Abstract
The uptake of iron into the body is tightly regulated in humans and in other mammals. Mutations in key proteins that transport, sense, metabolize, and facilitate the utilization of iron cause perturbations in iron homeostasis that result in iron deficiency or overload diseases. This review focuses on what is currently known about these diseases and the normal function of the proteins that are mutated in the disease-state. The proteins causing hereditary hemochromatosis and anemia are discussed in detail.
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References
1. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906-19912
2. Adamsky K, Weizer O, Amariglio N, Breda L, Harmelin A, Rivella S, Rachmilewitz E, Rechavi G (2004) Decreased hepcidin mRNA expression in thalassemic mice. Br J Haematol 124:123-124
3. Ahmad KA, Ahmann JR, Migas MC, Waheed A, Britton RS, Bacon BR, Sly WS, Fleming RE (2002) Decreased liver hepcidin expression in the hfe knockout mouse. Blood Cells Mol Dis 29:361-366
4. Ajioka RS, Kushner JP (2003) Clinical consequences of iron overload in hemochromatosis homozygotes. Blood 101:3351-3358
5. Allikmets R, Raskind W, Hutchinson A, Schueck N, Dean M, Koeller D (1999) Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 8:743-749
6. Andrews NC (1999) Disorders of iron metabolism. N Engl J Med 341:1986-1995
7. Arden KE, Wallace DF, Dixon JL, Summerville L, Searle JW, Anderson GJ, Ramm GA, Powell LW, Subramaniam VN (2003) A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient. Gut 52:1215-1217
8. Bahram S, Gilfillan S, Kuhn LC, Moret R, Schulze JB, Lebeau A, Schumann K (1999) Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc Natl Acad Sci USA 96:13312-13317
9. Barton JC, Acton RT, Rivers CA, Bertoli LF, Gelbart T, West C, Beutler E (2003) Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. Blood Cells Mol Dis 31:310-319
10. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, Bishop DF (2000) Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood 96:3256-3264
11. Bekri S, May A, Cotter PD, Al-Sabah AI, Guo X, Masters GS, Bishop DF (2003) A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia. Blood 102:698-704
12. Beutler E (2003) The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis. Blood 101:3347-3350
13. Beutler E, Barton JC, Felitti VJ, Gelbart T, West C, Lee PL, Waalen J, Vulpe C (2003) Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis 31:305-309
14. Borgna-Pignatti C, Solinas A, Bombieri C, Micciolo R, Gamberini MR, De Stefano P, De Menis E, Pignatti PF (1998) The haemochromatosis mutations do not modify the clinical picture of thalassaemia major in patients regularly transfused and chelated. Br J Haematol 103:813-816
15. Borot N, Roth M, Malfroy L, Demangel C, Vinel JP, Pascal JP, Coppin H (1997) Mutations in the MHC class I-like candidate gene for hemochromatosis in French patients. Immunogenetics 45:320-324
16. Camaschella C, Fargion S, Sampietro M, Roetto A, Bosio S, Garozzo G, Arosio C, Piperno A (1999) Inherited HFE-unrelated hemochromatosis in Italian families. Hepatology 29:1563-1564
17. Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25:14-15
18. Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P (1999) Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93:4406-4417
19. Canonne-Hergaux F, Zhang AS, Ponka P, Gros P (2001) Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood 98:3823-3830
20. Carella M, D'Ambrosio L, Totaro A, Grifa A, Valentino MA, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, Camaschella C (1997) Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet 60:828-832
21. Cazzola M, Cremonesi L, Papaioannou M, Soriani N, Kioumi A, Charalambidou A, Paroni R, Romtsou K, Levi S, Ferrari M, Arosio P, Christakis J (2002) Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3). Br J Haematol 119:539-546
22. Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B, Travaglino E, Rolandi V, Biasiotto G, Drysdale J, Arosio P (2003) Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 101:1996-2000
23. Chaisiripoomkere W, Jootar S, Chanjarunee S, Ungkanont A (1999) Serum erythropoietin levels in thalassemia major and intermedia. Southeast Asian J Trop Med Public Health 30:786-788
24. Collins TS, Arcasoy MO (2004) Iron overload due to X-linked sideroblastic anemia in an African American man. Am J Med Genet 116:501-502
