A novel mutation of HFE explains the classical phenotype of hereditary hemochromatosis in a C282Y carrier

Hereditary hemochromatosis (HH) is the most autosomal recessive disorder in Caucasians, affecting approximately 1 in 300 person. It is characterized by iron overload in many organs, leading to cirrhosis, hepatocellular carcinoma, diabetes, arthritis, heart failure and hypogonadism. Most of HH patients are homozygous for the C282Y mutations. Some C282Y-carrier patients have been identified to be compound heterozygous for other mutations (H63D, S65C, G93R, IVS3+1G>T, 203delT). We report a patient with classical HH who is compound heterozygous for C282Y and a novel missense mutation in the exon 4. This is a 848A>C mutation that causes glutamine to proline substitution at position 283 (Q283P). We hypothesize that the Q283P variant may disrupt the beta2-microglobulin binding site in the HFE protein.