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Articles

Molecular basis of hereditary iron homeostasis defects

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Pages 96-111 | Published online: 18 Jul 2013

References

  • Priwitzerova M, Pospisilova D, Prchal JT et al. Severe hypochromic microcytic anemia caused by a congenital defect of the iron transport pathway in erythroid cells. Blood 2004; 103: 3991–3992.
  • Mims MP, Guan Y, Pospisilova D et al. Identification of ahuman mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 2005; 105: 1337–1342.
  • Priwitzerova M, Nie G, Sheftel AD, Pospisilova D, Divoky V, Ponka P. Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake. Blood 2005; 106: 3985–3987.
  • Cammack R, Wrigglesworth JH, Baum H. Iron-dependentenzymes in mammalian systems. In: Ponka P, Schulman HM, Woodworth RD. (eds) Iron transport and storage. Boca Raton, FL: CRC, 1990; 17–40.
  • Koury MJ, Ponka P. New insights into erythropoiesis: the roles offolate, vitamin B12, and iron. Annu Rev Nutr 2004; 24: 105–131.
  • Shayeghi M, Latunde-Dada GO, Oakhill JS et al. Identification of an intestinal heme transporter. Cell 2005; 122: 789–801.
  • Qiu A, Jansen M, Sakaris A et al. Identification of an intestinalfolate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006; 127: 917–928.
  • Boni RE, Huch Boni RA, Galbraith RA, Drummond GS, Kappas A. Tin-mesoporphyrin inhibits heme oxygenase activity and heme-iron absorption in the intestine. Pharmacology 1993; 47: 318–329.
  • McKie AT, Barrow D, Latunde-Dada GO et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001; 291: 1755–1759.
  • Gunshin H, Starr CN, Direnzo C et al. Cybrdl (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 2005; 106: 2879–2883.
  • Fleming MD, Trenor CC III, Su MA et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997; 16: 383–386.
  • Gunshin H, Mackenzie B, Berger UV et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388: 482–488.
  • Garrick LM, Gniecko K, Hoke JE, Al-Nakeeb A, Ponka P, Garrick MD. Ferric-salicylaldehyde isonicotinoyl hydrazone, a synthetic iron chelate, alleviates defective iron utilization by reticulocytes of the Belgrade rat. J Cell Physiol 1991; 146: 460–465.
  • Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slcl 1 a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005; 115: 1258–1266.
  • Harrison PM, Arosio P. The ferritins: molecular properties, ironstorage function and cellular regulation. Biochim Biophys Acta 1996; 1275: 161–203.
  • Abboud S, Haile DJ. A novel mammalian iron-regulated proteininvolved in intracellular iron metabolism. J Biol Chem 2000; 275: 19906–19912.
  • Donovan A, Brownlie A, Zhou Y et al. Positional cloning of zebrafish ferroportinl identifies a conserved vertebrate iron exporter. Nature 2000; 403:776–781.
  • McKie AT, Marciani P, Rolfs A et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000; 5: 299–309.
  • Donovan A, Lima CA, Pinkus JL et al. The iron exporter ferroportin/S1c40a1 is essential for iron homeostasis. Cell Metab 2005; 1: 191–200.
  • Vulpe CD, Kuo YM, Murphy TL et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the SLA mouse. Nat Genet 1999; 21: 195–199.
  • Ponka P. Tissue-specific regulation of iron metabolism and hemesynthesis: distinct control mechanisms in erythroid cells. Blood 1997; 89: 1–25.
  • Trenor CC, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood 2000; 96: 1113–1118.
  • Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 1999; 21: 396–399.
  • Ohgami RS, Campagna DR, Greer EL et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 2005; 37: 1264–1269.
  • Shaw GC, Cope JJ, Li L et al. Mitoferrin is essential for erythroidiron assimilation. Nature 2006; 440: 96–100.
  • Ajioka RS, Phillips JD, Kushner JP. Biosynthesis of heme in mammals. Biochim Biophys Acta 2006; 1763: 723–736.
