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

Abstract

© 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...

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

“…It has been suggested that the EPO-triggered therapeutic improvement of iron-deficiency anemia could be due to the anti-apoptotic effect of EPO. 7,32 The present study confirms this hypothesis. Colony-forming assays showed significantly improved in vitro growth of our patient's DMT1-mutant post-treatment BFU-E progenitors compared to pre-treatment BFU-E pro- genitors.…”

“…19 The possible involvement of any substantial increase in iron utilization by individual erythroid cells as a contributing factor to the positive effects of EPO therapy can be ruled out by the fact that the patients' erythrocyte characteristics (MCV and MCH) remained unchanged with EPO supplementation. 7,32 Our observation of decreased MCV and MCH in the mk/mk mice following EPO treatment further supports this conclusion.…”

Dual‐wavelength excitation for fluorescence‐based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood

“…In the remaining forms of porphyria, erythrocyte non-heme protoporphyrins generally lie within the reference range [13]. Lead and other heavy metal intoxication [15][16][17] and a variety of sideroblastic [18] and inherited microcytic anemias [19] may also be responsible for alterations in erythrocyte PPIX and ZnPP. A recent study found decreased PPIX fluorescence in erythrocytes from diabetic compared to non-diabetic mice, suggesting the possible use of PPIX as a diagnostic marker for monitoring of diabetes [20].…”

Assessment of iron absorption in mice by ICP-MS measurements of 57Fe levels

“…The mouse also represents a unique model to identify novel players in iron homeostasis [7,8,9]. Finally, it has been shown that the occurrence, in mice, of genetic mutations responsible for human iron disorders, for example hemochromatosis and anemia, fully recapitulate the human diseases, thus stressing the importance of mouse models for studying the pathogenetic mechanisms of these diseases and for testing new therapies [10,11].…”