Forging a field: The golden age of iron biology

Blood

Volumn 112, Issue 2, 2008, Pages 219-230

  Andrews, Nancy C ^a,b  

^a DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FERRITIN; FERROPORTIN; HEPCIDIN; IRON; TRANSFERRIN; ANTIMICROBIAL CATIONIC PEPTIDE;

ANEMIA; ARTICLE; HEMOCHROMATOSIS; HOMEOSTASIS; HUMAN; INTESTINE ABSORPTION; IRON ABSORPTION; IRON BALANCE; IRON BINDING CAPACITY; IRON DEFICIENCY ANEMIA; IRON METABOLISM; NONHUMAN; PRIORITY JOURNAL; IRON METABOLISM DISORDER; METABOLISM; REVIEW;

ANTIMICROBIAL CATIONIC PEPTIDES; HOMEOSTASIS; HUMANS; IRON; IRON METABOLISM DISORDERS;

EID: 47649126246     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2007-12-077388     Document Type: Article

References (213)

1. Finch CA, Harker LA, Cook JD. Kinetics of the formed elements of human blood. Blood. 1977; 50:699-707.
2. Josephs HW. Absorption of iron as a problem in human physiology; a critical review. Blood. 1958; 13:1-54.
3. Laufberger V. Sur la cristallisation de la ferritine. Soc Chim Biol. 1937;19:1575-1582.
4. Schade AL, Caroline L. An iron-binding component in human blood plasma. Science. 1948;104: 340-341.
5. Harrison PM, Fischbach FA, Hoy TG, Haggis GH. Ferric oxyhydroxide core of ferritin. Nature. 1967: 216:1188-1190.
6. Munro HN. Back to basics: an evolutionary odyssey with reflections on the nutrition research of tomorrow. Annu Rev Nutr. 1986:6:1-12.
7. Chen TT, Li L Chung DH, et al. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med. 2005;202:955-965.
8. Wixom RL Prutkin L Munro HN. Hemosiderin: nature, formation and significance. Int Rev Exp Pathol. 1980;22:193.
9. Martin AW, Huebers E, Huebers H, Webb J, Finch GA. A mono-sited transferrin from a representative deuterostome: the ascidian Pyura stolonifera (subphylum Urochordata). Blood. 1984;64:1047-1052.
10. Ohgami RS, Gampagna 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.
11. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade 11.(b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci U SA. 1998;95:1148-1153.
12. Fleming MD, Trenor CC 3rd, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383-386.
13. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian protoncoupled metal-ion transporter. Nature. 1997;388: 482-488.
14. Andrews NC. Iron homeostasis: insights from genetics and animal models. Nat Rev Genet. 2000; 1:208-217.
15. Sacher A, Cohen A, Nelson N. Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1 p expressed in Xenopus laevis oocytes. J Exp Biol. 2001;204:1053-1061.
16. Foury F Roganti T. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem. 2002:277:24475-24483.
17. Shaw GC, Cope JJ, Li L, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006; 440:96-100.
18. 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.
19. Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood. 2003;102:3711-3718.
20. Quigley JG, Yang Z, Worthington MT, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell. 2004;118:757-766.
21. Keel SB, Doty RT, Yang Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319:825-828.
22. Aziz N, Munro HN. Iron regulates ferritin mRNA translation through a segment of its 5'- untranslated region. PNAS. 1987;84:8478.
23. Hentze MW, RouaultTA, Caughman SW, Dancis A, Harford JB, Klausner RD. A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci U SA. 1987;84:6730-6734.
24. Casey JL, Hentze MW, Koeller DM, et al. Ironresponsive elements: regulatory RN A sequences that control mRNA levels and translation. Science. 1988;240:924-928.
25. Caughman SW, Hentze MW, RouaultTA, Harford JB, Klausner RD. The iron-responsive element is the single element responsible for iron-dependent translational regulation of ferritin biosynthesis: evidence for function as the binding site for a translational repressor. J Biol Chem. 1988;263: 19048-19052.
26. Hentze MW, Caughman SW, RouaultTA, et al. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science. 1987;238:1570-1573.
27. Leibold EA, Munro HN. Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavyand lightsubunit mRNAs. Proc Natl Acad Sci USA. 1988: 85:2171-2175.
28. Rouault TA, Hentze MW, Caughman SW, Harford JB, Klausner RD. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science. 1988;241:1207-1210.
