Proteins of iron homeostasis

Iron Physiology and Pathophysiology in Humans

Volumn , Issue , 2012, Pages 3-25

  Srai, Surjit Kaila ^a   Sharp, Paul ^b  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

DMT1; Ferroportin; Heme; Hepcidin; HFE; Iron regulation; Iron storage; Iron transport

Indexed keywords

EID: 84897929383     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-60327-485-2_1     Document Type: Chapter

References (267)

1. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482-8.
2. Gruenheid S, Cellier M, Vidal S, Gros P. Identification and characterization of a second mouse Nramp gene. Genomics. 1995;25:514-25.
3. Fleming MD, Trenor III CC, Su MA, Foernzler D, Beier DR, Dietrich WF, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383-6.
4. Tandy S, Williams M, Leggett A, Lopez-Jimenez M, Dedes M, Ramesh B, et al. Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J Biol Chem. 2000;275:1023-9.
5. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005;115:1258-66.
6. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA. 1998;95:1148-53.
7. Mims MP, Guan Y, Pospisilova D, Priwitzerova M, Indrak K, Ponka P, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105:1337-42.
8. 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;107:4168-70.
9. 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;107:349-54.
10. Lam-Yuk-Tseung S, Camaschella C, Iolascon A, Gros P. A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Blood Cells Mol Dis. 2006;36:347-54.
11. Lee PL, Gelbart T, West C, Halloran C, Beutler E. The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis. 1998;24:199-215.
12. Hubert N, Hentze MW. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA. 2002;99:12345-50.
13. Mackenzie B, Takanaga H, Hubert N, Rolfs A, Hediger MA. Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J. 2007;403:59-69.
14. Canonne-Hergaux F, 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;93:4406-17.
15. Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F. Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol Biol Cell. 2002;13:4371-87.
16. Johnson DM, Yamaji S, Tennant J, Srai SK, Sharp PA. Regulation of divalent metal transporter expression in human intestinal epithelial cells following exposure to non-haem iron. FEBS Lett. 2005;579:1923-9.
17. Lam-Yuk-Tseung S, Gros P. Distinct targeting and recycling properties of two isoforms of the iron transporter DMT1 (NRAMP2, Slc11A2). Biochemistry. 2006;45:2294-301.
18. Trinder D, Oates PS, Thomas C, Sadleir J, Morgan EH. Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload. Gut. 2000;46:270-6.
19. Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology. 2002;123:835-44.
20. Wardrop SL, Richardson DR. The effect of intracellular iron concentration and nitrogen monoxide on Nramp2 expression and non-transferrin-bound iron uptake. Eur J Biochem. 1999;263:41-9.
21. Hahn PF, Bale WF, Ross JF, Balfour WM, Whipple GH. Radioactive iron absorption by gastro-intestinal tract: influence of anemia, anoxia, and antecedent feeding distribution in growing dogs. J Exp Med. 1943;78:169-88.
22. Hahn PF, Bale WF, Ross JF, Balfour WM, Whipple GH. Radioiron absorption in anemic dogs; fluctuations in the mucosal block and evidence for a gradient of absorption in the gastrointestinal tract. J Exp Med. 1950;92:375-82.
23. Beutler E. History of iron in medicine. Blood Cells Mol Dis. 2002;29:297-308.
24. Oates PS, Trinder D, Morgan EH. Gastrointestinal function, divalent metal transporter-1 expression and intestinal iron absorption. Pflugers Arch. 2000;440:496-502.
25. Yeh KY, Yeh M, Watkins JA, Rodriguez-Paris J, Glass J. Dietary iron induces rapid changes in rat intestinal divalent metal transporter expression. Am J Physiol Gastrointest Liver Physiol. 2000;279:G1070-9.
26. Frazer DM, Wilkins SJ, Becker EM, Murphy TL, Vulpe CD, McKie AT, et al. A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut. 2003;52:340-6.
27. Sharp P, Tandy S, Yamaji S, Tennant J, Williams M, Srai SKS. Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells. FEBS Lett. 2002;510:71-6.
28. Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 2009;119:1159-66.
