HFE

The HFE gene provides instructions for producing a protein that is located mainly on the surface of intestinal cells, liver cells, and some cells in the immune system. During digestion, this protein helps certain cells regulate the absorption of iron into the small intestine by interacting with other proteins located on the cell surface. The body uses this mechanism to help monitor its supply of iron. When the proteins involved in iron sensing and absorption are functioning properly, the body absorbs only about 10 percent of the iron ingested in the diet.

Research suggests that the HFE protein also helps control levels of another important iron regulatory protein, hepcidin. Adequate levels of hepcidin are necessary to ensure that the body does not absorb and store too much iron in its tissues and organs.

hemochromatosis - caused by mutations in the HFE gene

Researchers have identified more than 20 mutations in the HFE gene that cause type 1 hemochromatosis. These mutations alter the size of the HFE protein or disrupt its 3-dimensional shape. As a result, the HFE protein cannot function properly. Two particular mutations are responsible for most cases of type 1 hemochromatosis. Each of these mutations changes one of the building blocks (amino acids) used to make the HFE protein. The most common mutation replaces the amino acid cysteine with the amino acid tyrosine at position 282 in the protein's chain of amino acids (written as C282Y or Cys282Tyr). The other mutation replaces the amino acid histidine with the amino acid aspartic acid at position 63 (written as H63D or His63Asp). As a result of these substitutions, the altered protein is not sent to the cell surface and does not interact with a cell surface receptor called the transferrin receptor. The transferrin receptor plays a critical role in regulating the amount of iron that enters the cell. When the HFE protein does not bind to the transferrin receptor, too much iron enters the body through the cells of the small intestine. This increased absorption of iron leads to the iron overload characteristic of this disorder.

porphyria - increased risk from variations of the HFE gene

Mutations in the HFE gene that cause hemochromatosis are also believed to increase the risk of developing a form of porphyria called porphyria cutanea tarda. These mutations have been found more frequently in people with this condition than in unaffected people. Researchers are not certain how mutations in the HFE gene are related to the signs and symptoms of porphyria cutanea tarda. These mutations likely trigger this condition by increasing iron levels in the liver, as in hemochromatosis.

X-linked sideroblastic anemia - course of condition modified by mutations in the HFE gene

One particular mutation in the HFE gene may increase the severity of symptoms in X-linked sideroblastic anemia when it is present in patients who also have mutations in the ALAS2 gene. The mutation results in a substitution of the amino acid tyrosine for the amino acid cysteine at position 282 (written as C282Y or Cys282Tyr) in the HFE protein. Although it is not known exactly how the mutation affects symptoms, it may cause iron to build up more rapidly in the body's tissues.