Hereditary Hemochromatosis

RDB2045

Determination of the mutation C282Y and the predisposing allel H63D in the hemochromatosis (Hfe) gene

Clinical Relevance

Hereditary hemochromatosis is an autosomal recessively hereditary disorder of intestinal iron absorption. The disease has a prevalence of approx. 0.3-0.5% (1) in Caucasians, and is thus the most frequent hereditary disease in Europe.

The increased iron absorption causes iron to be deposited in various organs. This can, among other things, lead to cirrhosis of the liver, diabetes mellitus, hypogonadism and cardiac failure.

In 1996, Feder et al. were able for the first time to draw a connection between mutations in a hemochromatosis gene (3) and hereditary hemochromatosis. The Hfe gene encodes a protein similar in structure to the MHC class 1 molecules (4). Also, owing to its physical proximity to the HLA genes, it was originally termed as an HLA-H gene. The protein encoded by the Hfe gene interacts with the transferrine receptor and is involved in the regulation of iron absorption (5).

Feder et al. (3) found two point mutations which could repeatedly be found in patients with hereditary hemochromatosis. The replacement of G (guanine) by A (adenine) at position 845 in the Hfe gene causes in the protein a change from cysteine (C) to tyrosine (Y) at the amino acid position 282 (mutation C282Y). A mutation at position 187 leads to the substitution of C (cytosine) by G, and therefore to a change in the protein at position 63 from histidine (H) to asparaginic acid (D) (mutation H63D).

The clear association between the C282Y mutation and hereditary hemochromatosis has been proved in numerous studies. This mutation occurs heterozygously in approx. 5% of the total population (6). Over 90% of all patients with hemochromatosis carry the allele C282Y homozygously (1,6,7).

The association between the mutation H63D and hereditary hemochromatosis is much less clear. The mutated allele is widespread and occurs heterozygously in approx. 20% of the population (6,8). The homozygous presence of the mutation H63D does not cause a predisposition for hereditary hemochromatosis. However, the few patients suffering from hemochromatosis who have the mutation C282Y in heterozygous form also have very frequently the mutation H63D (1,3,7).

Owing to their physical proximity in the Hfe gene, both mutations have never been found simultaneously on one chromosome (6). This means that patients who are homozygous for the C282Y mutation are always negative for the H63D mutation and vice versa.

The detection of the specific mutations in the Hfe gene is a important diagnostic, because the disease does not reduce life expectancy if it is diagnosed and treated at an early stage.