Haemochromatosis: an inherited metal and toxicity syndrome

A newly-identified major histocompatibility Class I-like gene, HFE (originally HLA-H) located similar to 3.5 Mb telomeric to the Class I cluster on chromosome 6p 21.3 harbours mutations in haemochromatosis. Two of these, Cys(282)Tyr (C282Y) and His(63)Asp (H63D, a minor determinant) have diagnostic utility as similar to 90% of adults are homozygous or compound heterozygotes for these alleles. The pathophysiological role of HFE is unclear: it is expressed as a surface molecule on many cells and the C282Y mutation disrupts interactions with beta(2)-microglobulin, thus preventing surface expression. Lately, there has been experimental evidence that HFE protein interacts with the transferrin-receptor, affecting receptor turnover or its affinity for ligand.