25. Courselaud B, Pigeon C, Inoue Y, Inoue J, Gonzalez FJ, Leroyer P, Gilot D, Boudjema K, Guguen-Guillouzo C, Brissot P, Loreal O, Ilyin G (2002) 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 277:41163-41170
26. Csere P, Lill R, Kispal, G (1998) Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p. FEBS Lett 441:266-270
27. Davies PS, Zhang AS, Anderson EL, Roy CN, Lampson MA, McGraw TE, Enns CA (2003) Evidence for the interaction of the hereditary haemochromatosis protein, HFE, with the transferrin receptor in endocytic compartments. Biochem J 373:145-153
28. Deaglio S, Capobianco A, Cali A, Bellora F, Alberti F, Righi L, Sapino A, Camaschella C, Malavasi F (2002) Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and a polyclonal antiserum. Blood 100:3782-3789
29. Delatycki MB, Allen KJ, Gow P, MacFarlane J, Radomski C, Thompson J, Hayden MR, Goldberg YP, Samuels ME (2004) A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis. Clin Genet 65:378-383
30. Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS (2002) Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 100:695-697
31. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776-781
32. Dore F, Bonfigli S, Gaviano E, Pardini S, Cianciulli P, Papa G, Longinotti M (1993) Serum erythropoietin levels in thalassemia intermedia. Ann Hematol 67:183-186
33. Drakesmith H, Sweetland E, Schimanski L, Edwards J, Cowley D, Ashraf M, Bastin J, Townsend AR (2002) The hemochromatosis protein HFE inhibits iron export from macrophages. Proc Natl Acad Sci U S A 99:15602-15607
34. Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP (1988) Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318:1355-1362
35. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo RJ, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prasss CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399-408
36. Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 95:1472-1477
37. Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, Prass CE, Starnes SM, Wolff RK, Parkkila S, Sly WS, Schatzman RC (1997) The hemochromatosis founder mutation in HLA-H disrupts b2-microglobulin interaction and cell surface expression. J Biol Chem 272:14025-14028
38. Fleming MD (2002) The genetics of inherited sideroblastic anemias. Semin Hematol 39:270-281
39. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95:1148-1153
40. Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC (1997) Microcytic anaemia mice have a mutation in nramp2, a candidate iron transporter gene. Nat Genet 16:383-386
41. Fleming RE, Ahmann JR, Migas MC, Waheed A, Koeffler HP, Kawabata H, Britton RS, Bacon BR, Sly WS (2002) Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci USA 99:10653-10658
42. Fleming RE, Migas MC, Holden CC, Waheed A, Britton RS, Tomatsu S, Bacon BR, Sly WS (2000) Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci USA 97:2214-2219
43. Fleming RE, Sly WS (2001a) Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. J Clin Invest 108:521-522
44. Fleming RE, Sly WS (2001b) Hepcidin: A putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA 98:8160-8162
45. Fletcher LM, Halliday JW (2002) Haemochromatosis: Understanding the mechanism of disease and implications for diagnosis and patient management following the recent cloning of novel genes involved in iron metabolism. J Intern Med 251:181-192
46. Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, Anderson GJ (2002) Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 123:835-844
47. Frazer DM, Wilkins SJ, Millard KN, McKie AT, Vulpe CD, Anderson GJ (2004) Increased hepcidin expression and hypoferraemia associated with an acute phase response are not affected by inactivation of HFE. Br J Haematol 126:434-436
48. Furukawa T, Kohno H, Tokunaga R, Taketani S (1995) Nitric oxide-mediated inactivation of mammalian ferrochelatase in vivo and in vitro: possible involvement of the iron-sulphur cluster of the enzyme. Biochem J 310:533-538
49. Furuyama K, Harigae H, Kinoshita C, Shimada T, Miyaoka K, Kanda C, Maruyama Y, Shibahara S, Sassa S (2003) Late-onset X-linked sideroblastic anemia following hemodialysis. Blood 101:4623-4624
50. Garrick LM, Gniecko K, Hoke JE, al-Nakeeb A, Ponka P, Garrick MD (1991) Ferric-salicylaldehyde isonicotinoyl hydrazone, a synthetic iron chelate, alleviates defective iron utilization by reticulocytes of the Belgrade rat. J Cell Physiol 146:460-465
51. Gehrke SG, Kulaksiz H, Herrmann T, Riedel HD, Bents K, Veltkamp C, Stremmel W (2003) Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood 102:371-376