29. Shah YM, Matsubara T, Ito S, Yim SH, Gonzalez FJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9:152-64.
30. Wheby MS, Suttle GE, Ford III KT. Intestinal absorption of hemoglobin iron. Gastroenterology. 1970;58:647-54.
31. Raffin SB, Woo CH, Roost KT, Price DC, Schmid R. Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest. 1974;54:1344-52.
32. Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, et al. The stem cell marker Bcrp/ ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004;279:24218-25.
33. Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell. 2004;118:757-66.
34. Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789-801.
35. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917-28.
36. Rajagopal A, Rao AU, Amigo J, Tian M, Upadhyay SK, Hall C, et al. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature. 2008;453:1127-31.
37. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776-81.
38. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, 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.
39. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906-12.
40. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191-200.
41. Thomas C, Oates PS. Ferroportin/IREG-1/MTP-1/SLC40A1 modulates the uptake of iron at the apical membrane of enterocytes. Gut. 2004;53:444-9.
42. 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;106:3979-84.
43. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA. 2005;102:1324-8.
44. Delaby C, Pilard N, Puy H, Canonne-Hergaux F. Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. Biochem J. 2008;411:123-31.
45. Wang F, Paradkar PN, Custodio AO, McVey WD, Fleming MD, Campagna D, et al. Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet. 2007;39:1025-32.
46. Yang F, Wang X, Haile DJ, Piantadosi CA, Ghio AJ. Iron increases expression of iron-export protein MTP1 in lung cells. Am J Physiol Lung Cell Mol Physiol. 2002;283:L932-9.
47. Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab. 2009;9:461-73.
48. Chaston T, Chung B, Mascarenhas M, Marks J, Patel B, Srai SK, et al. Evidence for differential effects of hepcidin in macrophages and intestinal epithelial cells. Gut. 2008;57:374-82.
49. Mena NP, Esparza A, Tapia V, Valdes P, Nunez MT. Hepcidin inhibits apical iron uptake in intestinal cells. Am J Physiol Gastrointest Liver Physiol. 2008;294:G192-8.
50. Chung B, Chaston T, Marks J, Srai SK, Sharp PA. Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells. J Nutr. 2009;139:1457-62.
51. Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem. 1999;274:20826-32.
52. Zhang AS, Xiong S, Tsukamoto H, Enns CA. Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes. Blood. 2004;103:1509-14.
53. Aisen P. Transferrin receptor 1. Int J Biochem Cell Biol. 2004;36:2137-43.
54. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117:285-97.
55. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264-9.
56. Lebron JA, West Jr AP, Bjorkman PJ. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol. 1999;294:239-45.
57. Roy CN, Penny DM, Feder JN, Enns CA. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J Biol Chem. 1999;274:9022-8.
58. 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;21:396-69.
59. Wingert RA, Brownlie A, Galloway JL, Dooley K, Fraenkel P, Axe JL, et al. The chianti zebrafish mutant provides a model for erythroid-specific disruption of transferrin receptor 1. Development. 2004;131:6225-35.
60. Casey JL, Hentze MW, Koeller DM, Caughman SW, Rouault TA, Klausner RD, et al. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science. 1988;240:924-8.
61. Mullner EW, Kuhn LC. A stem-loop in the 3' untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell. 1988;53:815-25.
62. Mullner EW, Neupert B, Kuhn LC. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA. Cell. 1989;58:373-82.
63. Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem. 2000;275:16618-25.
64. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood. 2001;98:2714-9.
65. Camaschella C, Roetto A, Cali A, De GM, Garozzo G, Carella M, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14-5.
66. Fleming RE, Ahmann JR, Migas MC, Waheed A, Koeffler HP, Kawabata H, et al. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci USA. 2002;99:10653-8.
67. Wallace DF, Summerville L, Subramaniam VN. Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology. 2007;132:301-10.
68. Wallace DF, Summerville L, Crampton EM, Frazer DM, Anderson GJ, Subramaniam VN. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology. 2009;50:1992-2000.
69. Fleming RE, Migas MC, Holden CC, Waheed A, Britton RS, Tomatsu S, et al. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci USA. 2000;97:2214-9.
70. Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood. 2004;104:4287-93.
71. Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood. 2004;104:4294-9.
72. Chen J, Enns CA. The cytoplasmic domain of transferrin receptor 2 dictates its stability and response to holotransferrin in Hep3B cells. J Biol Chem. 2007;282:6201-9.
