The molecular regulation of iron metabolism

Hematology Journal

Volumn 5, Issue 5, 2004, Pages 373-380

  Donovan, Adriana ^a   Andrews, Nancy Catherine ^a  

^a BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

Anemia; Hemochromatosis; Iron metabolism

Indexed keywords

ASCORBIC ACID; CERULOPLASMIN; FERROPORTIN 1; HEPCIDIN; IRON; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; PROTEIN;

DISORDERS OF METAL METABOLISM; ERYTHROPOIESIS; GENETIC DISORDER; HEMOCHROMATOSIS; HUMAN; INTESTINE ABSORPTION; IRON ABSORPTION; IRON BALANCE; IRON DEFICIENCY ANEMIA; IRON KINETICS; IRON METABOLISM; IRON OVERLOAD; IRON STORAGE; IRON THERAPY; IRON TRANSPORT; MAMMAL; METABOLIC REGULATION; MOLECULAR RECOGNITION; NONHUMAN; PROTEIN METABOLISM; REVIEW; TISSUE METABOLISM;

ANEMIA, IRON-DEFICIENCY; ANIMALS; CARRIER PROTEINS; ERYTHROPOIESIS; HEMOCHROMATOSIS; HOMEOSTASIS; HUMANS; INTESTINAL ABSORPTION; IRON; IRON OVERLOAD; LIVER; MAMMALS; MEMBRANE PROTEINS; RETICULOENDOTHELIAL SYSTEM; TRANSFERRIN;

EID: 5444272365     PISSN: 14664860     EISSN: None     Source Type: Journal    
DOI: 10.1038/sj.thj.6200540     Document Type: Review

References (97)

