Autosomal dominant hereditary hemochromatosis associated with two novel Ferroportin 1 mutations in Spain

Bach, Vanessa; Remacha, Ángel F.; Altés, Albert; Barceló, Montserrat; Molina, M.A.; Baiget, Montserrat

doi:10.1016/j.bcmd.2005.09.001

Cited by 25 publications

(8 citation statements)

References 24 publications

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“…Patients 1 and 3, who had high levels of transferrin saturation, presented overweight related to metabolic syndrome reported to slightly increase hepcidin [Barisani et al 2008, Ruivard et al 2009], which may modify the clinical presentation of the disease. It is noteworthy that similar clinical observations have been reported by others for the FPN mutation R88T [Bach et al, 2006]. In addition, patient 1 exhibited a non insulin-dependent diabetes and was heterozygous p.His63Asp in HFE gene.…”

Section: Discussionsupporting

confidence: 86%

Ferroportin Diseases: Functional Studies, a Link Between Genetic and Clinical Phenotype

et al. 2013

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Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression.

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Section: Discussionsupporting

confidence: 86%

Ferroportin Diseases: Functional Studies, a Link Between Genetic and Clinical Phenotype

et al. 2013

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“…The mutant Cys282Tyr HFE protein is unable to bind β 2 microglobulin and fails to reach the cell membrane, resulting in a misfolded, non-functional protein 36. Mutations of the ferroportin gene (haemochromatosis type 4) may result in a loss of iron-export capacity, with hyperferritinaemia, but without elevation of transferrin saturation, and macrophage iron overload, or in a loss in hepcidin-binding activity, which is associated with iron overload 33 37…”

Section: Iron Overloadmentioning

confidence: 99%

Disorders of iron metabolism. Part II: iron deficiency and iron overload

2010

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Main disorders of iron metabolismIncreased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron deficiency anaemia. In chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, resulting in hypoferraemia and iron restricted erythropoiesis, despite normal iron stores (functional iron deficiency), and finally anaemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD+ID). In contrast, low hepcidin expression may lead to hereditary haemochromatosis (HH type I, mutations of the HFE gene) and type II (mutations of the hemojuvelin and hepcidin genes). Mutations of transferrin receptor 2 lead to HH type III, whereas those of the ferroportin gene lead to HH type IV. All these syndromes are characterised by iron overload. As transferrin becomes saturated in iron overload states, non-transferrin bound iron appears. Part of this iron is highly reactive (labile plasma iron), inducing free radical formation. Free radicals are responsible for the parenchymal cell injury associated with iron overload syndromes.Role of laboratory testing in diagnosisIn iron deficiency status, laboratory tests may provide evidence of iron depletion in the body or reflect iron deficient red cell production. Increased transferrin saturation and/or ferritin levels are the main cues for further investigation of iron overload. The appropriate combination of different laboratory tests with an integrated algorithm will help to establish a correct diagnosis of iron overload, iron deficiency and anaemia.Review of treatment optionsIndications, advantages and side effects of the different options for treating iron overload (phlebotomy and iron chelators) and iron deficiency (oral or intravenous iron formulations) will be discussed.

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“…However, further functional studies or larger population studies are required to unequivocally link these variants to impaired ferroportin function and iron overload in individuals carrying these variants. The other six SLC40A1 variants identified in the ExAC data set (c.-59_-45del, p.Ile180Thr, p.Gly204Ser, p.Gly267Asp, p.Arg371Gln, and p.Gly468Ser) have all been associated with iron overload in patients and/or families, [26][27][28][29][30][31][32][33] although ferroportin containing the p.Ile180Thr variant seemed to behave similarly to the wild type when analyzed in functional assays. 30 The SLC40A1 p.Val162del variant has been reported as a cause of ferroportin disease more frequently (in nine publications) than any other SLC40A1 mutation (Supplementary Table S1 online); however, we did not detect it in any of the genomic sequence databases.…”

Section: Discussionmentioning

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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Autosomal dominant hereditary hemochromatosis associated with two novel Ferroportin 1 mutations in Spain

Cited by 25 publications

References 24 publications

Ferroportin Diseases: Functional Studies, a Link Between Genetic and Clinical Phenotype

Ferroportin Diseases: Functional Studies, a Link Between Genetic and Clinical Phenotype

Disorders of iron metabolism. Part II: iron deficiency and iron overload

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

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