Researchers have identified more than 20 mutations in the HFE gene that cause a form of hereditary hemochromatosis called type 1. Two particular mutations are responsible for most cases of this disorder. 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, so it cannot interact with hepcidin and transferrin receptors. 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.