29. Hentze MW, Argos P. Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase. Nucleic Acids Res. 1991:19:1739-1740.
30. Kaptain S, Downey WE, Tang C, et al. A regulated RNA binding protein also possesses aconitase activity. Proc Natl Acad Sci U S A. 1991;88: 10109-10113.
31. Haile DJ, Rouault TA, Tang CK, Chin J, Harford JB, Klausner RD. Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Proc Natl Acad Sci U S A. 1992;89:7536-7540.
32. Guo B, Phillips JD, Yu Y, Leibold EA. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem. 1995;270:21645-21651.
33. Iwai K, Klausner RD. Rouault TA. Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2. EMBO J. 1995; 14:5350-5357.
34. 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 U S A. 1998;95:4924-4928.
35. Yamanaka K. Ishikawa H, Megumi Y, et al. Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cell Biol. 2003;5:336-340.
36. Wang J, Chen G, Muckenthaler M, Galy B, Hentze MW, Pantopoulos K. Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol. 2004;24:954-965.
37. Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science. 2004;306: 2087-2090.
38. Muckenthaler M, Gray NK, Hentze MW. IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex el F4F. Mol Cell. 1998;2:383-388.
39. Casey JL, Koeller DM, Ramin VC, Klausner RD, Harford JB. Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA. EMBO J. 1989;8: 3693-3699.
40. Leipuviene R, Theil EC. The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen. Cell Mol Life Sci. 2007;64: 2945-2955.
41. Meyron-Holtz EG, Ghosh MC, Iwai K, etal. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 2004;23:386-395.
42. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA. Microcytic anemia, erythropoietic protoporphyria and neurodegeneration in mice with targeted deletion of iron regulatory protein 2. Blood. 2005; 106:1084-1091.
43. Galy B. Ferring D, Minana B, et al. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood. 2005; 106:2580-2589.
44. LaVaute T, Smith S, Cooperman S, et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27:209-214.
45. Galy B, HolterSM, KlopstockT, etal. Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat Genet. 2006;38: 967-969; discussion 969-970.
46. Bonneau D, Winter-Fuseau I, Loiseau MN, et al. Bilateral cataract and high serum ferritin: a new dominant genetic disorder? J Med Genet. 1995; 32:778-779.
47. Girelli D, Corrocher R, Bisceglia L, et al. Molecular basis for the recently described hereditary hyperferritinemiacataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation"). Blood. 1995;86: 4050-4053.
48. Beaumont C, Leneuve P, Devaux I, et al. Mutation in the iron responsive element of the Lferritin mRNA in a family with dominant hyperferritinemia and cataract. Nat Genet. 1995; 11:444-446.
49. Kato J, Fujikawa K, Kanda M, et al. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet. 2001;69:191-197.
50. Mok H, Jelinek J, Pai S, et al. Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. Development. 2004;131:1859-1868.
51. Finch CA, Deubelbeiss K, CookJD, et al. Ferrokinetics in man. Medicine (Baltimore). 1970;49:17-53.
52. Russell ES, Nash DJ, Bernstein SE, etal. Characterization and genetic studies of microcytic anemia in house mouse. Blood. 1970;35:838-850.
53. McKieAT, Barrow D, Latunde-Dada GO, etal. Aniron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291: 1755-1759.
54. McKieAT, 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.
55. Gunshin H, Starr CN, Direnzo C, etal. Cybrdl (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood. 2005;16:16.
56. Ohgami RS, Gampagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood. 2006;108:1388-1394.
57. Hubert N, Hentze MW. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A. 2002;99: 12345-12350.
58. Lam-Yuk-Tseung S, Touret N, Grinstein S, Gros P. Carboxyl-terminus determinants of the iron transporter DMT1/SLC11A2 isoform II (-IRE/1B) mediate internalization from the plasma membrane into recycling endosomes. Biochemistry. 2005;44:12149-12159.
59. Ganonne-Hergaux R, Gruenheid S, Ponka P, Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood. 1999:93:4406-4417.
60. Vidal SM, Malo D, Vogan K, Skamene E, Gros P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell. 1993;73:469-485.
61. Gruenheid S, Pinner E. Desjardins M, Gros P. Natural resistance to infection with intracellular pathogens: the Nrarnpl protein is recruited to the membrane of the phagosome. J Exp Med. 1997; 185:717-730.