52. Girelli D, Bozzini C, Roetto A, Alberti F, Daraio F, Colombari R, Olivieri O, Corrocher R, Camaschella C (2002) Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene. Gastroenterology 122:1295-1302
53. Gordeuk VR, Caleffi A, Corradini E, Ferrara F, Jones RA, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G, Garuti C, Gangaidzo IT, Gomo ZA, Moyo VM, Rouault TA, MacPhail P, Pietrangelo A (2003) Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis 31:299-304
54. Gross CN, Irrinki A, Feder JN, Enns CA (1998) Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation. J Biol Chem 273:22068-22074
55. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482-488
56. Haile DJ (2000) Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q32 by in situ hybridization. Cytogenet Cell Genet 88:328-329
57. Harris ZL, Durley AP, Man TK, Gitlin JD (1999) Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 96:10812-10817
58. Holmstrom P, Dzikaite V, Hultcrantz R, Melefors O, Eckes K, Stal P, Kinnman N, Smedsrod B, Gafvels M, Eggertsen G (2003) Structure and liver cell expression pattern of the HFE gene in the rat. J Hepatol 39:308-314
59. Huang FW, Rubio-Aliaga I, Kushner JP, Andrews NC, Fleming MD (2004) Identification of a novel mutation (C321X) in HJV. Blood 104:2176-2177
60. Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)- 1: implications for regulation and cellular function. Proc Natl Acad Sci USA 99:12345-12350
61. Hunter HN, Fulton DB, Ganz T, Vogel HJ (2002) The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem 277:37597-37603
62. Ikuta K, Fujimoto Y, Suzuki Y, Tanaka K, Saito H, Ohhira M, Sasaki K, Kohgo Y (2000) Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells. Biochimica Biophysica Acta 1496:221-231
63. Ilyin G, Courselaud B, Troadec MB, Pigeon C, Alizadeh M, Leroyer P, Brissot P, Loreal O (2003) Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and co-inducibility during iron overload. FEBS Lett 542:22-26
64. Johnson MB, Enns CA (2004) Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104:4287-4293
65. Jouanolle AM, Douabin-Gicquel V, Halimi C, Loreal O, Fergelot P, Delacour T, de Lajarte-Thirouard AS, Turlin B, Le Gall JY, Cadet E, Rochette J, David V, Brissot P (2003) Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload. J Hepatol 39:286-289
66. Kaplan J (2002) Mechanisms of cellular iron acquisition: another iron in the fire. Cell 111:603-606
67. Kawabata H, Fleming RE, Gui D, Moon SY, Saitoh T, O'Kelly J, Umehara Y, Wano Y, Said JW, Koeffler HP (2005) Expression of hepcidin is downregulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105:376-381
68. Kawabata H, Germain RS, Ikezoe T, Tong X, Green EM, Gombart AF, Koeffler HP (2001a) Regulation of expression of murine transferrin receptor 2. Blood 98:1949-1954
69. Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP (2000) Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 275:16618-16625
70. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP (2001b) Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 98:2714-2719
71. Kawabata H, Tong X, Kawanami T, Wano Y, Hirose Y, Sugai S, Koeffler HP (2004) Analyses for binding of the transferrin family of proteins to the transferrin receptor 2. Br J Haematol 127:464-473
72. Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP (1999) Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 274:20826-20832
73. Kispal G, Csere P, Guiard B, Lill R (1997) The ABC transporter Atm1p is required for mitochondrial iron homeostasis. FEBS Lett 418:346-350
74. Kispal G, Csere P, Prohl C, Lill R (1999) The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J 18:3981-3989
75. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M (2005) Iron release from macrophages after erythrophagocytosis is upregulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA 102:1324-1328
76. Knutson MD, Vafa MR, Haile DJ, Wessling-Resnick M (2003) Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood 102:4191-4197
77. Koyama C, Wakusawa S, Hayashi H, Suzuki R, Yano M, Yoshioka K, Kozuru M, Takayamam Y, Okada T, Mabuchi H (2005) Two novel mutations, L490R and V561X, of the transferrin receptor 2 gene in Japanese patients with hemochromatosis. Haematologica 90:302-307
78. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K (2000) LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 480:147-150
79. Krijt J, Vokurka M, Chang KT, Necas E (2004) Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin. Blood 104:4308-4310
