Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy

Cassanelli, Stefano; Pignatti, Elisa; Montosi, Giuliana; Garuti, Cinzia; Mariano, Maria Teresa; Campioli, Daniele; Carbonieri, Anna; Baldini, E; Pietrangelo, Antonello

doi:10.1016/s0168-8278(01)00035-6

Cited by 62 publications

(24 citation statements)

References 28 publications

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“…In Italy, in spite of the smaller incidence of C282Y mutation, the prevalence of the H63D mutation is high (Restagno et al, 2000;Cassanelli et al, 2001;Girouard et al, 2002;Miniero et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Serum ferritin and transferrin saturation levels in β0 and β+ thalassemia patients

Estevão¹,

Peitl²,

Bonini-Domingos³

2011

Genet. Mol. Res.

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ABSTRACT.There have been few studies on the mutations that cause heterozygous beta-thalassemia and how they affect the iron profile. One hundred and thirty-eight individuals were analyzed, 90 thalasemic β 0 and 48 thalasemic β + , identified by classical and molecular methods. Mutations in the hemochromatosis (HFE) gene, detected using PCR-RFLP, were found in 30.4% of these beta-thalassemic patients; heterozygosity for H63D (20.3%) was the most frequent. Ferritin levels and transferrin saturation were similar in beta-thalassemics with and without mutations in the HFE gene. Ferritin concentrations were significantly higher in men and in individuals over 40 years of age. Transferrin saturation also was significantly higher in men, but only in those without HFE gene mutations. There was no significant difference in the iron profile among the β 0 and β + thalassemics, with and without HFE gene mutations. The frequency of ferritin values above 200 ng/mL in women and 300 ng/ mL in men was also similar in β 0 and β + thalassemics (P > 0.72). Our conclusion is that ferritin levels are variable in the beta-thalassemia, trait regardless of the type of beta-globin mutation. Furthermore, HFE gene polymorphisms do not change the iron profile in these individuals.

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Section: Discussionmentioning

confidence: 99%

Serum ferritin and transferrin saturation levels in β0 and β+ thalassemia patients

Estevão¹,

Peitl²,

Bonini-Domingos³

2011

Genet. Mol. Res.

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“…The contribution of the H63D mutation to HH has been an area of controversy. Individuals with HH have been reported who demonstrate compound heterozygosity for H63D and other HFE mutations, particularly C282Y (14). Nonetheless, normal iron parameters are observed in approximately half of individuals compound heterozygous for H63D and C282Y (15).…”

