The gene responsible for hemochromatosis, HFE, was discovered in 1996 and resides in chromosome 6 which involves the mutation of a cysteine to tyrosine at position 282 (C282Y). Iron is kept in a soluble state in the blood because it binds to the protein transferrin. Cellular iron uptake takes place at transferrin receptors. Figure 1 shows the transferrin shuttle pathway. Normally iron is separated from transferrin in the endosome and is shuttled into the interior of the cell.
The genetic mutation C282Y produces a mutant HFE protein that is not associated with the transferrin receptor and does not act as a brake on iron uptake into cells. The exact reason why iron absorption in the intestine is markedly increased has not been clarified and requires further investigation and research.