A hemochromatosis gene, HFE, was identified in 1996. Mutations in the HFE gene are found in the majority of patients diagnosed with HH. The locus for the gene is on the short arm of chromosome 6 where it codes for a membrane protein, HFE.
The exact mechanism of the role of HFE protein in iron metabolism is not entirely understood. It is thought that HFE, along with a second protein, beta-2 microglobulin, interacts with transferrin receptors (TfR) on cell membranes. This interaction suppresses the affinity of transferrin for TfR, thus lowering the uptake of transferrin and its attached iron into the cell. Transferrin receptors have been found on the surface of various cells, with the greatest concentration on cell membranes of intestinal cells, hepatocytes, and RBC precursors.
In addition to HFE, HH is also associated with mutations in other genes involved in iron homeostasis, including hemojuvelin (HJV), TfR, hepcidin, and ferroportin. Some mutations are linked with dominantly inherited HH, juvenile HH, and African iron overload. Unlike HH due to HFE mutations, these clinical disorders are rarely observed in the US population.12