MUTATION ANALYSIS IN HEREDITARY HEMOCHROMATOSIS (CORRECTED VERSION OFVF214)

The DNA of 147 patients of European origin clinically diagnosed with i diopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187, One hundred twenty-one (82.3%) of the hemochromatosis patients were homozygous and 10 (6.8%) heteroz ygous for the 845A (C282Y) mutation, All of the homozygous patients we re also homozygous for nt 187G, and all 845A heterozygotes had at leas t one copy of 187G. Thus, the nt 845 and nt 187 mutations were in comp lete linkage disequilibrium; nt 187 was a C on all chromosomes with th e 845A mutation, Eight of the 10 heterozygotes for 845A were heterozyg ous for 187G(H63D), The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations exi sting in trans with 845A and in linkage disequilibrium with 187G, or t hat the 187G itself is a deleterious mutation, which in concert with t he 845A can give rise to hemochromatosis, None of the 193 normal contr ols were homozygous for 845A and 29/193 (15%) were heterozygous for 84 5A, Although 47/193 (23.3%) of normal controls were heterozygous for t he 187G mutation only two of these carried the 845A mutation, If the 1 87G mutation complemented the 845A mutation with high penetrance in ca using hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygot es for the 845A mutation was much higher than that of the 845A/187G ge notype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5% and based on the data of Feder et al, only 0.5%. In contras t, the penetrance of the homozyous 845A/845A genotype seems to be very high, Thus, screening for this genotype should be very useful.