73. 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;18:743-54.
74. 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;281:28494-8.
75. 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;282:36862-70.
76. Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33:967-78.
77. Pan BT, Teng K, Wu C, Adam M, Johnstone RM. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol. 1985;101:942-8.
78. Kaup M, Dassler K, Weise C, Fuchs H. Shedding of the transferrin receptor is mediated constitutively by an integral membrane metalloprotease sensitive to tumor necrosis factor alpha protease inhibitor-2. J Biol Chem. 2002;277:38494-502.
79. Shih YJ, Baynes RD, Hudson BG, Flowers CH, Skikne BS, Cook JD. Serum transferrin receptor is a truncated form of tissue receptor. J Biol Chem. 1990;265:19077-81.
80. Fuchs H, Lucken U, Tauber R, Engel A, Gessner R. Structural model of phospholipid-reconstituted human transferrin receptor derived by electron microscopy. Structure. 1998;6:1235-43.
81. Ferguson BJ, Skikne BS, Simpson KM, Baynes RD, Cook JD. Serum transferrin receptor distinguishes the anemia of chronic disease from iron deficiency anemia. J Lab Clin Med. 1992;119:385-90.
82. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:101110-23.
83. Dassler K, Zydek M, Wandzik K, Kaup M, Fuchs H. Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin. J Biol Chem. 2006;281:3297-304.
84. Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006;440:96-100.
85. 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;277:24475-83.
86. Muhlenhoff U, Stadler JA, Richhardt N, Seubert A, Eickhorst T, Schweyen RJ, et al. A specific role of the yeast mitochondrial carriers MRS3/4p in mitochondrial iron acquisition under iron-limiting conditions. J Biol Chem. 2003;278:40612-20.
87. Li L, Kaplan J. A mitochondrial-vacuolar signaling pathway in yeast that affects iron and copper metabolism. J Biol Chem. 2004;279:33653-61.
88. Zhang Y, Lyver ER, Knight SA, Lesuisse E, Dancis A. Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis. J Biol Chem. 2005;280:19794-807.
89. 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;73:469-85.
90. West AH, Clark DJ, Martin J, Neupert W, Hartl FU, Horwich AL. Two related genes encoding extremely hydrophobic proteins suppress a lethal mutation in the yeast mitochondrial processing enhancing protein. J Biol Chem. 1992;267:24625-33.
91. 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;14:3007-20.
92. Nevo Y, Nelson N. The NRAMP family of metal-ion transporters. Biochim Biophys Acta. 2006;1763:609-20.
93. Fortier A, Min-Oo G, Forbes J, Lam-Yuk-Tseung S, Gros P. Single gene effects in mouse models of host: pathogen interactions. J Leukoc Biol. 2005;77:868-77.
94. Vidal S, Gros P, Skamene E. Natural resistance to infection with intracellular parasites: molecular genetics identifies Nramp1 as the Bcg/Ity/Lsh locus. J Leukoc Biol. 1995;58:382-90.
95. Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P. Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. J Exp Med. 2000;192:1237-48.
96. Forbes JR, Gros P. Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol. 2001;9:397-403.
97. Forbes JR, Gros P. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood. 2003;102:1884-92.
98. Kuhn DE, Baker BD, Lafuse WP, Zwilling BS. Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169. J Leukoc Biol. 1999;66:113-9.
99. Kuhn DE, Lafuse WP, Zwilling BS. Iron transport into mycobacterium avium-containing phagosomes from an Nramp1(Gly169)-transfected RAW264.7 macrophage cell line. J Leukoc Biol. 2001;69:43-9.
100. Goswami T, Bhattacharjee A, Babal P, Searle S, Moore E, Li M, et al. Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter. Biochem J. 2001;354:511-9.
101. Soe-Lin S, Apte SS, Mikhael MR, Kayembe LK, Nie G, Ponka P. Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling. Exp Hematol. 2010;38:609-17.
102. Soe-Lin S, Apte SS, Andriopoulos Jr B, Andrews MC, Schranzhofer M, Kahawita T, et al. Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci USA. 2009;106:5960-5.
