The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22

Camaschella, Clara; Roetto, Antonella; Calı̀, Angelita; Gobbi, Marco De; Garozzo, Giovanni; Carella, Massimo; Majorano, N.; Totaro, Angela; Gasparini, Paolo

doi:10.1038/75534

Cited by 748 publications

(509 citation statements)

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“…The median ferritin level for the whole group was 861.5 μg/L (range 17-10,000), and the median quantity of iron removed by phlebotomy was 4.25 g (range 0. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The iron removed was ≥5 g in 43 patients.…”

Section: Resultsmentioning

confidence: 99%

“…Type 3 is caused by mutations in the transferrin receptor 2 gene [8], and type 4 is described as an autosomal dominant iron overload that develops from a pathogenic mutation in the SLC40a1 gene (ferroportin disease) [16,17,20]. Some authors have described mutations in HAMP and HJV as genetic modifiers of the hemochromatosis phenotype in humans [10,12,15].…”

Section: Introductionmentioning

confidence: 99%

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Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

Altés

Bach²,

Ruiz³

et al. 2009

Ann Hematol

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Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

Altés

Bach²,

Ruiz³

et al. 2009

Ann Hematol

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“…Transferrin receptor 2 (TFR2) is involved in the regulation of iron metabolism; patients and mice harboring TFR2 mutations develop type III hereditary hemochromatosis, characterized by inappropriate hepcidin expression relative to body iron levels [9][10][11][12]. Analysis of mice with a hepatocyte-specific deletion of Tfr2 demonstrated the importance of hepatic TFR2 in iron metabolism [13], as they develop similar iron overload as the Tfr2 total knockout (KO) mice.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

et al. 2016

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Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required.

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“…12 Patients with type 3 HH (OMIM 604250) have mutations in the gene encoding another regulator of hepcidin, transferrin receptor 2 (TFR2). 13 An autosomal-dominant form of HH (type 4; OMIM 606069) is caused by heterozygous mutations in the ferroportin gene (SLC40A1) and can result in one of two phenotypes caused by either loss of iron transport ability or hepcidin insensitivity. 14 The population prevalence of HFE HH and the HFE variants p.Cys282Tyr and p.His63Asp have been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

Wallace

Subramaniam

2016

Genetics in Medicine

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Purpose:The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH.Methods: A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined.Results: Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. Conclusion:We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.

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The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22

Cited by 748 publications

References 14 publications

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

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