The HFE gene encodes an HLA class I-like protein that is displayed on the cell surface as part of a heterodimer with β-2 microglobulin. This heterodimer regulates the absorption of dietary iron by interacting with the transferrin receptor. Mutations in the HFE gene were shown to cause hemochromatosis in 1996 and this has allowed for DNA testing to be used in the diagnosis of hemochromatosis.
Variation in the HFE Gene
There are three mutations in the HFE gene that are known to cause hemochromatosis by affecting the function of the HFE protein and preventing the normal regulation of iron absorption.
These three mutations are C282Y (c.845G>A), H63D (c.187C>G) and S65C (c.193A>T), and each occurs due to a single nucleotide change that changes the amino acid sequence of the HFE protein. C282Y is the most common mutation causing hemochromatosis, and is associated with more severe symptoms compared to the other two mutations.
The most common HFE mutation that causes hemochromatosis is the C282Y mutation. This mutation is a single nucleotide substitution (c.845G>A), which changes a highly conserved cysteine (at amino acid position 282) to a tyrosine. This amino acid change prevents the formation of disulfide bond in the HFE – β-2 microglobulin complex and inhibits the regulation of iron absorption.
Approximately 80 – 85% of patients affected by hereditary hemochromatosis have two copies of this C282Y mutation (C282Y homozygotes). Iron overload is detected in 90% of male C282Y homozygotes but only in 50% of female C282Y homozygotes, and, overall, approximately 30% of C282Y homozygotes will not show any iron overload symptoms.
Individuals that have one HFE gene with the C282Y mutation and one normal HFE gene (C282Y heterozygotes) sometimes experience mild symptoms of hemochromatosis, such as lethargy and mild joint pain, but the disease is unlikely to develop further.
H63D is the second most significant mutation leading to hemochromatosis. This mutation is a single nucleotide substitution (c.187C>G), which changes a histidine (at amino acid position 63) to an aspartic acid. This mutation is thought to inhibit the formation of an intramolecular salt bridge during the interaction between the HFE protein and the transferrin receptor, thereby reducing the control of iron absorption.
Individuals that carry two copies of the H63D mutation (H63D homozygotes) have a slightly increased risk of hemochromatosis but often other precipitating factors (e.g. hepatitis or alcohol abuse) are also required before iron overload occurs.
S65C is a very rare mutation, which contributes slightly to hemochromatosis. This mutation is a single nucleotide substitution (c.193A>T), which changes a serine (at amino acid position 65) to a cysteine. The mechanism that this mutation prevents iron regulation is currently unknown.
Individuals that carry two copies of the S65C mutation (S65C homozygotes) do not appear to be at an increased risk of hemochromatosis. However, when this mutation occurs in a compound heterozygote with a C282Y mutation, there is slightly increased risk of hemochromatosis.
Compound heterozygotes have two mutated HFE genes, but each copy of the gene carries a different mutation. The C282Y/H63D compound heterozygote occurs in 3-8% of patients with hemochromatosis but it is associated with a milder form of disease than C282Y homozygotes, and often other factors (e.g. hepatitis or alcohol abuse) are also required.
The C282Y/S65C compound heterozygote is a very rare genotype that also slightly increases the risk of a mild form of hemochromatosis. The H63D/S65C compound heterozygote does not appear to increase the risk of hemochromatosis.