1. McKie AT, Latunde-Dada GO, Miret S, McGregor JA, Anderson GJ, Vulpe CD et al. Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans 2002; 30: 722-724.
2. 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: 482-488.
3. Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF et al. Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997; 16: 383-386.
4. Nash DJ, Kent E, Dickie MM, Russell ES. The inheritance of 'mick,' a new anemia in the house mouse [abstract]. Am Zool 1964; 4: 404-405.
5. 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: 4406-4417.
6. Xu H, Jin J, DeFelice LJ, Andrews NC, Clapham DE. A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway. PLoS Biol 2004; 2: E50.
7. 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: 776-781.
8. 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.
9. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000; 275: 19906-19912.
10. 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: 195-199.
11. 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: 2746-2751.
12. 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.
13. Falconer DS, Isaacson JH. The genetics of sex-linked anaemia in the mouse. Genet Res 1962; 3: 248-250.
14. 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: 201-206.
15. Edwards JA, Bannerman RM. Hereditary defect of intestinal iron transport in mice with sex-linked anemia. J Clin Invest 1970; 49: 1869-1871.
16. Manis J. Intestinal iron-transport defect in the mouse with sex-linked anemia. Am J Physiol 1971; 220: 135-139.
17. 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: 8780-8785.
18. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: 7806-7810.
19. 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: 7811-7819.
20. 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: 1037-1044.
21. 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: 4596-4601.
22. Hahn PF, Bale WF, Ross JF, Balfour WM, Whipple GH. Radioactive iron absorption by the gastrointestinal tract: influence of anemia, anoxia, and antecedent feeding. J Exp Med 1943; 78: 169-188.
23. Finch C. Regulators of iron balance in humans. Blood 1994; 84: 1697-1702.
24. Cook JD, Barry WE, Hershko C, Fillet G, Finch CA. Iron kinetics with emphasis on iron overload. Am J Pathol 1973; 72: 337-343.
25. 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: 3776-3781.
26. Cavill I, Worwood M, Jacobs A. Internal regulation of iron absorption. Nature 1975; 256: 328-329.
27. Jing SQ, Trowbridge IS. Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid-attachment site. EMBO J 1987; 6: 327-331.
28. Kuhn LC, McClelland A, Ruddle FH. Gene transfer, expression and molecular cloning of the human transferrin receptor gene. Cell 1984; 37: 95-103.
29. Schneider C, Kurkinen M, Greaves M. Isolation of cDNA clones for the human transferrin receptor. EMBO J 1983; 2: 2259-2263.
30. 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.
31. Rothenberger S, Iacopetta BJ, Kuhn LC. Endocytosis of the transferrin receptor requires the cytoplasmic domain but not its phosphorylation site. Cell 1987; 49: 423-431.
32. McGraw TE, Maxfield FR. Human transferrin receptor internalization is partly dependent upon an aromatic amino acid in the cytoplasmic domain. Cell Regul 1990; 1: 369-377.
33. Alvarez E, Girones N, Davis RJ. Inhibition of receptor-mediated endocytosis of diferric transferrin is associated with covalent modification of the transferrin receptor with palmitic acid. J Biol Chem 1990; 265: 16644-16655.
34. Alvarez E, Girones N, Davis RJ. A point mutation in the cytoplasmic domain of the transferrin receptor inhibits endocytosis. Biochem J 1990; 267: 31-35.
35. Girones N, Alvarez E, Seth A, Lin IM, Latour DA, Davis RJ. Mutational analysis of the cytoplasmic tail of the human transferrin receptor. Identification of a sub-domain that is required for rapid endocytosis. J Biol Chem 1991; 266: 19006-19012.
36. Dautry-Varsat A, Ciechanover A, Lodish HF. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Nat Acad Sci USA 1983; 80: 2258-2262.
37. Paterson S, Armstrong NJ, Iacopetta BJ, McArdle HJ, Morgan EH. Intravesicular pH and iron uptake by immature erythroid cells. J Cell Physiol 1984; 120: 225-232.
38. Van Renswoude J, Bridges KR, Harford JB, Klausner RD. Receptor-mediated endocytosis and the uptake of iron in K562 cells: identification of a non-lysosomal acidic compartment. Proc Nat Acad Sci USA 1982; 79: 6186-6190.
39. Yamashiro DJ, Tycko B, Fluss SR, Maxfield FR. Segregation of transferrin to a mildly acidic (pH 6.5) para-Golgi compartment in the recycling pathway. Cell 1984; 37: 789-800.
40. Bali PK, Zak O, Aisen P. A new role for the transferrin receptor in the release of iron from transferrin. Biochemistry 1991; 30: 324-328.
41. Sipe DM, Murphy RF. Binding to cellular receptors results in increased iron release from transferrin at mildly acidic pH. J Biol Chem 1991; 266: 8002-8007.
42. Nunez M-T, Gaete V, Watkins JA, Glass J. Mobilization of iron from endocytic vesicles. The effects of acidification and reduction. J Biol Chem 1990; 265: 6688-6692.
43. Thorstensen K, Romslo I. Uptake of iron from transferrin by isolated rat hepatocytes. A redox-mediated plasma membrane process? J Biol Chem 1988; 263: 8844-8850.
44. 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: 1148-1153.
45. Bernstein SE. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med 1987; 110: 690-705.
46. Huggenvik JI, Craven CM, Idzerda RL, Bernstein S, Kaplan J, McKnight GS. A splicing defect in the mouse transferrin gene leads to congenital atransferrinemia. Blood 1989; 74: 482-486.
47. Trenor CC, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood 2000; 96: 1113-1118.
48. Heilmeyer L, Keller W, Vivell O, Keiderling W, Betke K, Wohler F et al. Congenital transferrin deficiency in a seven-year old girl. German Med Mon 1961; 86: 1745-1751.
