Accumulation of iron in erythroblasts of patients with erythropoietic protoporphyria

Rademakers, L. H. P. M.; Koningsberger, J. C.; Sorber, C. W. J.; Faille, H. Baart de la; Hattum, Jan van; Marx, Jean L.

doi:10.1111/j.1365-2362.1993.tb00752.x

Cited by 57 publications

(35 citation statements)

References 37 publications

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“…37 Mice with an autosomal recessive ferrochelatase mutation display a mild hemolytic anemia, photosensitivity, cholestasis, and severe hepatic dysfunction, 35 but they lack neurologic symptoms. 35,38 Similar to mice 35 and humans 39 with ferrochelatase mutations, IRP2 Ϫ/Ϫ mice develop numerous skin and eye lesions (S.S.C., E.G.M.-H., H.O.-W., M.C.G., and T.A.R., unpublished observations made from 1999 to the present) that could possibly be caused by pruritus associated with release of protoporphyrin IX from red cells, as total protoporphyrin IX levels in serum and liver of IRP2 Ϫ/Ϫ mice were elevated.…”

Section: Discussionmentioning

confidence: 99%

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

Cooperman

Meyron-Holtz

Olivierre-Wilson

et al. 2005

Blood

203

198

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Iron-regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of transferrin receptor (TfR), ferritin, and other iron metabolism proteins. Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal iron metabolism in IRP2 ؊/؊ mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in ironlimited erythropoiesis. TfR expression in erythroid precursors of IRP2 ؊/؊ mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRPdependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2 ؊/؊ erythroid cells. IRP2 IntroductionIron functions as an indispensable cofactor for numerous enzymes and proteins in mammals, and regulation of iron uptake and distribution within animals is accordingly highly regulated. 1,2 Intestinal iron absorption and tissue iron storage are optimized to deliver the iron needed for numerous metabolic processes, including heme synthesis. The recently identified peptide hormone, hepcidin, is responsible for appropriately coordinating intestinal iron uptake and macrophage iron release to meet the needs of the organism and to maintain normal serum transferrin saturation levels. 3 In most tissues, the circulating pool of diferric transferrin serves as the major source of iron for individual cells. When diferric transferrin (Tf) binds to transferrin receptors (TfRs), the Tf-TfR complex internalizes in endosomes, where acidification facilitates release of free iron, 4 and the membrane iron transporter divalent metal transporter 1 (DMT1) (SLC11A2) transports iron into the cytosol. 5,6 In the cytosol, iron is incorporated into iron proteins or transported to cellular organelles, and excess cytosolic iron is sequestered and stored by ferritin. 6,7 Cells regulate expression of ferritin and TfR to optimize cytosolic iron levels. When cells are iron depleted, they increase TfR expression and uptake of transferrinbound iron, while they simultaneously decrease expression of ferritin and iron sequestration. Proteins known as iron regulatory proteins (IRPs) coordinately regulate expression of TfR, ferritin, and numerous other iron metabolism proteins. IRP1 and IRP2 are homologous genes that monitor cytosolic iron levels. When cells are iron depleted, IRPs bind to RNA motifs known as iron-responsive elements (IREs) within transcripts that encode iron metabolism proteins (reviewed in Rouault and Klausner 1 ; and Hentze et al 2 ). IREs are found in numerous transcripts, including ferritin H-and L-chains, TfR1, 7 erythrocyti...

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Section: Discussionmentioning

confidence: 99%

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

Cooperman

Meyron-Holtz

Olivierre-Wilson

et al. 2005

Blood

203

198

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“…112 FECH deficiency leads to accumulation of PPIX in normoblasts, erythrocytes, plasma, skin, and liver, causing lifelong acute photosensitivity and, in approximately 2% of patients, severe liver disease. Rademakers et al 113 conducted an ultrastructural examination of the bone marrow and consistently found finely dispersed electron-dense deposits (iron) localized in mithocondria of erythroblasts in patients with EPP, although these observations have never been confirmed. As molecular mechanisms continue to be identified, phenotype/genotype correlations should become apparent, and it may eventually be possible to identify those patients at risk of developing hepatic failure.…”