  • Paw BH, Shaw GC, Cope JJ et al. Frascati, a mitochondrial solute transporter, and its role in vertebrate erythropoiesis. Blood (ASH Annu Meet Abstr) 2004; 104: 49.
  • Zhang AS, Sheftel AD, Ponka P. Intracellular kinetics of iron inreticulocytes: evidence for endosome involvement in iron target-ing to mitochondria. Blood 2005; 105: 368–375.
  • Sheftel AD, Zhang AS, Brown C, Shirihai OS, Ponka P. Direct interorganellar transfer of iron from endosome to mitochondrion. Blood 2007; 110: 125–132.
  • White RA, Boydston LA, Brookshier TR et al. Iron metabolism mutant hbd mice have a deletion in Sec1511, which has homology to a yeast gene for vesicle docking. Genomics 2005; 86: 668–673.
  • Lim JE, Jin O, Bennett C et al. A mutation in Sec1511 causes anemia in hemoglobin deficit (hbd) mice. Nat Genet 2005; 37: 1270–1273.
  • Brenner DA, Didier JM, Frasier F, Christensen SR, Evans GA, Dailey HA. A molecular defect in human protoporphyria. Am J Hum Genet 1992; 50: 1203–1210.
  • Rees DC, Johnson E, Lewinson O. ABC transporters: the powerto change. Nat Rev Mol Cell Biol 2009; 10: 218–227.
  • Lill R, Mühlenhoff U. Maturation of iron-sulfur proteins in eukaryotes: mechanisms, connected processes, and diseases. Annu Rev Biochem 2008; 77: 669–700.
  • Camaschella C, Campanella A, de Falco L et al. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood 2007; 110: 1353–1358.
  • Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 1997; 94: 10919–10924.
  • Jabado N, Canonne-Hergaux F, Gruenheid S, Picard V, Gros P.Iron transporter Nramp2/DMT-1 is associated with the mem-brane of phagosomes in macrophages and Sertoli cells. Blood 2002; 100: 2617–2622.
  • Soe-Lin S, Apte SS, Andriopoulos B Jr et al. Nrampl promotesefficient macrophage recycling of iron following erythrophago-cytosis in vivo. Proc Natl Acad Sci USA 2009; 106: 5960–5965.
  • Harris ZL, Durley AP, Man TK, Gitlin JD. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 1999; 96: 10812–10817.
  • Ganz T, Nemeth E. Regulation of iron acquisition and iron distribution in mammals. Biochim Biophys Acta 2006; 1763: 690–699.
  • Muckenthaler MU, Galy B, Hentze MW. Systemic iron home-ostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 2008; 28: 197–213.
  • Eisenstein RS, Blemings KP. Iron regulatory proteins, iron responsive elements and iron homeostasis. J Nutr 1998; 128: 2295–2298.
  • Iwai K, Drake SK, Wehr NB et al. Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins. Proc Natl Acad Sci USA 1998; 95: 4924–4928.
  • Kaptain S, Downey WE, Tang C et al. A regulated RNA bindingprotein also possesses aconitase activity. Proc Natl Acad Sci USA 1991; 88: 10109–10113.
  • Cairo G, Pietrangelo A. Iron regulatory proteins in pathobiology.Biochem J 2000; 352: 241–250.
  • Ishikawa H, Kato M, Hon IH et al. Involvement of hemeregulatory motif in heme-mediated ubiquitination and degrada-tion of IRP2. Mol Cell 2005; 19: 171–181.
  • Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA. Microcytic anemia, erythro-poietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood 2005; 106: 1084–1091.
  • Galy B, Miter SM, Klopstock T et al. Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat Genet 2006; 38: 967–969.
  • LaVaute T, Smith S, Cooperman S et al. Targeted deletion of thegene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 2001; 27: 209–214.
  • Meyron-Holtz EG, Ghosh MC, Iwai K et al. Genetic ablations ofiron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J 2004; 23: 386–395.
