Hereditary hemochromatosis - HAMP, HFE, HFE2, SLC40A1 and TFR2 genes

Hereditary hemochromatosis (HH) is a disease that affects iron metabolism, causing excessive and incorrect accumulation of this metal in the organs and systems of the body, particularly in the skin, heart, liver, pancreas and joints. Because humans cannot increase iron excretion, excess iron can overload and eventually damage tissues and organs. That’s why hemochromatosis is considered an alteration due to iron overload.

The first symptoms of hemochromatosis are nonspecific and may include tiredness, arthralgia, abdominal pain and loss of libido. Later signs and symptoms may include arthritis, liver disease, diabetes, heart abnormalities and skin discoloration. The onset and progression of symptoms may be affected by environmental and lifestyle factors, such as the amount of iron in the diet, alcohol consumption and infections.

Hereditary hemochromatosis is classified into several types, depending on the age of onset and other factors such as its genetic cause and inheritance pattern. Type 1 (or classic) hemochromatosis, the most common form of the disease, and type 4 (also called ferroportin disease) are adult disorders. Men affected by either of these two types usually show symptoms between 40 and 60 years, while in women they usually occur after menopause. Type 2 hemochromatosis is a juvenile onset disease, in which iron accumulation occurs early in life and symptoms may begin to appear in childhood. At 20 years the decrease or absence in the secretion of sex hormones becomes evident. Women usually start menstruation in a normal way, but menstruations stop after a few years. On the other hand, men may have pubertal delay or lack of sex hormones. If hemochromatosis is not treated, heart disease manifests around 30 years. Finally, the age of onset of type 3 hemochromatosis is generally intermediate between types 1 and 2, and symptoms begin before age 30.

This process is due to changes in the HAMP, HFE, HFE2, SLC40A1 and TFR2 genes. These genes participate importantly in the regulation of iron absorption, transport and storage. Mutations in any of these genes alter the regulation of iron absorption during digestion and its distribution to other parts of the body. As a consequence, iron accumulates in tissues and organs, which can alter their normal functions.

The HAMP (hepcidin antimicrobial peptide) gene, located on the long arm of chromosome 19 (19q13.1), encodes the hepcidin protein. Hepcidin was originally identified as having antimicrobial properties, and has been found to carry out an important role in maintaining the balance of iron in the body. It is likely that hepcidin circulates in the blood and inhibits the absorption of iron by the small intestine when the iron supply is too high. It is believed that the coding of hepcidin in the liver increases when iron enters the blood liver cells. Hepcidin is released into the bloodstream and circulates throughout the body. This protein interacts primarily with other proteins in the intestines, liver and certain leukocytes to adjust the absorption and storage of iron. In this way, the amounts of iron are monitored and iron absorption is adjusted to reflect the body's needs. At least 14 mutations in the HAMP gene have been identified that give rise to hereditary juvenile or type 2 hemochromatosis. People with mutations in this gene are unable to encode normal hepcidin and cannot inhibit iron absorption, even when the body has a sufficient supply of iron. The organs of affected people are overloaded with iron, especially the liver and heart.

The HFE (hemochromatosis) gene, located on the short arm of chromosome 6 (6p21.3), encodes a protein that is found on the cell surface, mainly in the intestinal and liver cells. HFE protein is also found in some cells of the immune system. This protein interacts with other proteins on the cell surface to detect the amount of iron in the body. The HFE protein also regulates the coding of the hepcidin protein, which is considered the "key" hormone that regulates iron. When the proteins involved in iron detection and absorption are functioning properly, iron absorption is tightly regulated. On average, the body absorbs approximately 10% 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. More than 100 mutations in the HFE gene that give rise to type 1 hereditary hemochromatosis have been identified. Two particular mutations are responsible for most cases of the disease. A mutation replaces the amino acid cysteine ​​with the amino acid tyrosine at position 282 in the protein (Cys282Tyr or C282Y). The other mutation replaces the amino acid histidine with the amino acid aspartate at position 63 (His63Asp or H63D). The Cys282Tyr mutation prevents the altered HFE protein from reaching the cell surface, so it cannot interact with the transferrin and hepcidin receptors. As a consequence, iron regulation is disturbed and excess iron is absorbed from the diet.