103. Shaw MA, Collins A, Peacock CS, Miller EN, Black GF, Sibthorpe D, et al. Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. Tuber Lung Dis. 1997;78:35-45.
104. Yip SP, Leung KH, Lin CK. Extent and distribution of linkage disequilibrium around the SLC11A1 locus. Genes Immun. 2003;4:212-21.
105. Blackwell JM, Goswami T, Evans CA, Sibthorpe D, Papo N, White JK, et al. SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol. 2001;3:773-84.
106. McDermid JM, Prentice AM. Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host-pathogen interactions in tuberculosis and HIV. Clin Sci (Lond). 2006;110:503-24.
107. Bayele HK, Peyssonnaux C, Giatromanolaki A, Arrais-Silva WW, Mohamed HS, Collins H, et al. HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite. Blood. 2007;110:3039-48.
108. Han O, Failla ML, Hill AD, Morris ER, Smith Jr JC. Reduction of Fe(III) is required for uptake of nonheme iron by Caco-2 cells. J Nutr. 1995;125:1291-9.
109. Taylor PG, Martinez-Torres C, Romano EL, Layrisse M. The effect of cysteine-containing peptides released during meat digestion on iron absorption in humans. Am J Clin Nutr. 1986;43:68-71.
110. Huh EC, Hotchkiss A, Brouillette J, Glahn RP. Carbohydrate fractions from cooked fish promote iron uptake by Caco-2 cells. J Nutr. 2004;134:1681-9.
111. Hurrell RF, Reddy MB, Juillerat M, Cook JD. Meat protein fractions enhance nonheme iron absorption in humans. J Nutr. 2006;136:2808-12.
112. Armah CN, Sharp P, Mellon FA, Pariagh S, Lund EK, Dainty JR, et al. l -Alpha-glycerophosphocholine contributes to meat's enhancement of nonheme iron absorption. J Nutr. 2008;138:873-7.
113. Raja KB, Simpson RJ, Peters TJ. Investigation of a role for reduction in ferric iron uptake by mouse duodenum. Biochim Biophys Acta. 1992;1135:141-6.
114. Riedel HD, Remus AJ, Fitscher BA, Stremmel W. Characterization and partial purification of a ferrireductase from human duodenal microvillus membranes. Biochem J. 1995;309(Pt 3):745-8.
115. Ekmekcioglu C, Feyertag J, Marktl W. A ferric reductase activity is found in brush border membrane vesicles isolated from Caco-2 cells. J Nutr. 1996;126:2209-17.
116. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291:1755-9.
117. Su D, Asard H. Three mammalian cytochromes b561 are ascorbate-dependent ferrireductases. FEBS J. 2006;273:3722-34.
118. Muckenthaler M, Roy CN, Custodio AO, Minana B, deGraaf J, Montross LK, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 2003;34:102-7.
119. Latunde-Dada GO, Simpson RJ, McKie AT. Duodenal cytochrome B expression stimulates iron uptake by human intestinal epithelial cells. J Nutr. 2008;138:991-5.
120. Wyman S, Simpson RJ, McKie AT, Sharp PA. Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro. FEBS Lett. 2008;582:1901-6.
121. Gunshin H, Starr CN, Direnzo C, Fleming MD, Jin J, Greer EL, et al. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood. 2005;106:2879-83.
122. Constantine CC, Anderson GJ, Vulpe CD, McLaren CE, Bahlo M, Yeap HL, et al. A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis. Br J Haematol. 2009;147:140-9.
123. Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood. 2006;108:1388-94.
124. Fox PL. The copper-iron chronicles: the story of an intimate relationship. Biometals. 2003;16:9-40.
125. Sharp P. The molecular basis of copper and iron interactions. Proc Nutr Soc. 2004;63:563-9.
126. Smith SE, Medlicott M. The blood picture of iron and copper deficiency anemias in the rat. Am J Physiol. 1944;141:354-8.
127. Cartwright GE, Gubler CJ, Bus JA, Wintrobe MM. Studies of copper metabolism. XVII. Further observations on the anemia of copper deficiency in swine. Blood. 1956;11:143-53.
128. Holmberg CG, Laurell CB. Investigations in serum copper. II. Isolation of the copper containing protein and a description of some of its properties. Acta Chem Scand. 1948;2:550-6.