  • Smith SR, Ghosh MC, Ollivierre-Wilson H, Tong WH, Rouault TA. Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. Blood Cells Mol Dis 2006; 36: 283–287.
  • Galy B, Ferring-Appel D, Kaden S, Gröne HJ, Hentze MW. Ironregulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab 2008; 7: 79–85.
  • Sanchez M, Galy B, Muckenthale MU, Hentze MW. Iron regulatory proteins limit hypoxia-inducible factor-2a expression in iron deficiency. Nat Struct Mol Biol 2007; 14: 420–426.
  • Semenza GL. Involvement of oxygen-sensing pathways in physiological and pathological erythropoiesis. Blood 2009; 114: 2015–2019.
  • Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proc Natl Acad Sci USA 1991; 88: 5680–5684.
  • Patel SA, Simon MC. Biology of hypoxia-inducible factor 2a indevelopment and disease. Cell Death Differ 2008; 15: 628–634.
  • Yoon D, Pastore YD, Divoky V et al. Hypoxia-inducible factor-1deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. J Biol Chem 2006; 281: 25703–25711.
  • Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2a, but not HIF-1a, promotes iron absorption in mice. J Clin Invest 2009; 119: 1159–1166.
  • Ganz T. Hepcidin in iron metabolism. Curr Opin Hematol 2004;11: 251–254.
  • Levi S, Corsi B, Bosisio M et al. A human mitochondrial ferritinencoded by an intronless gene. J Biol Chem 2001; 276: 24437–24440.
  • Santambrogio P, Biasiotto G, Sanvito F, Olivieri S, Arosio P, Levi S. Mitochondrial ferritin expression in adult mouse tissues. J Histochem Cytochem 2007; 55: 1129–1137.
  • Cazzola M, Invernizzi R, Bergamaschi G et al. Mitochondrial ferritin expression in erythroid cells from patients with side-roblastic anemia. Blood 2003; 101: 1996–2000.
  • Bishop DF, Kitchen H, Wood WA. Evidence for erythroid and nonerythroid forms of delta-aminolevulinate synthase. Arch Biochem Biophys 1981; 206: 380–391.
  • Dierks P. Molecular biology of eukaryotic delta-aminolevulinatesynthase. In: Dailey HA. (ed) Biosynthesis of heme and chlorophylls. New York: McGraw-Hill, 1990; 201–233.
  • Schranzhofer M, Schifrer M, Cabrera JA et al. Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood 2006; 107: 4159–4167.
  • Welch JJ, Watts JA, Vakoc CR et al. Global regulation of erythroid gene expression by transcription factor GATA-1. Blood 2004; 104: 3136–3147.
  • Hardison R. Organization, evolution, and regulation of the globin genes. In: Steinberg MH, Forget BG, Higgs D, Nagel RL. (eds) Disorders of hemoglobin: genetics, pathophysiology and clinical management. 1st edn. Cambridge: University Press, 2001; 95–117.
  • Ney PA, Sorrentino BP, Lowrey CH, Nienhuis AW. Inducibilityof the HS II enhancer depends on binding of an erythroid specific nuclear protein. Nucleic Acids Res 1990; 18: 6011–6017.
  • Chen JJ. Regulation of protein synthesis by the heme-regulatedeIF2a kinase: relevance to anemias. Blood 2007; 109: 2693–2699.
  • Chefalo PJ, Oh J, Rafie-Kolpin M, Kan B, Chen JJ. Heme-regulated eIF-2a kinase purifies as a hemoprotein. Eur J Biochem 1998; 258: 820–830.
  • Rafie-Kolpin M, Chefalo PJ, Hussain Z et al. Two heme-bindingdomains of heme-regulated eukaryotic initiation factor-2a kinase. N terminus and kinase insertion. J Biol Chem 2000; 275: 5171–5178.
  • Uma S, Matts RL, Guo Y, White S, Chen JJ. The N-terminal region of the heme-regulated eIF2a kinase is an autonomous heme binding domain. Eur J Biochem 2000; 267: 498–506.
