Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands

Sequencing of HFE exons 2, 3, 4, and 5, and of portions of introns 2, 4, an d 5 revealed novel mutations in four of twenty hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D hom ozygosity. Probands 1 and 2 were heterozygous for previously undescribed mu tations: exon 2, nt 314T-->C (314C; I105T), and exon 2, nt 277G-->C (277C; G93R), respectively; these probands were also heterozygous for H63D and C28 2Y, respectively. Probands 3 and 4 were heterozygous for a previously descr ibed but uncommon HFE mutation: exon 2, nt 193A-->T (193T; S65C). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda, and Proba nd 4 had hereditary stomatocytosis. Each of these four probands had iron ov erload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mu tations in our probands. The I105T and G93R mutations were linked to haplot ypes bearing HLA-A3, -B7 and HLA-A2, -B62, respectively. The S65C mutation was linked to a haplotype characterized by HLA-32. Sixteen other probands d id not have an uncommon HFE exon mutation. In 176 normal control subjects, two were heterozygous for S65C, but I105T and G93R were not detected. Nine of twenty probands were heterozygous and two probands were homozygous for a previously described base-pair change at intron 3,, nt 3671T-->C. One prob and without a detectable missense mutation had a previously described intro n 5 allele (nt 6700G-->A). Heterozygosity for a previously described base-p air change in intron 4 (nt 5636T-->C) was detected in all persons we studie d who also had the S65C mutation. One proband was heterozygous for a previo usly undescribed base-pair change at intron 5 (nt 5807A-->G). We conclude t hat uncommon HFE exon and intron mutations may be discovered among hemochro matosis patients who have "atypical" HFE genotypes. (C) 1999 Academic Press .