Haemochromatosis is an autosomal recessive disorder of iron metabolism that affects approximately 0.2-0.5% of the Caucasian population, with a higher-than-average incidence in the Irish population. The disease is characterized by the excessive accumulation of iron in the body and caused by an increased absorption of dietary iron at the intestinal mucosa level.
The HFE gene is responsible for the disease and was identified in 1996 (Feder JN et al., 1996); it is localized on the short arm of chromosome 6, near the locus of the HLA-A gene. A mutation of this gene causes the synthesis of an abnormal protein unable to interact with the transferrin receptors, favoring the transport of iron through the intestinal mucosa. However, the exact mechanism with which the mutated HFE protein contributes to the increased intestinal absorption is not completely clear.
The two most frequent mutations found in the HFE gene correspond to the C282Y mutation (substitution of a cysteine with a tyrosine in position 282 of the protein) and the H63D mutation (substitution of the histidine with an aspartic acid in position 63 of the protein).
Homozygosity for C282Y accounts for 90% of haemochromatosis. The clinical penetrance (i.e., the risk of developing iron overload disease) in C282Y homozygous patients has been reported as being between 60 and 90% but the risk is not well defined.
Patients heterozygous for either the C282Y or H63D mutation have no significant risk of developing hemochromatosis but are carriers and as such should receive genetic counselling.
Compound heterozygotes (one copy of each of the C282Y and H63D mutations) have a very low risk of developing iron overload (0.5 to 1%).
Homozygous H63D patients also have a very low risk of developing iron overload (less than 0.2%).
