Genetics of hemochromatosis

Hereditary hemochromatosis (HHC) is a common autosomal recessive disorder o f iron metabolism that results in progressive iron overload and can be fata l if untreated. The hemochromatosis gene (HFE) was identified by positional cloning in 1996. Two missense mutations have been described in HFE. The ma jority of HHC patients are homozygous for a cysteine-to-tyrosine substituti on (C282Y); however, a small number are homozygous for a histidine-to-aspar tic-acid substitution (H63D) or are heterozygous for both of these mutation s. Mechanisms by which C282Y and H63D may disrupt the normal functioning of HFE have been suggested, but the role of HFE in the process of normal iron metabolism has yet to be clearly defined.