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Blood, 1 August 2005, Vol. 106, No. 3, pp. 1084-1091. Prepublished online as a Blood First Edition Paper on April 14, 2005; DOI 10.1182/blood-2004-12-4703. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-12-4703v1 106/3/1084    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cooperman, S. S. Articles by Rouault, T. A. Search for Related Content PubMed PubMed Citation Articles by Cooperman, S. S. Articles by Rouault, T. A. Related Collections Red Cells Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2 Sharon S. Cooperman, Esther G. Meyron-Holtz, Hayden Olivierre-Wilson, Manik C. Ghosh, Joseph P. McConnell, and Tracey A. Rouault From the National Institute of Child Health and Human Development, Bethesda, MD; and The Mayo Clinic and Foundation, Rochester, MN. 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 iron-limited 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 IRP-dependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2-/- erythroid cells. IRP2-/- mice represent a new paradigm of genetic microcytic anemia. We postulate that IRP2 mutations or deletions may be a cause of refractory microcytic anemia and bone marrow iron depletion in patients with normal transferrin saturations, elevated serum ferritins, elevated red cell protoporphyrin IX levels, and adult-onset neurodegeneration. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Iron regulatory protein 2 and anemia Victor R. Gordeuk Blood 2005 106: 774-775. [Full Text] [PDF] This article has been cited by other articles: K. B. Zumbrennen, M. L. Wallander, S. J. Romney, and E. A. Leibold Cysteine Oxidation Regulates the RNA-Binding Activity of Iron Regulatory Protein 2 Mol. Cell. Biol., April 15, 2009; 29(8): 2219 - 2229. [Abstract] [Full Text] [PDF] A. Iolascon, L. De Falco, and C. Beaumont Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis Haematologica, March 1, 2009; 94(3): 395 - 408. [Abstract] [Full Text] [PDF] D. 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