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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1353-1358. Prepublished online as a Blood First Edition Paper on May 7, 2007; DOI 10.1182/blood-2007-02-072520. This Article Full Text (PDF) Supplemental Methods, Table, and Figure All Versions of this Article: blood-2007-02-072520v1 110/4/1353    most recent Alert me when this article is cited Alert me if a correction is posted 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 Camaschella, C. Articles by Iolascon, A. Search for Related Content PubMed PubMed Citation Articles by Camaschella, C. Articles by Iolascon, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 5, 2007 Accepted April 25, 2007 The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload Clara Camaschella*, Alessandro Campanella, Luigia De Falco, Loredana Boschetto, Roberta Merlini, Laura Silvestri, Sonia Levi, and Achille Iolascon Vita-Salute University, Milan, Italy CEINGE Advanced Biotechnologies, Naples, Italy Department Clinical and Biological Sciences, University of Turin, Turin, Italy IRCCS San Raffaele, Milan, Italy Department of Biochemistry and Medical Biotechnologies, University Federico II, Naples, Italy * Corresponding author; email: camaschella.clara{at}hsr.it. Inherited microcytic-hypochromic anemias in rodents and zebrafish suggest the existence of corresponding human disorders. The zebrafish mutant shiraz has severe anemia and is embryonically lethal because of glutaredoxin 5 (GRLX5) deletion, insufficient biogenesis of mitochondrial iron sulfur (Fe/S) clusters and deregulated Iron-Regulatory-Protein-1 (IRP1) activity. This leads to stabilization of transferring-receptor-1 (TfR) RNA, repression of ferritin and ALA-synthase 2 (ALAS2) translation with impaired heme synthesis. We report the first case of GLRX5 deficiency in a middle-aged anemic male with iron overload and low number of ringed sideroblasts. Anemia was worsened by blood transfusions, but partially reversed by iron chelation. The patient had a homozygous (c.294A>G) mutation, which interferes with intron 1 splicing and drastically reduces GLRX5 RNA. As in shiraz, aconitase and H-ferritin were low and TfR high in patient cells, compatible with increased IRP1 binding. Based on the biochemical and clinical phenotype we hypothesize that IRP2, less degraded by low heme, contributes to erythroblasts ferritin and ALAS2 repression, increasing mitochondrial iron. Iron chelation, redistributing iron to the cytosol, might relief IRP2 excess, improving heme synthesis and anemia. GLRX5 function is highly conserved, but at variance with zebrafish, its defect in humans leads to anemia and iron overload. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Heme/Fe-S intimacies make RBCs blush Carole Beaumont Blood 2007 110: 1085-1086. [Full Text] [PDF] This article has been cited by other articles: Y. Shi, M. C. Ghosh, W.-H. Tong, and T. A. Rouault Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis Hum. Mol. Genet., August 15, 2009; 18(16): 3014 - 3025. [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. Ferring-Appel, M. W. Hentze, and B. Galy Cell-autonomous and systemic context-dependent functions of iron regulatory protein 2 in mammalian iron metabolism Blood, January 15, 2009; 113(3): 679 - 687. [Abstract] [Full Text] [PDF] O. Stehling, D. J. A. Netz, B. Niggemeyer, R. Rosser, R. S. Eisenstein, H. Puccio, A. J. Pierik, and R. Lill Human Nbp35 Is Essential for both Cytosolic Iron-Sulfur Protein Assembly and Iron Homeostasis Mol. Cell. Biol., September 1, 2008; 28(17): 5517 - 5528. [Abstract] [Full Text] [PDF] A. Izquierdo, C. Casas, U. Muhlenhoff, C. H. Lillig, and E. Herrero Saccharomyces cerevisiae Grx6 and Grx7 Are Monothiol Glutaredoxins Associated with the Early Secretory Pathway Eukaryot. Cell, August 1, 2008; 7(8): 1415 - 1426. [Abstract] [Full Text] [PDF] N. C. Andrews Forging a field: the golden age of iron biology Blood, July 15, 2008; 112(2): 219 - 230. [Full Text] [PDF] D. Carradice and G. J. Lieschke Zebrafish in hematology: sushi or science? Blood, April 1, 2008; 111(7): 3331 - 3342. [Abstract] [Full Text] [PDF]

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