49. Heilmeyer L. Atransferrinemias [German]. Acta Haematol 1966; 36: 40-49.
50. Goya N, Miyazaki S, Kodate S, Ushio B. A family of congenital atransferrinemia. Blood 1972; 40: 239-245.
51. Asada-Senju M, Maeda T, Sakata T, Hayashi A, Suzuki T. Molecular analysis of the transferrin gene in a patient with hereditary hypotransferrinemia. J Hum Genet 2002; 47: 355-359.
52. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood 2000; 96: 4071-4074.
53. 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.
54. Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood 2003; 102: 3711-3718.
55. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101: 2461-2463.
56. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK et al. Interleukin-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron-regulatory hormone hepcidin. J Clin Invest 2004, in press.
57. Weinberg ED. Iron depletion: a defense against intracellular infection and neoplasia. Life Sci 1992; 50: 1289-1297.
58. 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.
59. Buchanan GR, Sheehan RG. Malabsorption and defective utilization of iron in three siblings. J Pediatr 1981; 98: 723-728.
60. Hartman KR, Barker JA. Microcytic anemia with iron malabsorption: an inherited disorder of iron metabolism. Am J Hematol 1996; 51: 269-275.
61. Pearson HA, Lukens JN. Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J Pediatr Hematol Oncol 1999; 21: 412-417.
62. Priwitzerova M, Pospisilova D, Prchal JT, Hlobilkova A, Mihal V, Indrak K et al. The first human mutation of DMT1 (Nramp2) causes severe defect of erythropoiesis that can be rescued in vitro. [Abstract #538]. Blood 2003; 102.
63. 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.
64. Ajioka RS, Jorde LB, Gruen JR, Yu P, Dimitrova D, Barrow J et al. Haplotype analysis of hemochromatosis: evaluation of different linkage- disequilibrium approaches and evolution of disease chromosomes. Am J Hum Genet 1997; 60: 1439-1447.
65. Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988; 318: 1355-1362.
66. Ajioka RS, Kushner JP. Clinical consequences of iron overload in hemochromatosis homozygotes. Blood 2003; 101: 3351-3353.
67. Beutler E. The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis. Blood 2003; 101: 3347-3350.
68. Edwards CQ, Griffen LM, Ajioka RS, Kushner JP. Screening for hemochromatosis: phenotype versus genotype. Semin Hematol 1998; 35: 72-76.
69. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999; 341: 718-724.
70. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G-> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211-218.
71. Cullen LM, Anderson GJ, Ramm GA, Jazwinska EC, Powell LW. Genetics of hemochromatosis. Annu Rev Med 1999; 50: 87-98.
72. Tomatsu S, Orii KO, Fleming RE, Holden CC, Waheed A, Britton RS et al. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc Natl Acad Sci USA 2003; 100: 15788-15793.
73. 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: 111-123.
74. 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: 13198-13202.
75. Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 1998; 95: 1472-1477.
76. Eisenstein RS. Interaction of the hemochromatosis gene product HFE with transferrin receptor modulates cellular iron metabolism. Nutr Rev 1998; 56: 356-358.
77. Zhou XY, Tomatsu S, Fleming RE et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 1998; 95: 2492-2497.
78. Levy JE, Montross LK, Cohen DE, Fleming MD, Andrews NC. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 1999; 94: 9-11.
79. Bahram S, Gilfillan S, Kuhn LC, Moret R, Schulze JB, Lebeau A et al. Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc Natl Acad Sci USA 1999; 96: 13312-13317.
80. 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: 21-22.
81. 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.
82. Monnier PP, Sierra A, Macchi P, Dietinghoff L, Andersen JS, Mann M et al. RGM is a repulsive guidance molecule for retinal axons. Nature 2002; 419: 392-395.
83. Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000; 25: 14-15.
84. 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: 20826-20832.
85. Pietrangelo A, Montosi G, Totaro A, Garuti C, Conte D, Cassanelli S et al. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 1999; 341: 725-732.
86. Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001; 28: 213-214.
87. Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001; 108: 619-623.
88. Njajou OT, de Jong G, Berghuis B, Vaessen N, Snijders PJ, Goossens JP et al. Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics. Blood Cells Mol Dis 2002; 29: 439-443.
89. Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis 2004; 32: 131-138.
90. Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G et al. A valine deletion of ferroportin 1: a common mutation in hemochromatosis type 4. Blood 2002; 100: 733-734.
91. Gordeuk V, Mukiibi J, Hasstedt SJ, Samowitz W, Edwards CQ, West G et al. Iron overload in Africa. Interaction between a gene and dietary iron content. N Engl J Med 1992; 326: 95-100.
92. Gangaidzo IT, Moyo VM, Saungweme T, Khumalo H, Charakupa RM, Gomo ZA et al. Iron overload in urban africans in the 1990s. Gut 1999; 45: 278-283.
93. Gordeuk VR, Caleffi A, Corradini E, Ferrara F, Jones RA, Castro O 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.
94. Barton JC, Acton RT, Rivers CA, Bertoli LF, Gelbert T, West C et al. Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. Blood Cells Mol Dis 2003; 31: 310-319.
95. 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 USA 1995; 92: 2539-2543.
96. 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: 10653-10658.
97. Andrews NC. Iron homeostasis: insights from genetics and animal models. Nat Rev Genet 2000; 1: 208-217.