129. Curzon G, Vallet L. The purification of human ceruloplasmin. Biochem J. 1960;74:279-87.
130. Osaki S, Johnson DA, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem. 1966;241:2746-51.
131. Osaki S, Johnson DA. Mobilization of liver iron by ferroxidase (ceruloplasmin). J Biol Chem. 1969;244:5757-8.
132. Harris ZL. Aceruloplasminemia. J Neurol Sci. 2003;207:108-9.
133. Patel BN, David S. A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem. 1997;272:20185-90.
134. Patel BN, Dunn RJ, David S. Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem. 2000;275:4305-10.
135. Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr. 2002;22:439-58.
136. Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem. 2003;278:27144-8.
137. De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, et al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823-31.
138. Askwith C, Eide D, Van HA, Bernard PS, Li L, vis-Kaplan S, et al. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell. 1994;76:403-10.
139. Dancis A, Haile D, Yuan DS, Askwith C, Eide D, Moehle C, et al. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell. 1994;76:393-402.
140. Anderson GJ, Murphy TL, Cowley L, Evans BA, Halliday JW, McLaren GD. Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse. Genomics. 1998;48:34-9.
141. Vulpe CD, Kuo YM, Murphy TL, Cowley L, Askwith C, Libina N, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999;21:195-9.
142. Frazer DM, Vulpe CD, McKie AT, Wilkins SJ, Trinder D, Cleghorn GJ, et al. Cloning and gastrointestinal expression of rat hephaestin: relationship to other iron transport proteins. Am J Physiol Gastrointest Liver Physiol. 2001;281:G931-9.
143. Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, et al. Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol. 2002;282:G598-607.
144. Chen H, Attieh ZK, Su T, Syed BA, Gao H, Alaeddine RM, et al. Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice. Blood. 2004;103:3933-9.
145. Syed BA, Beaumont NJ, Patel A, Naylor CE, Bayele HK, Joannou CL, et al. Analysis of the human hephaestin gene and protein: comparative modelling of the N-terminus ecto-domain based upon ceruloplasmin. Protein Eng. 2002;15:205-14.
146. Kuo YM, Su T, Chen H, Attieh Z, Syed BA, McKie AT, et al. Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse. Gut. 2004;53:20120-6.
147. Syed BA, Sargent PJ, Farnaud S, Evans RW. An overview of molecular aspects of iron metabolism. Hemoglobin. 2006;30:69-80.
148. Giblett ER, Hickman CG, Smithies O. Serum transferrins. Nature. 1959;183:1589-90.
149. Crichton RR. Proteins of iron storage and transport. Adv Protein Chem. 1990;40:281-363.
150. Saltman P, Charley PJ. The regulation of iron metabolism by equilibrium binding and chelation. In: Seven MJ, editor. Metal-binding in medicine. Philadelphia: Lippincott; 1960. p. 241-4.
151. Fletcher J. Iron transport in the blood. Proc R Soc Med. 1970;63:1216-8.
152. Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol Rev. 1987;67:520-82.
153. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161-203.
154. Drysdale JW, Munro HN. Regulation of synthesis and turnover of ferritin in rat liver. J Biol Chem. 1966;241:3630-7.
155. Roberts S, Bomford A. Ferritin iron kinetics and protein turnover in K562 cells. J Biol Chem. 1988;263:19181-7.
156. Shi H, Bencze KZ, Stemmler TL, Philpott CC. A cytosolic iron chaperone that delivers iron to ferritin. Science. 2008;320:1207-10.
157. Granick S. Protein apoferritin and ferritin in iron feeding and absorption. Science. 1946;103:107.
158. Aziz N, Munro HN. Iron regulates ferritin mRNA translation through a segment of its 5 untranslated region. Proc Natl Acad Sci USA. 1987;84:8478-82.
159. Hentze MW, Rouault TA, 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 USA. 1987;84:6730-4.
160. Hentze MW, Caughman SW, Rouault TA, Barriocanal JG, Dancis A, Harford JB, et al. Identification of the ironresponsive element for the translational regulation of human ferritin mRNA. Science. 1987;238:1570-3.
161. Leibold EA, Munro HN. Characterization and evolution of the expressed rat ferritin light subunit gene and its pseudogene family. Conservation of sequences within noncoding regions of ferritin genes. J Biol Chem. 1987;262:7335-41.