The HFE2 (hemochromatosis type 2) gene, located on the long arm of chromosome 1 (1q21.1), encodes the hemojuvelin protein (HJV). This protein is encoded in the liver, heart and skeletal muscles, and also participates in maintaining the balance of iron in the body. Although its exact function is unknown, it seems to regulate the concentration of hepcidin protein. More than 30 HFE2 genetic mutations have been identified that give rise to type 2 of hereditary hemochromatosis. Most mutations of the HFE2 gene change amino acids that are used to encode hemojuvelin. Most often, the amino acid glycine is replaced by the amino acid valine at position 320 of the protein (Gly320Val). Other mutations create an early stop signal in hemojuvelin coding, which results in an abnormally small protein that cannot function properly. As a consequence, hepcidin concentrations are reduced and iron balance is disturbed, which causes excess iron absorption during digestion.

The SLC40A1 (solute carrier family 40 member 1) gene, located on the long arm of chromosome 2 (2q32.2), encodes the ferroportin protein, involved in the process of iron absorption in the body. Dietary iron is absorbed through the walls of the small intestine, and ferroportin transports iron from the small intestine to the bloodstream, to be transported to the tissues and organs of the body. Ferroportin also transports iron from reticuloendothelial cells in the liver, spleen and bone marrow. The amount of iron that is absorbed by the body depends on the amount of iron stored and released by intestinal and reticuloendothelial cells. The amount of ferroportin available for transport of iron outside the cells is controlled by the hepcidin iron regulatory protein. Hepcidin binds to ferroportin and causes it to break down when the body's iron amounts are adequate. When the body lacks iron, hepcidin levels decrease so that more ferroportin is available. Approximately 37 mutations in the SLC40A1 gene have been identified that give rise to type 4 hereditary hemochromatosis or ferroportin disease. Almost all of these mutations change an amino acid in ferroportin, and consequently abnormal versions of ferroportin are encoded that do not allow normal iron transport and release from intestinal or reticuloendothelial cells, thereby altering the regulation of iron concentrations in the body.

The TFR2 (transferrin receptor 2) gene, located on the long arm of chromosome 7 (7q22), encodes a transferrin receptor 2, which helps iron get into hepatocytes. Iron binds to the transferrin protein in the blood for transport and entry to liver cells and other tissues. Transferrin binds to the transferrin receptor 2 on the cell surface, allowing iron to enter the cell. In addition, this receptor regulates iron storage concentrations in the body by controlling the amount of hepcidin protein (which, as mentioned, is a protein that determines the amounts of iron that are absorbed from the diet and released from the storage sites en the body in response to iron concentrations). At least 50 different mutations in the TFR2 gene responsible for type 3 hemochromatosis have been identified. Some mutations in the TFR2 gene inhibit the transferrin receptor 2, while others give rise to proteins that have an incorrect amino acid sequence or to proteins that are too short to function properly. These mutations negatively affect the ability to regulate the importation of iron into certain cells. In addition, mutations in the TFR2 gene contribute to low concentrations of hepcidin in the body, which allows excess iron to be absorbed from the diet. When this occurs, excess iron is stored in body tissues, especially in the liver. Iron overload leads to organ damage and other signs and symptoms of type 3 disease.

Hereditary hemochromatosis types 1, 2 or 3 are inherited with an autosomal recessive pattern, that is both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. On the other hand, type 4 hemochromatosis is distinguished by its autosomal dominant inheritance pattern, in which a copy of the altered gene in each cell is sufficient to express the disease. In most cases an affected person has a parent with the alteration.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with hereditary hemochromatosis, by means of the complete PCR amplification of the exons of the HAMP, HFE, HFE2, SLC40A1 and TFR2 genes, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).