Section: Erythropoietic Protoporphyriamentioning

confidence: 99%

Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis

Iolascon¹,

Falco²,

Beaumont³

2009

Haematologica

134

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© F e r r a t a S t o r t i F o u n d a t i o nAIn this paper we will review the new information available on the iron acquisition pathway by developing erythrocytes and its regulation, and we will consider only inherited microcytosis due to heme synthesis or to iron metabolism defects. Iron and erythropoiesis Iron acquisition pathway in erythroid cellsDeveloping erythroid cells in the bone marrow acquire iron from the plasma iron-transferrin (Tf) complex, through the transferrin receptor (TfR) mediated pathway ( Figure 1). All proliferating cells express transferrin receptors on their cell surface at levels varying from 10 3 to 10 5 molecules per cell. Erythroid precursors, which have an extraordinary requirement for iron to allow for production of hemoglobin, may have over 10 6 transferrin receptors per cell.3 The transferrin-Fe(III) complex in plasma is transported into cells principally through transferrin receptor 1 (TfR1), which is expressed on all dividing cells and is particularly abundant on erythroid precursors. TfR2, encoded by a different gene, is expressed primarily in the liver and binds the transferrin-Fe(III) complex at a much lower affinity than TfR1 and appears to be a signaling molecule rather than an iron transporter. 4 At the pH of the cell surface, TfR1 binds only diferric transferrin. The Tf-Fe(III)/TfR1 complex is internalized into a clathrin-coated pit that, assisted by an adaptor protein complex designated AP-2, 5 rapidly matures to a proton-pumping, pH-lowering endosome. At the lowered pH, iron is released from Tf and subsequently reduced to Fe(II) and transported across the endosomal membrane by Divalent Metal Transporter 1 (DMT1).6 DMT1/Nramp2, a member of the Natural Resistance-Associated-Macrophage Protein (Nramp) family, is a proton-coupled divalent metal transporter found at the plasma membrane and in endosomes of cells of both the duodenum and peripheral tissues. Iron-depleted Tf is then returned to the cell surface where, again encountering a pH of 7.4, the protein is released for another cycle of iron transport. Recently, Steap3 (6-transmembrane epithelial antigen of the prostate 3), an endosomal ferrireductase that facilitates Tf-mediated uptake of iron in erythroid precursors has been identified. 8Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tfbound iron uptake. Erythroid cells from mice deficient in Steap3 (nm1054) are defective in Tf-dependent iron uptake, resulting in a hypochromic, microcytic anemia typical of iron deficiency 9 whereas overexpression of Steap3 stimulates the reduction of iron. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells. However, nml054 and Steap3 −/− erythroid precursors retain some residual ferrireductase as well as iron uptake activity, indicating that there are other ways of reducing iron in the Tf-cycle endosome and/or that there are other endosomal iron transporters that are not res...

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“…[40][41][42][43][44] In one report of patients with decreased ferrochelatase activity, the nature of the defect was not reported. 42 However, it would be expected that for the 2 patients with a reported chromosome 18 deletion, the lowered activity results from the loss of one ferrochelatase allele because the gene is located on 18q21.3.…”

Section: Org Frommentioning

confidence: 99%

Production and characterization of erythropoietic protoporphyric heterodimeric ferrochelatases

Najahi‐Missaoui

Dailey

2005

Blood

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Mutations resulting in diminished activity of the dimeric enzyme ferrochelatase are a prerequisite for the inherited disorder erythropoietic protoporphyria (EPP). Patients with clinical EPP have only 10% to 30% of normal levels of ferrochelatase activity, and although many patients with EPP have one mutant allele and one "low-expression" normal allele, the possibility remains that, for some, low ferrochelatase activity may result from an EPP mutation that has an impact on both subunits of the wild-type/mutant heterodimer. Here we present data for 12 ferrochelatase wild-type/EPP mutant heterodimers showing that some mutations result in heterodimers with the residual activity anticipated from individual constituents, whereas others result in heterodimers with significantly lower activity than would be predicted. Although the data do not allow an a priori prediction of heterodimeric residual activity based solely on the in vitro activity of EPP homodimers or the position of the mutated residue within ferrochelatase, mutations that affect the dimer interface or [2Fe-2S] cluster have a significantly greater impact on residual activity than would be predicted. These data suggest that some EPP mutations may result in clinically overt EPP in the absence of a low-expression, wild-type allele; this is of potential significance for genetic counseling of patients with EPP. (Blood. 2005;106:1098-1104)

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Accumulation of iron in erythroblasts of patients with erythropoietic protoporphyria

Cited by 57 publications

References 37 publications

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis

Production and characterization of erythropoietic protoporphyric heterodimeric ferrochelatases

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