162. 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 eIF4F. Mol Cell. 1998;2:383-8.
163. Addison GM, Beamish MR, Hales CN, Hodgkins M, Jacobs A, Llewellin P. An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. J Clin Pathol. 1972;25:326-9.
164. Jacobs A, Worwood M. Ferritin in serum. Clinical and biochemical implications. N Engl J Med. 1975;292: 95195-6.
165. Cragg SJ, Wagstaff M, Worwood M. Sialic acid and the microheterogeneity of human serum ferritin. Clin Sci (Lond). 1980;58:259-62.
166. Cragg SJ, Wagstaff M, Worwood M. Detection of a glycosylated subunit in human serum ferritin. Biochem J. 1981;199:565-71.
167. Worwood M, Dawkins S, Wagstaff M, Jacobs A. The purification and properties of ferritin from human serum. Biochem J. 1976;157:97-103.
168. Arosio P, Yokota M, Drysdale JW. Characterization of serum ferritin in iron overload: possible identity to natural apoferritin. Br J Haematol. 1977;36:199-207.
169. Walters GO, Miller FM, Worwood M. Serum ferritin concentration and iron stores in normal subjects. J Clin Pathol. 1973;26:770-2.
170. Cook JD. Defining optimal body iron. Proc Nutr Soc. 1999;58:489-95.
171. Mack U, Cooksley WG, Ferris RA, Powell LW, Halliday JW. Regulation of plasma ferritin by the isolated perfused rat liver. Br J Haematol. 1981;47:403-12.
172. Tran TN, Eubanks SK, Schaffer KJ, Zhou CY, Linder MC. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood. 1997;90:4979-86.
173. Dorner MH, Silverstone A, Nishiya K, de Sostoa A, Munn G, de Sousa M. Ferritin synthesis by human T lymphocytes. Science. 1980;209:1019-21.
174. Ghosh S, Hevi S, Chuck SL. Regulated secretion of glycosylated human ferritin from hepatocytes. Blood. 2004;103:2369-76.
175. Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, et al. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem. 2001;276:24437-40.
176. Drysdale J, Arosio P, Invernizzi R, Cazzola M, Volz A, Corsi B, et al. Mitochondrial ferritin: a new player in iron metabolism. Blood Cells Mol Dis. 2002;29:376-83.
177. Santambrogio P, Biasiotto G, Sanvito F, Olivieri S, Arosio P, Levi S. Mitochondrial ferritin expression in adult mouse tissues. J Histochem Cytochem. 2007;55:1129-37.
178. Wixom RL, Prutkin L, Munro HN. Hemosiderin: nature, formation, and significance. Int Rev Exp Pathol. 1980;22:193-225.
179. Richter GW. Studies of iron overload. Rat liver siderosome ferritin. Lab Invest. 1984;50:26-35.
180. Iancu TC. Ultrastructural pathology of iron overload. Baillieres Clin Haematol. 1989;2:475-95.
181. Weir MP, Gibson JF, Peters TJ. Biochemical studies on the isolation and characterization of human spleen haemosiderin. Biochem J. 1984;223:31-8.
182. Andrews SC, Brady MC, Treffry A, Williams JM, Mann S, Cleton MI, et al. Studies on haemosiderin and ferritin from iron-loaded rat liver. Biol Met. 1988;1:33-42.
183. Rouault TA, Stout CD, Kaptain S, Harford JB, Klausner RD. Structural relationship between an iron-regulated RNA-binding protein (IRE-BP) and aconitase: functional implications. Cell. 1991;64:881-3.
184. Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA. 1996;93:8175-82.
185. Eisenstein RS, Blemings KP. Iron regulatory proteins, iron responsive elements and iron homeostasis. J Nutr. 1998;128:2295-8.
186. Cairo G, Pietrangelo A. Iron regulatory proteins in pathobiology. Biochem J. 2000;352:241-50.
187. Iwai K, Drake SK, Wehr NB, Weissman AM, LaVaute T, Minato N, 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;95:4924-8.
188. Samaniego F, Chin J, Iwai K, Rouault TA, Klausner RD. Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2. Structure, function, and post-translational regulation. J Biol Chem. 1994;269:30904-10.