62. Rorbes JR. Gros P. Iron, manganese, and cobalt transport by Nrarnpl (Slc11a1) and Nramp2 (Sld 1 a2) expressed at the plasma membrane. Blood. 2003;102:1884-1892.
63. Supek R Supekova L, Nelson H, Nelson N. A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Proc Natl Acad Sci U S A. 1996; 93:5105-5110.
64. Rodrigues V, Cheah PY, Ray K, Chia W. Malvolio, the Drosophila homologue of mouse NRAMP-1 (Bcg), is expressed in macrophages and in the nervous system and is required for normal taste behaviour. EMBO J. 1995;14:3007-3020.
65. Donovan A, Brownlie A, Dorschner MO, et al. The zebrafish mutant gene chardonnay (cdy) encodes divalent metal transporter 1 (DMT1). Blood. 2002; 100:4655-4659.
66. Gunshin H, RujiwaraY, Custodio AO, Direnzo C, Robine S. Andrews NG. Slc11 a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005;115:1258-1266.
67. Barisani D, Berg CL, Wessling-Resnick M, Gollan JL. Evidence for a low Km transporter for nontransferrin-bound iron in isolated rat hepatocytes. Am J Physiol. 1995;269:G570-576.
68. Inman RS, Coughlan MM, Wessling-Resnick M. Extracellular ferrireductase activity of K562 cells is coupled to transferrin-independent iron transport. Biochemistry. 1994;33:11850-11857.
69. Kaplan J, Jordan I, Sturrock A. Regulation of the transferrin-independent iron transport system in cultured cells. J Biol Chem. 1991;266:2997-3004.
70. Parkes JG, Randell EW, Olivieri NR, Templeton DM. Modulation by iron loading and chelation of the uptake of non-transferrin-bound iron by human liver cells. Biochim Biophys Acta. 1995;1243: 373-380.
71. Randell EW, Parkes JG, Olivieri NR, Templeton DM. Uptake of non-transferrin bound iron by both reductive and non-reductive processes is modulated by intracellular iron. J Biol Chem. 1994;269: 16046-16053.
72. Sturrock A. Alexander J, Lamb J, Craven CM, Kaplan J. Characterization of a transferrinindependent uptake system for iron in HeLa cells. J Biol Chem. 1990;265:3139-3145.
73. Oudit GY, Sun H, Trivieri MG.etal. L-type Ca(2+) channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med. 2003;9:1187-1194.
74. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 2002;10:1033-1043.
75. Yang J, Goetz D, Li JY, et al. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002; 10:1045-1056.
76. Devireddy LR, Gazin C, Zhu X, Green MR. A cellsurface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 2005;123: 1293-1305.
77. Abboud S, Haile DJ. Anovel mammalian ironregulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906-19912.
78. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportinl identifies a conserved vertebrate iron exporter. Nature. 2000; 403:776-781.
79. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191-200.
80. Osaki S, Johnson DA. Mobilization of liver iron by ferroxidase (ceruloplasmin). J Biol Chem. 1969; 244:5757-5758.
81. Osaki S, Johnson DA, Rrieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem. 1966;241:2746-2751.
82. Roeser HP, Lee GR, Nacht S, Cartwright GE. The role of ceruloplasmin in iron metabolism. J Glin Invest. 1970;49:2408-2417.
83. 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.
84. De Domenico I, Ward DM, di Patti MC, et al. Peroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823-2831.
85. Askwith C, Eide D, Van HoA, et al. The RET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell. 1994; 76:403-410.
86. Stearman R, Yuan DS, Yamaguchi-lwai Y, Klausner RD, Dancis A. A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science. 1996;271:1552-1557.
87. Shayeghi M, Latunde-Dada GO, Oakhill JS. et al. Identification of an intestinal heme transporter. Cell. 2005;122:789-801.
88. Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917-928.
89. Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004;279:24218-24225.
90. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. REBS Lett. 2000; 480:147-150.
91. Park CH, Valore EV. Waring AJ. Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806-7810.
92. Pigeon C, llyin G, Courselaud B, et al. Anew mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811-7819.
93. Nemeth E, Turtle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093.
94. De Domenico I, Ward DM, Langelier C, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18: 2569-2578.
95. Conrad ME, Crosby WH. Intestinal mucosal mechanisms controlling iron absorption. Blood. 1963:22:406-415.
96. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acutephase protein. Blood. 2003;101:2461-2463.
