Hereditary hemochromatosis (Hereditary hemochromatosis) - Genes HAMP, HFE, HFE2, SLC40A1 and TFR2.  

Hereditary hemochromatosis is a disease that affects iron metabolism, resulting in excessive and improper accumulation of this metal in the organs and body systems, particularly in the skin, heart, liver, pancreas and joints. Since humans can not increase iron excretion, excess iron overload and can eventually damage the tissues and organs. For this reason, hemochromatosis is considered impaired iron overload.

Early symptoms of hemochromatosis are nonspecific and may include fatigue, arthralgia, abdominal pain and loss of libido. Signs and symptoms may include arthritis later, liver disease, diabetes, cardiac 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 infection factors.

Hereditary hemochromatosis is classified into various types depending on the age of onset and other factors such as genetic cause and inheritance pattern. Type 1 hemochromatosis, the most common form of the disease, and type 4 (also called ferroportin disease) are disorders of adult. Men with hemochromatosis type 1 or type 4 typically develop symptoms between 40 and 60 years of age, while women generally develop symptoms after menopause. Type 2 hemochromatosis is a disease of juvenile onset. Iron accumulation occurs early in life and symptoms may begin to appear in childhood. At 20, it is evident decreased or absent secretion of sex hormones. Women often start menstruating in a normal way, but menses stop after a few years. Males may have delayed puberty or sex hormone deficiency. If untreated hemochromatosis, heart disease manifests around 30 years. In general, the age of onset of type 3 hemochromatosis is intermediate between types 1 and 2. Type 3 symptoms of hemochromatosis usually begin before age 30.

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

HAMP (hepcidin antimicrobial peptide) gene, located on the long arm of chromosome 19 (19q13.1), encodes hepcidin protein. Hepcidin was originally identified as having antimicrobial properties. It has been discovered that hepcidin plays an important role in maintaining the balance of iron in the body. It is likely that hepcidin in the blood flow and inhibits the absorption of iron by the small intestine when the supply of iron is too high. It is believed that encoding hepcidin in liver iron increases when blood enters liver cells. Hepcidin is released into the bloodstream and circulates throughout the body. This protein interacts with other proteins primarily in the intestines, liver and certain leukocytes to adjust the absorption and storage of iron. Thus, the amounts of iron are monitored and iron absorption is adjusted to reflect the body 's needs. Have identified at least eight mutations in the HAMP gene that result in juvenile hereditary hemochromatosis or hereditary hemochromatosis type 2. People with mutations in this gene are incapable of encoding the normal hepcidin and can not inhibit the absorption of iron, even when the organism It has a sufficient supply of iron. The bodies of those affected are overloaded with iron, especially the liver and heart.

HFE gene (hemochromatosis), located on the short arm of chromosome 6 (6p21.3), encodes a protein found on the surface of cells, primarily in the intestinal and liver cells. The HFE protein is also found in certain 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 regulates hepcidin protein coding, which is considered the hormone "key" regulatory iron. When the proteins involved in the detection and iron absorption are functioning properly, iron absorption is tightly regulated. On average, the body absorbs about 10% iron obtained from the diet. The HFE protein also interacts with two proteins called transferrin receptors; however, the role of these interactions in regulating iron is unclear. There are more than 20 mutations in the HFE gene leading to hereditary hemochromatosis type 1. Two particular mutations are responsible for most cases of the disease. A mutation replaces the amino acid cysteine by amino acid tyrosine at position 282 in the protein (Cys282Tyr or C282Y). The other mutation replaces the amino acid histidine by the amino acid aspartic acid at position 63 (His63Asp or H63D). Cys282Tyr HFE mutation prevents the altered protein reach the cell surface, so can not interact with transferrin receptors and hepcidin. Consequently, iron regulation is altered and excess dietary iron is absorbed.

The HFE2 gene (hemochromatosis type 2), located on the long arm of chromosome 1 (1q21.1), encoding the protein hemojuvelin. This protein is encoded in the liver, heart and skeletal muscles. Hemojuvelin plays a role in maintaining the balance of iron in the body. Although its exact function is unclear, it appears to regulate the levels of hepcidin protein. There are more than 20 genetic mutations that lead to HFE2 type 2 hereditary hemochromatosis. Most gene mutations HFE2 change amino acids used for coding hemojuvelin. Most often, the amino acid glycine is replaced by the amino acid valine at position 320 of the protein (Gly320Val). Other mutations create a premature stop signal coding Hemojuvelin leading to abnormally small protein can not function properly. As a result, concentrations of hepcidin are reduced and iron balance is disturbed, resulting in excess iron absorption during digestion.

The SLC40A1 gene (solute carrier family 40 member 1), located on the long arm of chromosome 2 (2q32), encoding ferroportin protein, involved in the process of absorption of iron in the body. The dietary iron is absorbed through the walls of the small intestine. Then ferroportin transports iron from the small intestine into the bloodstream to be transported by blood to the tissues and organs of the body. Ferroportin also transports iron reticuloendothelial cells, found in liver, spleen and bone marrow. The amount of iron absorbed by the body depends on the amount of iron stored and released by intestinal and reticuloendothelial cells. The amount of ferroportin available to transport iron out of cells is controlled by the iron regulatory protein, hepcidin. Hepcidin binds ferroportin and makes decomposes when the amounts of iron in the body are suitable. When the body lacks iron, hepcidin levels decrease so that more ferroportin available. They have identified approximately 15 mutations in the SLC40A1 gene giving rise to type 4 hereditary hemochromatosis, also called ferroportin disease. Almost all of these mutations change an amino acid in ferroportin. As a result, abnormal versions of ferroportin not allow normal transport and release of iron from the intestinal or reticuloendothelial cells are encoded. As a result, the regulation of the concentrations of iron in the body is altered.

The TFR2 (transferrin receptor 2) gene, located on the long arm of chromosome 7 (7q22), encoding a transferrin receptor 2. This receiver helps the iron into hepatocytes. In the blood, iron binds to transferrin protein for transportation and delivery to the liver and other tissues. On the cell surface, transferrin binds to transferrin receptor 2, which allows the iron to enter the cell. In addition, this receptor regulates the concentrations of iron storage in the body by controlling the concentrations of hepcidin protein. Hepcidin is a protein that determines the amounts of iron absorbed from the diet and are released from storage sites in the body in response to concentrations of iron. They have identified at least nine different mutations in the gene responsible TFR2 type 3 hemochromatosis. Some mutations in the TFR2 gene encoding inhibit transferrin receptor 2. Other mutations result in proteins having an incorrect amino acid sequence or proteins that are too short to work properly. These mutations adversely affect the ability to regulate the importation of iron in certain cells. In addition, mutations in the gene TFR2 contribute to low levels of hepcidin in the body, allowing excess dietary iron is absorbed. When this occurs, the excess iron is stored in body tissues, especially the liver. Iron overload leads to organ damage and other signs and symptoms of type 3 disease.

Hereditary hemochromatosis types 1, 2 and 3 is inherited as an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Meanwhile, type 4 hemochromatosis has an autosomal dominant inheritance. With this type of inheritance, 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 disorder.

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

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).