  • Jarman AP, Wood WG, Sharpe JA, Gourdon G, Ayyub H, Higgs DR. Characterization of the major regulatory element upstream of the human alpha-globin gene cluster. Mol Cell Biol 1991; 11: 4679–4689.
  • Sun J, Brand M, Zenke Y, Tashiro S, Groudine M, Igarashi K. Heme regulates the dynamic exchange of Bachl and NF-E2-related factors in the Maf transcription factor network. Proc Natl Acad Sci USA 2004; 101: 1461–1466.
  • Reichard JF, Motz GT, Puga A. Heme oxygenase-1 induction byNRF2 requires inactivation of the transcriptional repressor BACH1. Nucleic Acids Res 2007; 35: 7074–7086.
  • Fukuda Y, Fujita H, Garbaczewski L, Sassa S. Regulation of beta-globin mRNA accumulation by heme in dimethyl sulfoxide (DMS0)-sensitive and DMSO-resistant murine erythroleukemia cells. Blood 1994; 83: 1662–1667.
  • Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide the first report synthesized in the liver. J Biol Chem 2001; 276: 7806–7810.
  • Nicolas G, Bennoun M, Devaux I et al. Lack of hepcidin geneexpression and severe tissue iron overload in upstream stimula-tory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001; 98: 8780–8785.
  • Viatte L, Lesbordes-Brion JC, Lou DQ et al. Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood 2005; 105: 4861–4864.
  • Nicolas G, Bennoun M, Porteu A et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002; 99: 4596–4601.
  • Nemeth E, Tuttle MS, Powelson J et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090–2093.
  • Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 2005; 106: 3979–3984.
  • Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflamma-tion, is a type II acute-phase protein. Blood 2003; 101: 2461–2463.
  • Pigeon C, Ilyin G, Courselaud B et al. A new mouse liver-specificgene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276: 7811–7819.
  • Nicolas G, Chauvet C, Viatte L et al. The gene encoding the ironregulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110: 1037–1044.
  • Finch C. Regulators of iron balance in humans. Blood 1994; 84:1697–1702.
  • Papanikolaou G, Tzilianos M, Christakis JI et al. Hepcidin in iron overload disorders. Blood 2005; 105: 4103–4105.
  • Tanno T, Bhanu NV, Oneal PA et al. High levels of GDF15 inthalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13: 1096–1101.
  • Kanda J, Mizumoto C, Kawabata H et al. Serum hepcidin leveland erythropoietic activity after hematopoietic stem cell trans-plantation. Haematologica 2008; 93: 1550–1554.
  • Tanno T, Porayette P, Sripichai O et al. Identification of TWSG1as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 2009; 114: 181–186.
  • Fleming RE, Ahmann JR, Migas MC et al. Targeted mutagenesisof the murine transferrin receptor-2 gene produces hemochroma-tosis. Proc Natl Acad Sci USA 2002; 99: 10653–10658.
  • Salter-Cid L, Brunmark A, Li Y et al. Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci USA 1999; 96: 5434–5439.
  • Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidinmRNA by soluble and cell-associated hemojuvelin. Blood 2005; 106: 2884–2889.
  • Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest 2005; 115: 2187–2191.
  • Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 2005; 115: 2180–2186.
  • Babitt JL, Huang FW, Wrighting DM et al. Bone morphogeneticprotein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006; 38: 531–539.
  • Wang RH, Li C, Xu X et al. A role of SMAD4 in iron metabolismthrough the positive regulation of hepcidin expression. Cell Metab 2005; 2: 399–409.
  • Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem 2007; 282: 12547–12556.
  • Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 2008; 111: 924–931.
  • Peyssonnaux C, Zinkernagel AS, Schuepbach RA et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007; 117: 1926–1932.
  • Andriopoulos B Jr, Corradini E, Xia Y et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabo-lism. Nat Gen 2009; 41: 482–487.
  • Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Gen 2009; 41: 478–481.
  • Kautz L, Meynard D, Monnier A et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id], and Atoh8 in the mouse liver. Blood 2008; 112: 1503–1509.
