Hereditary hemochromatosis - new aspects after discovery of the HFE-gene

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, resulting in an increased iron deposition and multiorgan failur e. Recently a candidate gene of HH, termed HFE, has been identified on chro mosome 6, coding for a protein homologous to major histocompatibility compl ex (MHC) class I molecules. Two mutations of the hemochromatosis gene leadi ng to an exchange of cysteine to tyrosine at aminoacid 282 and histidine to asparagine at aminoacid 63, are retained responsible far the development o f hereditary hemochromatosis. The Cys282Tyr-mutation disrupts a disulfid bo nd and thus abrogates binding of the mutant HFE-protein to beta 2-microglob ulin and its presentation on the cell surface. The His63Asp-mutation seems to play a role in pH-regulated dissociation of the transferrin in recptor/t ransferrin complex in the lysosome. Mutations of tile HFE-protein alter the affinity of the transferrin receptor for its ligand transferrin and may th us cause an intracellular accumulation of iron. Knowledge of the responsibl e gene allows a molecular diagnosis of HH. The new genetic marker can be us ed for screening and confirmation of HH reducing tile need for confirmatory liver biopsies. Compared to standard screening parameters like ferritin an d transferrin saturation genetic testing will allow the diagnosis of IIII i n an early, asymptomatic state before iron accumulation has occurred. rls a normal life expectancy of patients with HH can be achieved if iron reducti on is initiated early, genetic testing may thus be of great benefit for pat ients with HH.