Several mutations of the HFE gene have been described. The most common mutation in patients with HH is the C282Y mutation. In the C282Y mutation, a base substitution changes the amino acid in position 282 from cysteine (C) to tyrosine (Y). The loss of the sulfhydryl-containing amino acid disrupts the tertiary structure of HFE so that it no longer binds to beta-2 microglobulin. Beta-2 microglobulin appears to act with other proteins to escort the newly synthesized HFE out of the Golgi apparatus and to the cell surface, where it can bind to TfR. In the C282Y mutation, HFE remains in the Golgi, never reaching the cell surface. The result is that transferrin binding to TfR is enhanced, and excessive amounts of iron enter the cells of the small intestine, liver, and other tissues.
Due to the C282Y mutation, HH is considered an autosomal recessive disorder with low penetrance. In other words, some individuals homozygous for the mutation (carry two copies of the gene) do not develop clinical symptoms of the disease. Among symptomatic patients with HH, the majority are homozygous for C282Y.