  • Constante M, Jiang WL, Wang DM, Raymond VA, Bilodeau M, Santos MM. Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation. Am J Physiol Gastrointest Liver Physiol 2006; 291: G229–237
  • Kawabata H, Fleming RE, Gui D et al. Expression of hepcidin is downregulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 2005; 105: 376–381.
  • Pietrangelo A, Caleffi A, Henrion J et al. Juvenile hemochroma-tosis associated with pathogenic mutations of adult hemochro-matosis genes. Gastroenterology 2005; 128: 470–479.
  • Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009; 9: 217–227.
  • Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 2004; 104: 4287–4293.
  • Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood 2004; 104: 4294–4299.
  • Johnson MB, Chen J, Murchison N, Green FA, Enns CA. Transferrin receptor 2: evidence for ligand-induced stabilization and redirection to a recycling pathway. Mol Biol Cell 2007; 18: 743–754.
  • Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regula-tion of hepcidin expression. Cell Metab 2008; 7: 205–214.
  • Chen J, Chloupkova M, Gao J, Chapman-Arvedson TL, Enns CA. HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1/HFE interactions. J Biol Chem 2007; 282: 36862–36870.
  • Lee PL, Beutler E. Regulation of hepcidin and iron-overload disease. Annu Rev Pathol Mech Dis 2009; 4: 489–515.
  • Corradini E, Garuti C, Montosi G et al. Bone morphogenetic protein signaling is impaired in an Hfe knockout mouse model of hemochromatosis. Gastroenterology 2009; 137: 1489–1497.
  • Du X, She E, Gelbart T et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008; 320: 1088–1092.
  • Silvestri L, Pagani A, Nai A, de Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 2008; 8: 502–511.
  • Nemeth E, Rivera S, Gabayan V et al. IL-6 mediates hypoferre-mia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113: 1271–1276.
  • Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006; 108: 3204–3209.
  • Ganz T. Molecular pathogenesis of anemia of chronic disease. Pediatr Blood Cancer 2006; 46: 554–557.
  • Lee PL, Peng H, Gelbart T, Beutler E. The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE, transferrin receptor-2, and (12 microglobulin deficient hepato-cytes. Proc Natl Acad Sci USA 2004; 101: 9263–9265.
  • Frazer DM, Wilkins SJ, Millard KN et al. Increased hepcidin expression and hypoferritaemia associated with an acute phase response are not affected by inactivation of HFE. Br J Haematol 2004; 126: 434–436.
  • Feder JN, Gnirke A, Thomas W et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13: 399–408.
  • Pietrangelo A. Hereditary hemochromatosis - a new look at an old disease. N Engl J Med 2004; 350: 2383–2397.
  • Papanikolaou G, Samuels ME, Ludwig EH et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004; 36: 77–82.
  • Roetto A, Papanikolaou G, Politou M et al. Mutant antimicro-bial peptide hepcidin is associated with severe juvenile hemo-chromatosis. Nat Genet 2003; 33: 21–22.
  • Camaschella C, Roetto A, Cali A et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000; 25: 14–15.
  • Fleming RE, Britton RS, Waheed A, Sly WS, Bacon BR. Pathophysiology of hereditary hemochromatosis. Semin Liver Dis 2005; 25: 411–419.
  • Waheed A, Parkkila S, Zhou XY et al. Hereditary hemochroma-tosis: effects of C282Y and H63D mutations on association with #2-microglobulin, intracellular processing, and cell surface expres-sion of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997; 94: 12384–12389.
  • Piperno A, Roetto A, Mariani R et al. Homozygosity for transferrin receptor-2 Y250X mutation induces early iron over-load. Haematologica 2004; 89: 359–360.
  • Montosi G, Donovan A, Totaro A et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001; 108: 619–623.
  • Wallace DF, Pedersen P, Dixon JL et al. Novel mutation in ferroportinl is associated with autosomal dominant hemochro-matosis. Blood 2002; 100: 692–694.
