Haemochromatosis: an inherited metal and toxicity syndrome

Abstract

A newly-identified major histocompatibility Class I-like gene, HFE (originally HLA-H) located approximately 3.5 Mb telomeric to the Class I cluster on chromosome 6p 21.3 harbours mutations in haemochromatosis. Two of these, Cys282Tyr (C282Y) and His63Asp (H63D, a minor determinant) have diagnostic utility as approximately 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.