HFE mutations analysis in 711 hemochromatosis probands: Evidence for S65C implication in mild form of hemochromatosis

Hereditary hemochromatosis (HH) is a common autosomal recessive genetic dis order of iron metabolism. The HFE candidate gene encoding an HLA class I-li ke protein involved in Hn was identified in 1996. Two missense mutations ha ve been described: C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40 % to 70% of non C282Y HH chromosomes. We report here on the analysis of C28 2Y, H63D, and the 193A-->T substitution leading to the S65C missense substi tution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution re presented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significan tly enriched in probands with at least one chromosome without an assigned m utation. This substitution accounted for 7.8% of HH chromosomes that were n either C282Y nor H63D. This enrichment of S65C among HH chromosomes suggest s that: the S65C substitution is associated with the mild form of hemochrom atosis. (C) 1999 by The American Society of Hematology.