A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis

Morris, Tara; Литвинова, М.М.; Ralston, Diana; Mattman, André; Holmes, Daniel T.; Lockitch, Gillian

doi:10.1016/j.bcmd.2005.07.007

Cited by 19 publications

(7 citation statements)

References 33 publications

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“…Some do not tolerate phlebotomy and develop a mild anemia. [36][37][38] Furthermore, in contrast to the other forms of hemochromatosis associated with hepcidin deficiency, hepcidin levels are elevated in these patients. 39 These patients rarely develop liver fibrosis or cirrhosis and they have few, if any, clinical manifestations of iron-storage disease.…”

Section: Discussionmentioning

confidence: 99%

Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice

Viatte

Nicolas

Lou

et al. 2006

Blood

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We report the generation of a tetracyclineregulated (Tet ON) transgenic mouse model for acute and chronic expression of the iron regulatory peptide hepcidin in the liver. We demonstrate that short-term and long-term tetracycline-dependent activation of hepcidin in adult mice leads to hypoferremia and iron-limited erythropoiesis, respectively. This clearly establishes the key role of hepcidin in regulating the extracellular iron concentration. We previously demonstrated that, when expressed early in fetal development, constitutive transgenic hepcidin expression prevented iron accumulation in an Hfe ؊/؊ mouse model of hemochromatosis. We now explore the effect of chronic hepcidin expression in adult Hfe ؊/؊ mice that have already developed liver iron overload. We demonstrate that induction of chronic hepcidin expression in 2-monthold Hfe ؊/؊ mice alters their pattern of cellular iron accumulation, leading to increased iron in tissue macrophages and duodenal cells but less iron in hepatocytes. These hepcidin-induced changes in the pattern of cellular iron accumulation are associated with decreased expression of the iron exporter ferroportin in macrophages but no detectable alteration of ferroportin expression in the hepatocytes. We speculate that this change in iron homeostasis could offer a therapeutic advantage by protecting against damage to parenchymal cells.

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Section: Discussionmentioning

confidence: 99%

Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice

Viatte

Nicolas

Lou

et al. 2006

Blood

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“…We investigated the cellular effects of mutations identified in bio‐clinically characterized patients having iron overload disease with FPN gene mutations [Le Lan et al., ], by performing functional studies for the newly discovered mutations, NM‐01458 5.5: c.473G>T p.Trp158Leu (W158L), c.610G>A p.Gly204Ser (G204S), and c.1112G>A p.Arg371Gln (R371Q), and for two mutations previously reported in patients but not previously characterized in vitro, c.262A>G p.Arg88Gly (R88G) [Cunat et al., ] and c.553A>G p.Asn185Asp (N185D) [Morris et al., ]. These studies were performed to have an understanding of the impact of the mutations presenting, from in silico analysis, a potential deleterious impact.…”

Section: Introductionmentioning

confidence: 99%

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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“…By contrast, the wild-type sibling II-4 had the main features of the IR-HIO characterized by hyperferritinemia with normal transferrin saturation, prevalent sinusoidal iron accumulation (as shown by the high SIS/TIS ratio) and a HII lower than 1.9, that is the diagnostic cutoff of HH (41,42). Previous studies showed that either young age or female gender might affect penetrance and expression of ferroportin disease (20). This observation might explain the results observed in sibling II-3 and offspring III-4, whereas the alterations induced by marathon races on erythrocyte turnover and hepcidinmediated iron regulation might have protected subject II-6 from the development of iron overload (43,44).…”

Section: Discussionmentioning

confidence: 99%

“…The dominant form of HH links to SLC40A1 (10) that encodes ferroportin, an iron export protein that plays an essential role in releasing iron from cells (11,12). In contrast to the Northwest European preponderance of HFE-related HH, iron overload associated with ferroportin mutations has been identified in different ethnic groups worldwide (13)(14)(15)(16)(17)(18)(19)(20)(21), suggesting that ferroportin disease (HH type 4) (OMIM 606069) might be more common than believed (10,22). Also, unlike the other adult forms of HH, characterized by high transferrin saturation and iron accumulation in hepatocytes, some phenotypic variation is observed in ferroportin disease.…”

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confidence: 99%

Novel mutations of the ferroportin gene (SLC40A1): analysis of 56 consecutive patients with unexplained iron overload

Pelucchi¹,

Mariani

Salvioni

et al. 2007

Clinical Genetics

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The aim of this study was to search for SLC40A1 mutations in iron overloaded patients, which tested negative for HFE mutations and other iron-related genes. After a careful differential diagnosis, we selected 56 patients with unexplained iron overload whose phenotype could suggest the ferroportin disease. Iron overload was assessed by liver biopsy or by superconducting quantum interference device. SLC40A1 exons and intron-exon boundaries were amplified by polymerase chain reaction and sequenced. We also evaluated the presence of the insulin-resistance hepatic iron overload and of non-alcoholic fatty liver disease. Iron status was assessed in 44 families. We identified two novel mutations (D157N and V72F) at the heterozygous state in two probands. Phenotype heterogeneity was observed in both families, suggesting variable penetrance and expression. Including the two affected ones, 25 of the 44 families (57%) available for the iron study had one or more relatives with increased serum iron indices. Our findings not only suggest that the presence of major alterations of serum iron parameters in probands' relatives is a main criteria to improve the power of the genetic testing for ferroportin disease but also indicate that a number of patients exists in which the etiology of iron overload remains still undefined.

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A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis

Cited by 19 publications

References 33 publications

Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice

Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice

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

Novel mutations of the ferroportin gene (SLC40A1): analysis of 56 consecutive patients with unexplained iron overload

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