Inherited Hfe–Unrelated Hemochromatosis in Italian Families

Camaschella, Clara; Fargion, Silvia; Sampietro, Maurizio; Roetto, Antonella; Bosio, S.; Garozzo, Giovanni; Arosio, Cristina; Piperno, Alberto

doi:10.1002/hep.510290509

Cited by 52 publications

(27 citation statements)

References 10 publications

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“…These findings are different from those reported for Northern Europe, where more than 90% of the patients are C282Y homozygotes or C282Y and H63D compound heterozygotes (5,(20)(21)(22)(23)(24)(25), but agree with recent data reported for Italy, where approximately one third of the patients with HH showed neither C282Y or H63D mutations, nor any other mutation in the HFE gene by sequence analysis (26)(27)(28). Similarly, none of these mutations were detected in African Americans with HH or in subjects with African iron overload, another hereditary disorder of iron metabolism that is much more heterogeneous than HH (12,13).…”

Section: Discussioncontrasting

confidence: 84%

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Bittencourt

Palácios

Couto

et al. 2002

Braz J Med Biol Res

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The hemochromatosis gene, HFE, is located on chromosome 6 in close proximity to the HLA-A locus. Most Caucasian patients with hereditary hemochromatosis (HH) are homozygous for HLA-A3 and for the C282Y mutation of the HFE gene, while a minority are compound heterozygotes for C282Y and H63D. The prevalence of these mutations in non-Caucasian patients with HH is lower than expected. The objective of the present study was to evaluate the frequencies of HLA-A antigens and the C282Y and H63D mutations of the HFE gene in Brazilian patients with HH and to compare clinical and laboratory profiles of C282Y-positive and -negative patients with HH. The frequencies of HLA-A and C282Y and H63D mutations were determined by PCR-based methods in 15 male patients (median age 44 (20-72) years) with HH. Eight patients (53%) were homozygous and one (7%) was heterozygous for the C282Y mutation. None had compound heterozygosity for C282Y and H63D mutations. All but three C282Y homozygotes were positive for HLA-A3 and three other patients without C282Y were shown to be either heterozygous (N = 2) or homozygous (N = 1) for HLA-A3. Patients homozygous for the C282Y mutation had higher ferritin levels and lower age at onset, but the difference was not significant. The presence of C282Y homozygosity in roughly half of the Brazilian patients with HH, together with the findings of HLA-A homozygosity in C282Y-negative subjects, suggest that other mutations in the HFE gene or in other genes involved in iron homeostasis might also be linked to HH in Brazil.

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Section: Discussioncontrasting

confidence: 84%

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Bittencourt

Palácios

Couto

et al. 2002

Braz J Med Biol Res

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“…Alternatively, another iron regulatory, B2m-interacting protein may be encoded by a gene located on a different chromosome. If so, it might be a candidate for the causative gene in non-HFE hemochromatosis (35,36) or in juvenile hemochromatosis (37). Each of these diseases resembles HH clinically, but can be distinguished genetically.…”

Section: Figurementioning

confidence: 99%

Genes that modify the hemochromatosis phenotype in mice

Levy¹,

Montross²,

Andrews³

2000

J. Clin. Invest.

214

154

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“…A truncation mutant of transferrin receptor 2 (TfR2), TfR2/ Y250X, causes a rare form of hereditary hemochromatosis (type 3, HFE3), an iron overload disorder characterized by excess absorption of dietary iron and consequent deposition of iron in liver and other parenchymal tissues (Camaschella et al, 1999(Camaschella et al, , 2000. The analogous mutation or knockout of Trfr2 in mice reproduces the disease phenotype (Fleming et al, 2002;Wallace et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway

Johnson

Chen

Murchison

et al. 2007

MBoC

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Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1), the protein that delivers iron to cells through receptor-mediated endocytosis of diferric transferrin (Fe 2 Tf). TfR2 also binds Fe 2 Tf, but it seems to function primarily in the regulation of systemic iron homeostasis. In contrast to TfR1, the trafficking of TfR2 within the cell has not been extensively characterized. Previously, we showed that Fe 2 Tf increases TfR2 stability, suggesting that trafficking of TfR2 may be regulated by interaction with its ligand. In the present study, therefore, we sought to identify the mode of TfR2 degradation, to characterize TfR2 trafficking, and to determine how Fe 2 Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe 2 Tf increases the fraction of TfR2 localizing to recycling endosomes and decreases the fraction of TfR2 localizing to late endosomes. Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to Fe 2 Tf, increases the rate of receptor turnover and prevents stabilization by Fe 2 Tf, indicating a direct role of Fe 2 Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif. INTRODUCTIONA truncation mutant of transferrin receptor 2 (TfR2), TfR2/ Y250X, causes a rare form of hereditary hemochromatosis (type 3, HFE3), an iron overload disorder characterized by excess absorption of dietary iron and consequent deposition of iron in liver and other parenchymal tissues (Camaschella et al., 1999(Camaschella et al., , 2000. The analogous mutation or knockout of Trfr2 in mice reproduces the disease phenotype (Fleming et al., 2002;Wallace et al., 2005). Thus, TfR2 is required for normal iron homeostasis.TfR2, cloned in 1999, is a homologue of transferrin receptor 1 (TfR1; Kawabata et al., 1999). The extracellular domains of the two receptors are 45% identical and 67% similar. TfR1 functions to deliver iron to cells through receptor-mediated endocytosis of its ligand transferrin (Tf), a serum protein that transports iron (Dautry-Varsat et al., 1983;Klausner et al., 1983). On the cell surface, TfR1 binds iron-saturated transferrin (Fe 2 Tf) at slightly basic pH. Fe 2 Tf-TfR1 then internalizes in clathrin-coated vesicles to early endosomes.In the acidic pH of early endosomes, iron releases from Tf, whereas Tf remains bound to TfR1. The complex then recycles, from either early or recycling endosomes, to the cell surface. At the slightly basic pH of the cell surface, TfR1 releases unsaturated Tf (apoTf) and again binds Fe 2 Tf. TfR1 expression is ubiquitous, consistent with its role in cellular iron delivery. The stability of TfR1 mRNA is negatively regulated by intracellular iron levels through iron-responsive elements (IREs) in the 3Ј untranslated region (Mattia et al., 1984;Ward et al., 1984;Rao et al., 1985;Sciot et al., 1987;Owen and Kuhn, 19...

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Inherited Hfe–Unrelated Hemochromatosis in Italian Families

Cited by 52 publications

References 10 publications

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Genes that modify the hemochromatosis phenotype in mice

Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway

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