Section: H Ereditary Hemochromatosis (Hh) Is An Autosomal Recessivementioning

confidence: 99%

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis

Tomatsu

Orii

Fleming

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by iron accumulation in several organs, followed by organ damage and failure. The C282Y mutation in the HFE gene explains 80 -90% of all diagnosed cases of HH in populations of northwestern European ancestry. Targeted disruption of the mouse Hfe gene (or introduction of the murine mutation analogous to the C282Y human mutation) produces a murine model of HH. Another mutation in the HFE gene, H63D, is more prevalent than C282Y. However, the physiological consequences of the H63D mutation (as well as C282Y͞H63D compound heterozygosity) on iron homeostasis are less well established. To evaluate the phenotypic consequences of the C282Y͞H63D and H63D͞H63D genotypes, we produced H67D (corresponding to H63D in humans) and C294Y (corresponding to C282Y in humans) knock-in mice. H67D homozygous mice, C294Y homozygous mice, and H67D͞ C294Y compound heterozygous mice each demonstrated hepatic iron loading. Even on a standard diet, by 10 weeks of age, hepatic iron levels in mice of these three genotypes were significantly higher than those of wild-type littermates. The relative severity of hepatic iron loading was C294Y͞C294Y > C294Y͞H67D > H67D͞ H67D. We conclude that the H67D allele, when homozygous or combined with a more consequential mutation like C294Y, leads to hepatic iron loading. These observations indicate that the H67D mutation leads to partial loss of Hfe function and can contribute to murine HH.knock-in mice ͉ C282Y mutation ͉ H63D mutation ͉ Cre-loxP H ereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by elevated transferrin saturations, hepatic iron overload, and variable clinical manifestations including liver cirrhosis, hypogonadism, heart failure, and arthropathy. Prevalence of mutations in the gene responsible for HH is estimated to be 2-5 per 1,000 in Caucasians. The gene mutated in HH, the hemochromatosis gene (HFE), encodes an MHC class I-like protein (1) that heterodimerizes with ␤ 2 -microglobulin (␤ 2 M). Most cases of HH arise from a founder mutation in HFE (845G to -A) that results in the amino acid substitution C282Y and prevents the association of HFE with ␤ 2 M (1-3). Functional significance of HFE-␤ 2 M complex in iron homeostasis was supported from the observations that HFE-␤ 2 M is physically associated with transferrin receptor 1 (TfR1) in human placenta (4), in crypt enterocytes of duodenum (5), and in cultured human cell lines (6, 7). The effect of HFE on transferrin-mediated iron uptake seems to depend on the particular cell type studied as well as the magnitude of expression of ␤ 2 M (8).Although the most common HFE mutation associated with HH is C282Y, the most common HFE mutation overall is H63D. Among Caucasian populations, the allele frequency of C282Y is 2-5% and that of H63D is 15-20% (9, 10). The H63D allele frequency has been reported to be as high as 30% in the Basque population of Spain (11). The H63D mutation seems to have evolutionarily predated C282Y and to have ar...

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“…DHPLC elution profiles and DNA sequencing of the identified mutants in the TfR2 amplicon for exon 2 at the temperature of 64.2°C. 32 ) and show an enrichment of C282Y allele frequency of approximately sixfold compared with unselected blood donors (33,34 ). We found six new HFE substitutions, four of which can be considered silent polymorphisms because they do not cause amino acid modification (88CϾT, 696CϾT, and 867GϾC) or are intronic and do not appear to introduce alternative splicing (IVS3 ϩ 21TϾC).…”

Section: Hfe Mutationsmentioning

confidence: 99%

Identification of New Mutations of the HFE, Hepcidin, and Transferrin Receptor 2 Genes by Denaturing HPLC Analysis of Individuals with Biochemical Indications of Iron Overload

et al. 2003

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Background:Hereditary hemochromatosis is a recessive disorder characterized by iron accumulation in parenchymal cells, followed by organ damage and failure. The disorder is mainly attributable to the C282Y and H63D mutations in the HFE gene, but additional mutations in the HFE, transferrin receptor 2 (TfR2), and hepcidin genes have been reported. The copresence of mutations in different genes may explain the phenotypic heterogeneity of the disorder and its variable penetrance. Methods: We used denaturing HPLC (DHPLC) for rapid DNA scanning of the HFE (exons 2, 3, and 4), hepcidin, and TfR2 (exons 2, 4 and 6) genes in a cohort of 657 individuals with altered indicators of iron status. Results: DHPLC identification of C282Y and H63D HFE alleles was in perfect agreement with the restriction endonuclease assay. Fourteen DNA samples were heterozygous for the HFE S65C mutation. In addition, we found novel mutations: two in HFE (R66C in exon 2 and R224G in exon 4), one in the hepcidin gene (G71D), and one in TfR2 (V22I), plus several intronic or silent substitutions. Six of the seven individuals with hepcidin or TfR2 coding mutations carried also HFE C282Y or S65C mutations. Conclusion: DHPLC is an efficient method for mutational screening for the genes involved in hereditary hemochromatosis and for the study of their copresence.

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Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy

Cited by 62 publications

References 28 publications

Serum ferritin and transferrin saturation levels in β0 and β+ thalassemia patients

Serum ferritin and transferrin saturation levels in β0 and β+ thalassemia patients

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis

Identification of New Mutations of the HFE, Hepcidin, and Transferrin Receptor 2 Genes by Denaturing HPLC Analysis of Individuals with Biochemical Indications of Iron Overload

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