189. Henderson BR, Seiser C, Kuhn LC. Characterization of a second RNA-binding protein in rodents with specificity for iron-responsive elements. J Biol Chem. 1993;268:27327-34.
190. Butt J, Kim HY, Basilion JP, Cohen S, Iwai K, Philpott CC, et al. Differences in the RNA binding sites of iron regulatory proteins and potential target diversity. Proc Natl Acad Sci USA. 1996;93:4345-9.
191. Henderson BR, Menotti E, Kuhn LC. Iron regulatory proteins 1 and 2 bind distinct sets of RNA target sequences. J Biol Chem. 1996;271:4900-8.
192. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399-408.
193. Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol. 2007;13:4673-89.
194. Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93:111-23.
195. Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem. 1997;272:14025-8.
196. Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, Feder JN, et al. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA. 1997;94:12384-9.
197. Waheed A, Grubb JH, Zhou XY, Tomatsu S, Fleming RE, Costaldi ME, et al. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA. 2002;99:3117-22.
198. Parkkila S, Waheed A, Britton RS, Bacon BR, Zhou XY, Tomatsu S, et al. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA. 1997;94:13198-202.
199. Bastin JM, Jones M, O'Callaghan CA, Schimanski L, Mason DY, Townsend AR. Kupffer cell staining by an HFE-specific monoclonal antibody: implications for hereditary haemochromatosis. Br J Haematol. 1998;103:931-41.
200. Parkkila S, Waheed A, Britton RS, Feder JN, Tsuchihashi Z, Schatzman RC, et al. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA. 1997;94:2534-9.
201. Parkkila S, Parkkila AK, Waheed A, Britton RS, Zhou XY, Fleming RE, et al. Cell surface expression of HFE protein in epithelial cells, macrophages, and monocytes. Haematologica. 2000;85:340-5.
202. Zhou XY, Tomatsu S, Fleming RE, Parkkila S, Waheed A, Jiang J, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA. 1998;95:2492-7.
203. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2008;40:132-8.
204. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147-50.
205. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806-10.
206. Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277:37597-603.
207. Jordan JB, Poppe L, Haniu M, Arvedson T, Syed R, Li V, et al. Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem. 2009;284:24155-67.
208. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811-9.
209. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037-44.
210. Frazer DM, Inglis HR, Wilkins SJ, Millard KN, Steele TM, McLaren GD, et al. Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut. 2004;53:1509-15.
211. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA. 2001;98:8780-5.
212. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA. 2002;99:4596-601.
213. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33:21-2.
214. Wallace DF, Subramaniam VN. Non-HFE haemochromatosis. World J Gastroenterol. 2007;13:4690-8.
215. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100:3776-81.
216. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-6.
217. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-3.
218. De Domenico I, Ward DM, Nemeth E, Vaughn MB, Musci G, Ganz T, et al. The molecular basis of ferroportinlinked hemochromatosis. Proc Natl Acad Sci USA. 2005;102:8955-60.
219. Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood. 2005;106:1092-7.
220. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569-78.
221. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40:569-71.
222. Guillem F, Lawson S, Kannengiesser C, Westerman M, Beaumont C, Grandchamp B. Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood. 2008;112:2089-91.
223. Melis MA, Cau M, Congiu R, Sole G, Barella S, Cao A, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica. 2008;93:1473-9.
224. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320:1088-92.
225. Folgueras AR, de Martin LF, Pendas AM, Garabaya C, Rodriguez F, Astudillo A, et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood. 2008;112:2539-45.
226. 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;8:502-11.
227. De Falco L, Totaro F, Nai A, Pagani A, Girelli D, Silvestri L, et al. Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Hum Mutat. 2010;31:E1390-405.
228. Edison ES, Athiyarath R, Rajasekar T, Westerman M, Srivastava A, Chandy M. A novel splice site mutation c.2278 (-1) G > C in the TMPRSS6 gene causes deletion of the substrate binding site of the serine protease resulting in refractory iron deficiency anaemia. Br J Haematol. 2009;147:766-9.
229. Ramsay AJ, Quesada V, Sanchez M, Garabaya C, Sarda MP, Baiget M, et al. Matriptase-2 mutations in ironrefractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Hum Mol Genet. 2009;18:3673-83.