97. Kemna EH. Tjalsma H, Podust VN, Swinkels DW. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 2007;53:620-628.
98. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2008;40:132-138.
99. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037-1044.
100. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications forthe anemia of chronic disease. Blood. 2002;100:3776-3781.
101. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USR2) knockout mice. Proc Natl Acad Sci U S A. 2001; 98:8780-8785.
102. Lesbordes-Brion JC, Viatte L, Bennoun M, et al. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood. 2006;108: 1402-1405.
103. Nicolas G. Bennoun M. Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99:4596-4601.
104. Roy GN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. 2007;109:4038-4044.
105. Adamsky K, Weizer O, Amariglio N, et al. Decreased hepcidin m RNAexpression in thalassemic mice. Br J Haematol. 2004:124:123-124.
106. Ganz T Hepcidin-a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol. 2006;306:183-198.
107. Wrighting DM, Andrews NC. lnterleukin-6 induces hepcidin expression through STAT3. Blood. 2006; 108:3204-3209.
108. Verga Ralzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109:353-358.
109. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIRs). J Clin Invest. 2007:117:1926-1932.
110. Courselaud B, Pigeon C, Inoue Y, et al. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism: cross-talk between C/EBP pathway and iron metabolism. J Biol Chem. 2002;277:41163-41170.
111. Bayele HK, McArdle H, Srai SK. Cis and trans regulation of hepcidin expression by upstream stimulatory factor. Blood. 2006;108:4237-4245.
112. Weizer-Stern O, Adamsky K, Margalit O, et al. Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. Br J Haematol. 2007;138:253-262.
113. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399-409.
114. Babitt JL, Huang RW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006; 38:531-539.
115. Truksa J, Peng H, Lee P, Beutler E. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br J Haematol. 2007;139:138-147.
116. Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci U S A. 2006;103:10289-10293.
117. Babitt JL. Huang RW, Xia Y. Sidis Y, Andrews NC, Lin HY Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933-1939.
118. Trousseau A. Glycosurie; diabete sucre. Clinique medicale de I'Hotel-Dieu de Paris. 1865;2:663-698.
119. Sheldon JH. Haemochromatosis. London, United Kingdom: Oxford University Press; 1935.
120. Simon M, Bourel M, Fauchet R, Genetet B. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut. 1976;17:332-334.
121. Feder JN, Gnirke A. Thomas W, et al. A novel MHC class l-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996; 13:399-408.
122. Allen KJ, Gurrin LC, Constantino CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221-230.
123. Levy JE, Montross LK, Andrews NC. Genes that modify the hemochromatosis phenotype in mice. J Clin Invest. 2000;105:1209-1216.
124. Sachot S, Moirand R, Jouanolle AM, et al. Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region. Blood Cells Mol Dis. 2001;27:518-529.
125. SprouleTJ, Jazwinska EC, Britton RS, et al. Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice. Proc Natl Acad Sci U S A. 2001;98:5170-5174.
126. Cardoso EM, Macedo MG, Rohrlich P, et al. Increased hepatic iron in mice lacking classical MHC class I molecules. Blood. 2002;100:4239-4241.
127. Bensaid M, Fruchon S, Mazeres C, Bahram S. Roth MP, Coppin H. Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology. 2004;126:1400-1408.
128. Biasiotto G, Roetto A, Daraio F, et al. Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood Cells Mol Dis. 2004;33:338-343.
129. Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood. 2004; 103:2835-2840.
130. Le Gac G, Scotet V, Ka C, et al. The recently identified type 2Ajuvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet. 2004;13:1913-1918.
131. Nicolas G, Andrews NC, Kahn A, Vaulont S. Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice. Blood. 2004;103:2841-2843.
132. Tolosano E, Fagoonee S, Garuti C, et al. Haptoglobin modifies the hemochromatosis phenotype in mice. Blood. 2004;105:3353-3355.
133. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood. 2005;106:3710-3717.
134. Merryweather-Clarke AT, Cadet E, Bomford A, et al. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet. 2003;12:2241-2247.
135. Wang F, Paradkar PN, Custodio AO, et al. Genetic variation in Mon 1 a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet. 2007;39:1025-1032.
136. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361:669-673.
137. Nemeth E, Roetto A, Garozzo G, GanzT, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105:1803-1806.
138. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1 q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77-82.
