A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi–organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage–disequilibrium and full haplotype analysis, we have identified a 250–kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical–by–descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA–H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class Mike proteins in iron metabolism.