Hereditary hemochromatosis associated with gene HFE gene (Hemochromatosis type I, HFE-HCC) is an inherited autosomal recessive disorder characterized by an increased absorption of iron at the level of the gastrointestinal mucosa, with consequent accumulation of the same at the level of the liver, the skin, pancreas, heart, joints and testes. It is the most common autosomal recessive disease in Caucasians. Abdominal pain, weakness, lethargy and weight loss are the earliest symptoms in the absence of a ’proper therapy may develop in men aged 40-60 years and in women after menopause. Outcomes dreaded disease are made from cirrhosis and liver fibrosis, together with endocrine dysfunction. The HFE gene is located on chromosome 6 (6p21.3) and encodes a protein of 348 aa (precursor) very similar to proteins of HLA class I. The mature protein is expressed on the cell surface as a heterodimer with the beta2-microglobulin. The HFE protein consists of two extracellular domains, a1 and a2, which interact with the transferrin receptor; from a domain a3, immunoglobulin-like, which binds to the beta2-microglobulin; by a transmembrane domain, and finally by a cytoplasmic one. The HFE protein, binding to the transferrin receptor 1, it would set in a negative way, by reducing the release of iron in the cell cytoplasm and then the uptake of iron. At least 28 distinct mutations in the HFE gene have been reported, but only two of them represent the majority of alleles that can cause disease.

The first mutation, Cys282Tyr (C282Y, 845G>A), is the most common mutation responsible for hemochromatosis. It removes a highly conserved cysteine ​​residue preventing the formation of an intramolecular disulfide bridge that allows the a3 domain to interact with the beta2-microglobulin, which normally plays a stabilizing function on the HFE protein. Consequently an entrapment of the protein inside of the endoplasmic reticulum and of the Golgi apparatus, with reduced expression at the level of the cell surface.

The second mutation, His63Asp (H63D, 187C>G), rather results in a lack of formation of an intramolecular salt bridge in the a2 domain that normally binds the transferrin receptor, decreasing the function of the HFE protein.

A third mutation in HFE is a substitution A193T exon 2 which involves an amino acid change S65C. It has been shown to be generally benign, although a genotype C282Y/S65C may confer an increased risk of development of hemochromatosis, contributing to a mild phenotype of the disease.

The diagnosis of HFE-HHC in patients with clinical symptoms suggestive of hemochromatosis uses a biochemical screening test based on the percentage of serum transferrin saturation plus the plasma concentration of ferritin, and molecular confirmation of a test aimed at finding mutations C282Y and H63D in the HFE gene. Even the histopathological diagnosis of liver biopsy can confirm the accumulation of iron in the organ. Approximately 60-90% of individuals of European origin with HFE-HHC are homozygous for the C282Y mutation, 3-8% of them are compound heterozygous for C282Y and H63D mutations and 1% are homozygous for H63D. Regarding the homozygosity of H63D mutation there is no evidence that it is associated with a clinical phenotype of hemochromatosis in the absence of other causes that could lead to iron accumulation. Approximately 5% of subjects with a clinical picture suggestive of hemochromatosis are only heterozygous for the C282Y mutation. They probably have another rare mutation in HFE or mutations in other genes responsible for iron accumulation. The incidence of homozygous for C282Y in the European population is between 1:200 and 1:400, while it is lower in African-Americans and even more among Asians.

Download information sheet (Adobe PDF)