HFE

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. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). 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. 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.

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. 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. The His63Asp 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. This increase in the absorption of dietary iron leads to the iron overload characteristic of type 1 hemochromatosis.

The Cys282Tyr mutation, which is a common cause of type 1 hereditary hemochromatosis (described above), may also 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 of X-linked sideroblastic anemia by further increasing the absorption of dietary iron, leading to an even greater iron overload.