African iron overload Some studies have indicated that a particular variation in the SLC40A1 gene slightly increases the risk of increased iron stores in people of African descent, which may lead to African iron overload. This effect seems to be more pronounced in men, which may be related to gender differences in the processing of iron. The SLC40A1 gene variation associated with increased iron stores replaces the amino acid glutamine with the amino acid histidine at position 248 in the ferroportin protein sequence and is written as Q248H or Gln248His. It is found in 5 to 20 percent of people of African descent but is not generally found in other populations. The Q248H variation may affect the way ferroportin helps to regulate iron levels in the body, resulting in an increased risk of African iron overload. People with the variation may inherit an increased risk of this condition, but not the condition itself. Not all people with this condition have the variation in the gene, and not all people with the variation will develop the disorder. hereditary hemochromatosis Researchers have identified approximately 15 mutations in the SLC40A1 gene that cause a form of hereditary hemochromatosis called ferroportin disease, which is also sometimes referred to as type 4 hemochromatosis. Almost all of these mutations change a single protein building block (amino acid) in ferroportin. Abnormal versions of ferroportin do not permit the normal transport and release of iron from intestinal or reticuloendothelial cells. As a result, the regulation of iron levels in the body is impaired and iron overload results. One mutated copy of this gene in each cell is sufficient to cause ferroportin disease.

     The SLC40A1 gene provides instructions for making a protein called ferroportin. This protein is involved in the process of iron absorption in the body. Iron from the diet is absorbed through the walls of the small intestine. Ferroportin then transports iron from the small intestine into the bloodstream, and the iron is carried by the blood to the tissues and organs of the body. Ferroportin also transports iron out of specialized immune system cells (called reticuloendothelial cells) that are found in the liver, spleen, and bone marrow. The amount of iron absorbed by the body depends on the amount of iron stored and released from intestinal and reticuloendothelial cells. Research suggests that the amount of ferroportin available to transport iron out of cells is controlled by another iron regulatory protein, hepcidin. Hepcidin binds to ferroportin and causes it to be broken down when the body's iron supplies are adequate. When the body is lacking iron, hepcidin levels drop and more ferroportin is available to bring iron into the body and to release it from storage.

The following transcription factors affect gene expression:

• HNF-1A
• HNF-1
• GATA-1
• Lmo2
• E4BP4
• Pax-2

Tissue specificity:

Detected in erythrocytes (at protein level). Expressed in placenta, intestine, muscle and spleen.

Molecular Function:

• Ferrous Iron Transmembrane Transporter Activity
• Iron Channel Activity
• Iron Ion Transmembrane Transporter Activity
• Peptide Hormone Binding
• Receptor Activity

Biological Processes:

• Cellular Iron Ion Homeostasis
• Endothelium Development
• Ferrous Iron Export
• Iron Ion Transmembrane Transport
• Lymphocyte Homeostasis
• Multicellular Organismal Iron Ion Homeostasis
• Negative Regulation Of Apoptotic Process
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Regulation Of Transcription From Rna Polymerase Ii Promoter In Response To Iron
• Spleen Trabecula Formation