Hemochromatosis: Recent advances in molecular genetics

Hemochromatosis is an autosomal recessive disease of iron metabolism, chara cterized by progressive iron lending in parenchymal cells of the major orga ns of the body. This iron overload may result in cirrhosis, diabetes, cardi ac failure and arrythmia, hypogonadism, arthritis, hepatocellular carcinoma , and reduced life expectancy. These major complications, which usually dev elop after the third or fourth decade of Life, are often fatal. However, pr evention by phlebotomy leads to normal life expectancy if iron excess is de tected at a very early stage. Hemochromatosis gene (HFE) has been localized 4.5 Mb telomeric to the HLA-A locus. This gene encodes a 343 AA protein ho mologous to major histocompatibility class I molecules. Two missense mutati ons, C282Y and H63D, have been identified in patients. In view of its high frequency in normal subjects (15% - 20%), the involvement of the H63D mutat ion in the pathogenesis of the disease remains controversial and is general ly considered as a minor mutation. The C282Y is tightly linked to the disea se, as it accounts for 80 to 100% of GH chromosomes in Northern Europe. As the C282Y mutation is observed with lower frequency in Southern Italy and S outhern France, the existence of other mutations or other genetic factors c ould be evoked. Gene HFE encodes a protein bearing homology to major histoc ompatibility class I molecules. In cellular models, this protein is express ed at the cell membrane in association with beta 2 microglobulin. Mutation C282Y, as it substitutes a conserved cysteine for a tyrosine, disrupts the association with beta 2m and thus impairs the transfer to the cell surface. Recently HFE has been shown to interact with the transferrin receptor and to decrease the affinity of its Ligand. Even if the biologic role of HFE in iron metabolism is unclear, diagnosis and genetic counseling of hemochroma tosis were enhanced by the availability of a convenient genotypic test. J. Trace Elem. Exp. Med. 12:361-365, 1999. (C) 1999 Wiley-Liss, Inc.