139. Papanikolaou G, Tzilianos M, Christakis J I, et al. Hepcidin in iron overload disorders. Blood. 2005; 105:4103-4105.
140. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115:2187-2191.
141. Kawabata H, Fleming RE, Gui D, et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 2005;105:376-381.
142. Muckenthaler M, Roy CN, Custodio AO, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrdl expression in mouse hemochromatosis. Nat Genet. 2003;34: 102-107.
143. Nicolas G, Viatte L, Lou DQ, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 2003;34:97-101.
144. NiederkoflerV, 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.
145. Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93:111-123.
146. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U SA. 1998;95: 1472-1477.
147. Parkkila S, Waheed A, Britton RS, et al. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 1997;94:13198-13202.
148. Roy CN, Enns CA. Iron homeostasis: new tales from the crypt. Blood. 2000;96:4020-4027.
149. Schmidt PJ. Toran PT. Giannetti AM. Bjorkman PJ, Andrews NC The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7:205-214.
150. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281: 28494-28498.
151. Chen J, Enns GA. The cytoplasmic domain of transferrin receptor 2 dictates its stability and response to holo-transferrin in Hep3B cells. J Biol Chem. 2007;282:6201-6209.
152. Kawabata H, Yang R, HiramaT, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem. 1999;274:20826-20832.
153. 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.
154. Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood. 2004;104:4294-4299.
155. Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood. 2004:104:4287-4293.
156. Montosi G, Donovan A, Totaro A, et al. Autosomal-do mi n ant hemochromatosis is associated with a mutation in the ferroportin (SLC11 A3) gene. J Clin Invest. 2001;108:619-623.
157. Njajou OT, Vaessen N, Joosse M, et al. Amutation in SLC11 A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28: 213-214.
158. De Domenico I, Ward DM, Nemeth E, et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci U S A. 2005;102: 8955-8960.
159. Drakesmith H, Schimanski LM, Ormerod E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood. 2005;106:1092-1097.
160. Zohn IE, De Domenico I, Pollock A, et al. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood. 2007;109:4174-4180.
161. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33:21-22.
162. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosisassociated FPN mutations. Blood. 2005;105: 4096-4102.
163. Beutler E. History of iron in medicine. Blood Cells Mol Dis. 2002;29:297-308.
164. Blaud P. Sur les maladies chlorotiques et sur un mode de traitement specifique dans ces affections. Rev Med Franc Etrang. 1832;45:357-367.
165. Heath CW, Strauss MB, Castle WB. Quantitative aspects of iron deficiency in hypochromic anemia. J Clin Invest. 1932;11:1293-1312.
166. Carnicer J, Badia R, Argemi J. Helicobacter pylori gastritis and sideropenic refractory anemia. J Pediatr Gastroenterol Nutr. 1997;25:441.
167. Marignani M, Angeletti S, Bordi C, etal. Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection. Scand J Gastroenterol. 1997;32:617-622.
168. Hershko C, Patz J, Ronson A. The anemia of achylia gastrica revisited. Blood Cells Mol Dis. 2007;39:178-183.
169. Faber K. Achylia gastrica mit Anamie. MedizinisheKlinik. 1909;5:1310-1325.
170. Wintrobe MM, Beebe RT. Idiopathic hypocrhomic anemia. Medicine. 1933;12:187-243.
171. 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.
172. Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005:105:1337-1342.
173. 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.
174. Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood. 2006;107:4168-4170.
175. lolascon A, d'Apolito M, Servedio V, Cimmino F, Piga A, Gamaschella G. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006;107:349-354.
176. Lam-Yuk-Tseung S, Camaschella C, lolascon A, Gros P. A novel R4 16C mutation in human DMT1 (SLC11 A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Blood Cells Mol Dis. 2006;36:347-354.
177. Wingert RA, Galloway JL, Barut B, et al. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature. 2005;436:1035-1039.
178. Beutler E, Gelbart T Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood. 2000;96:4071-4074.
179. Trenor CC 3rd, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood. 2000;96:1113-1118.
180. Heilmeyer L, Keller W, Vivell O, et al. Congenital transferrin deficiency in a seven-year old girl. German Medical Monthly. 1961;86:1745-1751.
