The HFE gene encodes a membrane protein with similarity to MHC class I-type proteins. Functionally, the HFE protein binds to the transferrin receptor (TFR) and reduces its affinity for iron-loaded transferring. Therefore, HFE regulates iron absorption. The subcellular localization of HFE is in the crypts of the small intestine in close proximity to the sites of iron absorption. Functionally deficient HFE results in disturbed cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen, as in the case of autosomal recessive disorder of hereditary hemochromatosis.