HFE Mutations Analysis in 711 Hemochromatosis Probands: Evidence for S65C Implication in Mild Form of Hemochromatosis

Abstract

Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have 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 C282Y, H63D, and the 193A→T substitution leading to the S65C missense substitution 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 represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

HFE mutations and transferrin receptor polymorphism analysis in porphyria cutanea tarda: a prospective study of 36 cases from southern France

“…Genomic DNA was extracted from peripheral blood leucocytes and analysed both for the three main HFE mutations (C282Y, H63D, S65C) and for the main transferrin receptor polymorphism using polymerase chain reaction (PCR) and restriction analysis of the amplified fragment as previously described. 20,34,36 The frequencies of the alleles and genotypes were compared with the results obtained from a previous survey conducted in the general population from the same geographical area for HFE 18 or with data reported in the general population in a previous large-scale study by other authors. 34…”

“…15±17 Other minor mutations, especially the missense mutation S65C, have more recently been identified, and are likely to be associated with mild forms of GH. 20,21 The possible role of HFE mutations in PCT has already prompted some studies that consistently concluded that HFE mutations were significantly higher in patients with PCT than in controls, and that genetic abnormalities of iron metabolism pathways might play a significant part in the physiopathology of the disease. 22±32 We present here a prospective study which further supports this hypothesis and confirms the relative importance of homozygous H63D mutations in patients from southern France.…”

Analysis of HFE Genes C282Y, H63D, and S65D in Patients With Hyperferritinemia From Northeastern Brazil

“…The H63D mutation is two or three times more frequent than C282Y mutation and the prevalence of heterozygous and homozygous for H63D mutation varies between 15 and 40% and 2.5 and 3.6%, respectively, and the frequency of C282Y/H63D genotype is approximately 2% (15,16). Regarding the S65C mutation, the frequency in Caucasians varies between 1% and 4% (9,10,18,19).…”

Mutation analysis in the HFE gene in patients with hereditary haemochromatosis in Saguenay–Lac‐Saint‐Jean (Quebec, Canada)

“…Cardoso Nielsen et al, 1998Datz et al, 1997UK consortium, 1997Willis et al, 1997Ryan et al, 1998Mura et al, 1999Moirand et al, 1999 Country HH patients had discordant HFE genotypes in four sibships. A non-expressing HH parent is a likely explanation for the discrepancy observed in two sibships.…”