181. Goya N, Miyazaki S, Kodate S, Ushio B. Afamily of congenital atransferrinemia. Blood. 1972;40: 239-245.
182. Bernstein SE. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med. 110:690-705.
183. Hamill RL, Woods JC, Cook BA. Congenital atransferrinemia: a case report and review of the literature. Am J Clin Pathol. 1991;96:215-218.
184. Harris ZL. Takahashi Y, Miyajima H. Serizawa M, MacGillivray RT, Gitlin JD. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A. 1995;92: 2539-2543.
185. Buchanan DD, Silburn PA, Chalk JB, Le Couteur DG, Mellick GD. The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients. Neurosci Lett. 2002;327:91-94.
186. Hartman KR, Barker JA. Microcytic anemia with iron malabsorption: an inherited disorder of iron metabolism. Am J Hematol. 1996;51:269-275.
187. Parsons SK, Fleming MD, Nathan DG, Andrews NC. Iron deficiency anemia associated with an error of iron metabolism in two siblings: a thirty year follow up. Hematology. 1996:1:65-73.
188. Pearson HA. Lukens JN. Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J Pediatr Hematol Oncol. 1999;21:412-417.
189. Mayo MM, Samuel SM. Iron deficiency anemia due to a defect in iron metabolism: a case report. Clin Lab Sci. 2001; 14:135-138.
190. Finberg KA, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008. Prepublished on April 13, 2008 as DOI 10.1038/ug,130.
191. Andrews NC, Fleming M D. Commentary on: ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J Pediatr Hematol Oncol. 1999;21:353-355.
192. Beutler E, Lee P, Gelbart T, et al. The Mask mutation identifies TMPRSS6 as an essential suppressor of hepcidin gene expression, required for normal uptake of dietary iron, [abstract] Blood. 2007; 110: Abstract 3.
193. Roy CN, Andrews NC. Anemia of inflammation: the hepcidin link. CurrOpin Hematol. 2005;12: 107-111.
194. Cartwright GE. The anemia of chronic disorders. Semin Hematol. 1966;3:351-375.
195. Means RT. Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia. Stem Cells. 1995;13:32-37.
196. Roy CN, Weinstein DA, Andrews NC. 2002 E. Mead Johnson Award for Research in Pediatrics Lecture: the molecular biology of the anemia of chronic disease: a hypothesis. Pediatr Res. 2003; 53:507-512.
197. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of
198. Bennett MJ, Lebron J A, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000;403:46-53.
199. Lawrence CM, Ray S, Babyonyshev M, Galluser R, Borhani DW, Harrison SC. Crystal structure of the ectodomain of human transferrin receptor. Science. 1999;286:779-782.
200. Walden WE, SeleznevaAl, Dupuy J, et al. Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science. 2006; 314:1903-1908.
201. MacPhailAP, Derman DP, Bothwell TH, et al. Serum ferritin concentrations in black miners. S Afr Med J. 1979;55:758-760.
202. Gordeuk VR. Boyd RD, Brittenham GM. Dietary iron overload persists in rural sub-Saharan Africa. Lancet. 1986;1:1310-1313.
203. Barton JC, Edwards CQ, Bertoli LF, ShroyerTW, Hudson SL. Iron overload in African Americans. Am J Med. 1995;99:616-623.
204. Wurapa RK, Gordeuk VR, Brittenham GM, Khiyami A, Schechter GP, Edwards CQ. Primary iron overload in African Americans [see comments]. Am J Med. 1996;101:9-18.
205. Moyo VM, Mandishona E, Hasstedt SJ, et al. Evidence of genetic transmission in African iron overload. Blood. 1998;91:1076-1082.
206. Gangaidzo IT, Moyo VM, SaungwemeT, et al. Iron overload in urban Africans in the 1990s. Gut. 1999;45:278-283.
207. Gordeuk VR. African iron overload. Semin Hematol. 2002;39:263-269.
208. Barton JC, Acton RT, Rivers CA, et al. Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. Blood Cells Mol Dis. 2003:31:310-319.
209. Brown KE, Khan CM, Zimmerman MB, Brunt EM. Hepatic iron overload in blacks and whites: a comparative autopsy study. Am J Gastroenterol. 2003;98:1594-1598.
210. GordeukVR, Caleffi A, Corradini E, et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis. 2003;31:299-304.
211. Zecca L Youdim MB, Riederer P, Connor J R, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5:863-873.
212. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion [see comments]. Science. 1996;271:1423-1427.
213. Camaschella C, Roetto A, Cali A. etal. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14-15.