Uncommon mutations and polymorphisms in the hemochromatosis gene

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism, Iron absorption from the gut is inappropriately high, resulting in increasing iron overload. The hemochromatosis gene (HFE) was identified in 1996 by extensive positional cloning by many groups over a period of about 20 years. Two missense mutations were identified. Homozygosity for one of these, a substitution of a tyrosine for a conserved cysteine (C282Y), has now clearly been shown to be associated with HH in 60-100% of patients, The role of the second mutation, the substitution of an aspartic acid for a histidine (H63D), is not so clear but compound heterozygotes for both these mutations have a significant risk of developing HH, Here me review other putative mutations in the HFE gene and document a number of diallelic polymorphisms in HFE introns

[Reply to letters to the editor] H63D is an haemochromatosis associated allele

Free to read on publisher website We thank Fairbanks et al for their comments and agree with their conclusion that the H63D mutation may be associated with iron accumulation. This is supported by the recent finding that the HFE protein with the H63D mutation does not reduce the affinity of transferrin for its receptor in the same way as the wild type protein. 1 However, we have reservations about combining data from various groups of patients and controls where the frequency of the mutations in the general population varies greatly..