  • Schimanski LM, Drakesmith H, Merryweather-Clarke AT et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood 2005; 105: 4096–4102.
  • De Domenico I, Ward DM, Nemeth E et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci USA 2005; 102: 8955–8960.
  • Drakesmith H, Schimanski LM, Ormerod E et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 2005; 106: 1092–1097.
  • Devalia V, Carter K, Walker AP et al. Autosomal dominant reticulo-endothelial iron overload associated with a three base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 2002; 100: 695–697.
  • Cazzola M, Cremonesi L, Papaioannou M et al. Genetic hyperferritinaemia and reticuloendothelial iron overload asso-ciated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3). Br J Haematol 2002; 119: 539–546.
  • Ponka P. Rare causes of hereditary iron overload. Semin Hematol2002; 39: 249–262.
  • Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransfer-rinemia. Blood 2000; 96: 4071–4074.
  • Trenor CC III, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood 2000; 96: 1113–1118.
  • Xu X, Pin S, Gathinji M, Fuchs R, Harris ZL. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci 2004; 1012: 299–305.
  • Iolascon A, d'Apolito M, Servedio V, Cimmino F, Piga A, Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood 2006; 107: 349–354.
  • Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G. Two new human DMTI gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood 2006; 107: 4168–4170.
  • Ponka P, Schulman HM. Acquisition of iron from transferrin regulates reticulocyte heme synthesis. J Biol Chem 1985; 260: 14717–14721.
  • Priwitzerova M, Pospisilova D, Prchal JT et al. The first human mutation of DMT1 (Nramp2) causes severe defect of erythropoi-esis that can be rescued in vitro by Fe-SIH. Blood 2003; 102\(Suppl. 1): 562.
  • Pospisilova D, Mims MP, Nemeth E, Ganz T, Prchal JT. DMT1 mutation: Response of anemia to darbepoetin adminis-tration, implications for iron homeostasis. Blood 2006; 108: 404–405.
  • Iolascon A, Camaschella C, Pospisilova D, Piscopo C, Tchernia G, Beaumont C. Natural history of recessive inheritance of DMT1 mutations. J Pediatr 2008; 152: 136–139.
  • Iolascon A, De Falco L, Beaumont C. Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematologica 2009; 94: 395–408.
  • Blanco E, Kannengiesser C, Grandchamp B, Tasso M, Beaumont C. Not all DMT1 mutations lead to iron overload. Blood Cells Mol Dis 2009; 43: 199–201.
  • Finberg KE, Heeney MM, Campagna DR et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008; 40: 569–571.
  • Bessis MC, Jensen WN. Sideroblastic anaemia, mitochondria and erythroblastic iron. Br J Haematol 1965; 11: 49–51.
  • Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol 2008; 143: 27–38.
  • Cox TC, Bottomley SS, Wiley JS, Bawden MJ, Matthews CS, May BK. X-linked pyridoxine-responsive sideroblastic anemia due to a Thr388-to-Ser substitution in erythroid 5-aminolevuli-nate synthase. N Engl J Med 1994; 330: 675–679.
  • Fleming MD. The genetics of inherited sideroblastic anemias. Semin Hematol 2002; 39: 270–281.
  • Cazzola M, May A, Bergamaschi G, Cerani P, Rosti V, Bishop DF. Familial-skewed X-chromosome inactivation as a predispos-ing factor for late-onset X-linked sideroblastic anemia in carrier females. Blood 2000; 96: 4363–4365.
  • Bekri S, May A, Cotter PD et al. A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia. Blood 2003; 102: 698–704.
  • Bottomley SS. Congenital sideroblastic anemias. Curr Hematol Rep 2006; 5: 41–49.
  • Whatley SD, Ducamp S, Gouya L et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 2008; 83: 408–414.
  • Guernsey DL, Jiang H, Campagna DR et al. Mutations in mitochondrial carrier family gene 5LC25A38 cause nonsyndro-mic autosomal recessive congenital sideroblastic anemia. Nat Gen 2009; 41: 651–653.

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