230. Tanaka T, Roy CN, Yao W, Matteini A, Semba RD, Arking D, et al. A genome-wide association analysis of serum iron concentrations. Blood. 2010;115:94-6.
231. Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP, et al. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet. 2009;41:1173-5.
232. Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D, et al. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet. 2009;41:1170-2.
233. Beutler E, Van GC, te Loo DM, Gelbart T, Crain K, Truksa J, et al. Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia. Blood Cells Mol Dis. 2010;44:16-21.
234. Lee PL, Barton JC, Brandhagen D, Beutler E. Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Br J Haematol. 2004;127:224-9.
235. Lee PL, Beutler E, Rao SV, Barton JC. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood. 2004;103:4669-71.
236. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77-82.
237. Daraio F, Ryan E, Gleeson F, Roetto A, Crowe J, Camaschella C. Juvenile hemochromatosis due to G320V/ Q116X compound heterozygosity of hemojuvelin in an Irish patient. Blood Cells Mol Dis. 2005;35:174-6.
238. Gehrke SG, Pietrangelo A, Kascak M, Braner A, Eisold M, Kulaksiz H, et al. HJV gene mutations in European patients with juvenile hemochromatosis. Clin Genet. 2005;67:425-8.
239. Wallace DF, Dixon JL, Ramm GA, Anderson GJ, Powell LW, Subramaniam N. Hemojuvelin (HJV)-associated hemochromatosis: analysis of HJV and HFE mutations and iron overload in three families. Haematologica. 2005;90:254-5.
240. Aguilar-Martinez P, Lok CY, Cunat S, Cadet E, Robson K, Rochette J. Juvenile hemochromatosis caused by a novel combination of hemojuvelin G320V/R176C mutations in a 5-year old girl. Haematologica. 2007;92:421-2.
241. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115:2187-91.
242. 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;115:2180-6.
243. Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P. Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. BMC Biochem. 2008;9:9.
244. Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol Dis. 2008;40:122-31.
245. Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008;111:924-31.
246. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106:2884-9.
247. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531-5349.
248. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399-409.
249. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112:1503-9.
250. 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 Genet. 2009;41:478-81.
251. Andriopoulos Jr B, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482-7.
252. Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005;105:1867-74.
253. Bencze KZ, Kondapalli KC, Cook JD, McMahon S, Millan-Pacheco C, Pastor N, et al. The structure and function of frataxin. Crit Rev Biochem Mol Biol. 2006;41:269-91.
254. Wilson RB. Iron dysregulation in Friedreich ataxia. Semin Pediatr Neurol. 2006;13:166-75.
255. Gibson TJ, Koonin EV, Musco G, Pastore A, Bork P. Friedreich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction. Trends Neurosci. 1996;19:465-8.
256. Babcock M, de Silva D, Oaks R, vis-Kaplan S, Jiralerspong S, Montermini L, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276:1709-12.
257. Chen OS, Hemenway S, Kaplan J. Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis. Proc Natl Acad Sci USA. 2002;99:12321-6.
258. Cavadini P, Gellera C, Patel PI, Isaya G. Human frataxin maintains mitochondrial iron homeostasis in S. cerevisiae . Hum Mol Genet. 2000;9:2523-30.
259. Gerber J, Muhlenhoff U, Lill R. An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO Rep. 2003;4:906-11.
260. Yoon T, Cowan JA. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J Am Chem Soc. 2003;125:6078-84.
261. Yoon T, Cowan JA. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem. 2004;279:25943-6.
262. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096-101.
263. Finkenstedt A, Bianchi P, Theurl I, Vogel W, Witcher DR, Wroblewski VJ, et al. Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency. Br J Haematol. 2009;144:789-93.
264. Tanno T, Porayette P, Sripichai O, Noh SJ, Byrnes C, Bhupatiraju A, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114:181-6.
265. Zhang AS, Yang F, Meyer K, Hernandez C, Chapman-Arvedson T, Bjorkman PJ, et al. Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. J Biol Chem. 2008;283:17494-502.
266. 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;282:12547-56.
267. Zhang AS, West Jr AP, Wyman AE, Bjorkman PJ, Enns CA. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem. 2005;280:33885-94.