| 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 gene belongs to a family of genes called immunoglobulin superfamily, C1-set domain containing (immunoglobulin superfamily, C1-set domain containing). The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. The HFE protein regulates the production of another protein called hepcidin, which is considered the "master" iron regulatory hormone. 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 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. The HFE protein also interacts with two proteins called transferrin receptors; however, the role of these interactions in iron regulation is unclear. Researchers have identified more than 20 mutations in the HFE gene that cause a form of hereditary hemochromatosis called type 1. Two particular mutations are responsible for most cases of this disorder. Each of these mutations changes one of the protein building blocks (amino acids) in the HFE protein. One mutation replaces the amino acid cysteine with the amino acid tyrosine at position 282 in the protein's chain of amino acids (written as Cys282Tyr or C282Y). The other mutation replaces the amino acid histidine with the amino acid aspartic acid at position 63 (written as His63Asp or H63D). The Cys282Tyr mutation prevents the altered HFE protein from reaching the cell surface, so it cannot interact with hepcidin and transferrin receptors. As a result, iron regulation is disrupted, and too much iron is absorbed from the diet. This increase in the absorption of dietary iron leads to the iron overload characteristic of type 1 hemochromatosis.|
Mutations in the HFE gene that cause hereditary hemochromatosis also increase the risk of developing the most common form of porphyria, porphyria cutanea tarda. These mutations are found more frequently in people with 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. Heme is a component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). A blockage in heme production allows other compounds called porphyrins to build up to toxic levels in the liver and other organs. These compounds are formed during the normal process of heme production, but excess iron and other factors allow them to accumulate to toxic levels. The abnormal buildup of porphyrins leads to the characteristic features of porphyria cutanea tarda.
The Cys282Tyr mutation, which is a common cause of hereditary hemochromatosis, may also increase the severity of the iron overload in X-linked sideroblastic anemia when it is inherited with a mutation in the ALAS2 gene. The combination of HFE and ALAS2 mutations leads to more severe signs and symptoms of X-linked sideroblastic anemia by further increasing the absorption of dietary iron, leading to an even greater iron overload.