meyahealth
HomeGeneticsGeneHFE gene
Back to Gene
HFE gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

HFE gene

The HFE gene provides instructions for producing a protein that regulates iron levels in the body, and mutations in this gene are associated with conditions like hereditary hemochromatosis and porphyria.

Normal Function

The HFE gene provides instructions for producing a protein that is located on the surface of cells, primarily liver and intestinal cells. The HFE protein is also found on some immune system cells.

The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. When the HFE protein is attached (bound) to a protein called transferrin receptor 1, the receptor cannot bind to a protein called transferrin. When transferrin receptor 1 is bound to transferrin, iron enters liver cells. So, it is likely that the HFE protein regulates iron levels in liver cells by preventing transferrin from binding to transferrin receptor 1.

The HFE protein regulates the production of a protein called hepcidin. Hepcidin is produced by the liver, and it determines how much iron is absorbed from the diet and released from storage sites in the body. When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. The formation of this protein complex triggers the production of hepcidin. So when the HFE protein is bound to transferrin receptor 1, hepcidin production is turned off and when the HFE protein is not bound to transferrin receptor 1, hepcidin production is turned on.

When the proteins involved in iron sensing and absorption are functioning properly, iron absorption is tightly regulated. On average, the body absorbs about 10 percent of the iron obtained from the diet.

Health Conditions Related to Genetic Changes

Porphyria

Mutations in the HFE gene can increase the risk of developing a condition called porphyria. Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is a vital molecule for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. HFE gene mutations are found more frequently in people with the most common form of porphyria, known as porphyria cutanea tarda, than in unaffected people.

Researchers suspect that HFE gene mutations may trigger this type of porphyria by increasing the absorption of iron. A buildup of excess iron, in combination with other genetic and nongenetic factors, interferes with the production of a molecule called heme. A blockage in heme production allows other compounds called porphyrins to build up to toxic levels in the liver and other organs. The abnormal buildup of porphyrins leads to the characteristic features of porphyria cutanea tarda.

Hereditary hemochromatosis

Researchers have identified more than 100 mutations in the HFE gene that cause type 1 hemochromatosis, a form of hereditary hemochromatosis that begins during adulthood. Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron accumulates in, and eventually damages, the body's tissues and organs.

Two particular mutations are responsible for most cases of type 1 hemochromatosis:

  • Cys282Tyr (C282Y): Replaces the amino acid cysteine with tyrosine at position 282. This mutation prevents the altered HFE protein from reaching the cell surface.
  • His63Asp (H63D): Replaces the amino acid histidine with aspartic acid at position 63. This mutation likely alters the three-dimensional shape of the protein.

These mutations prevent the HFE protein from interacting with transferrin receptor 1 and other proteins. As a result, iron regulation is disrupted, and too much iron is absorbed from the diet, leading to the iron overload characteristic of type 1 hemochromatosis.

X-linked sideroblastic anemia

The Cys282Tyr mutation may increase the severity of the iron overload in X-linked sideroblastic anemia when it is inherited along with a mutation in the ALAS2 gene. The combination of HFE and ALAS2 gene mutations leads to more severe signs and symptoms by further increasing the absorption of dietary iron.

Frequently Asked Questions

Early symptoms are often subtle and may include extreme fatigue, joint pain (particularly in the hands and knees), or abdominal discomfort. As iron builds up in organs, more serious signs can develop, such as bronze or gray skin discoloration, diabetes, or an enlarged liver. You should seek immediate medical attention if you experience sudden shortness of breath, chest pain, or signs of heart failure, as excess iron can damage the heart muscle.
standard blood test checks for specific mutations in the HFE gene, most commonly the C282Y and H63D variants. If you have two copies of the C282Y mutation (homozygous), you are at high risk for developing hereditary hemochromatosis, though not everyone with the genetic risk will develop the disease. If you have one copy of C282Y or two copies of H63D, you are a carrier or have a lower risk, and your doctor will likely monitor your iron levels periodically rather than starting treatment immediately.
Generally, if you have hereditary hemochromatosis and are undergoing regular phlebotomy, you may be eligible to donate blood, but this depends on your specific iron levels and the policies of the blood bank. However, if your hemoglobin levels are low due to frequent blood draws or other health issues, you will be deferred from donating. It is important to inform the blood donation staff about your condition and provide recent lab results to ensure it is safe for you to donate.
Dietary changes alone are rarely sufficient to manage established hereditary hemochromatosis, especially if iron levels are already elevated. While limiting red meat and avoiding alcohol can help prevent further rapid iron accumulation, the body absorbs iron from all sources, including vegetables. The primary treatment is usually therapeutic phlebotomy (blood removal) to safely reduce iron stores. Always consult your healthcare provider before making significant dietary changes or starting supplements, as vitamin C, for example, can increase iron absorption.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

Meyahealth

Ⓒ 2026. All rights reserved by MEYA

About UsTerms & PolicyFAQ