80. Kulaksiz H, Gehrke SG, Janetzko A, Rost D, Bruckner T, Kallinowski B, Stremmel W (2004) Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut 53:735-743
81. Kulaksiz H, Theilig F, Bachmann S, Gehrke SG, Rost D, Janetzko A, Cetin Y, Stremmel W (2005) The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 184:361-370
82. Lanzara C, Roetto A, Daraio F, Rivard S, Ficarella R, Simard H, Cox TM, Cazzola M, Piperno A, Gimenez-Roqueplo AP, Grammatico P, Volinia S, Gasparini P, Camaschella C (2004) Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 103:4317-4321
83. Le Gac G, Mons F, Jacolot S, Scotet V, Ferec C, Frebourg T (2004) Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Br J Haematol 125:674-678
84. Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ (1998) Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93:111-123
85. Lebron JA, West AP Jr, Bjorkman PJ (1999) The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol 294:239-245
86. Lee P, Peng H, Gelbart T, Beutler E (2004a) The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes. Proc Natl Acad Sci USA 101:9263-9265
87. Lee P, Peng H, Gelbart T, Wang L, Beutler E (2005) Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 102:1906-1910
88. Lee PL, Barton JC, Brandhagen D, Beutler E (2004b) Hemojuvelin (HJV) mutations in persons of European, African-American, and Asian ancestry with adult onset haemochromatosis. Br J Haematol 127:224-229
89. Lee PL, Beutler E, Rao SV, Barton JC (2004c) Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 103:4669-4671
90. Lee PL, Gelbart T, West C, Halloran C, Beutler E (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 24:199-215
91. Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J (2001) A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276:24437-24440
92. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC (1999a) Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 21:396-399
93. Levy JE, Montross LK, Cohen DE, Fleming MD, Andrews NC (1999b) The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94:9-11
94. List A, Vardiman J, Issa JP, Dewitte TM (2004) Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program):297-317
95. List AF, Vardiman J, Issa JP, Dewitte TM (2004) Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program):297-317
96. Martins R, Picanco I, Fonseca A, Ferreira L, Rodrigues O, Coelho M, Seixas T, Miranda A, Nunes B, Costa L, Romao L, Faustino P (2004) The role of HFE mutations on iron metabolism in beta-thalassemia carriers. J Hum Genet 49:651-655
97. Matthes T, Aguilar-Martinez P, Pizzi-Bosman L, Darbellay R, Rubbia-Brandt L, Giostra E, Michel M, Ganz T, Beris P (2004) Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'-UTR of the HAMP gene. Blood 104:2181-2183
98. Mattman A, Huntsman D, Lockitch G, Langlois S, Buskard N, Ralston D, Butterfield Y, Rodrigues P, Jones S, Porto G, Marra M, De Sousa M, Vatcher G (2002) Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood 100:1075-1077
99. Mazur A, Feillet-Coudray C, Romier B, Bayle D, Gueux E, Ruivard M, Coudray C, Rayssiguier Y (2003) Dietary iron regulates hepatic hepcidin 1 and 2 mRNAs in mice. Metabolism 52:1229-1231
100. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291:1755-1759
101. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299-309
102. Melis M, Cau M, Deidda F, Barella S, Cao A, Galanello R (2002) H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers. Haematologica 87:242-245
103. Mims MP, Guan Y, Pospisilova D, Priwitzerova M, Indrak K, Ponka P, Divoky V, Prchal JT (2005) Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 105:1337-1342
104. Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A (2001) Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108:619-623
105. Montosi G, Paglia P, Garuti C, Guzman CA, Bastin JM, Colombo MP, Pietrangelo A (2000) Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. Blood 96:1125-1129
106. Muckenthaler M, Roy CN, Custodio AO, Minana B, DeGraaf J, Montross LK, Andrews NC, Hentze MW (2003) Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 34:102-107
107. Mukhopadhyay CK, Attieh ZK, Fox PL (1998) Role of ceruloplasmin in cellular iron uptake. Science 279:714-717
108. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T (2004a) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113:1271-1276
109. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C (2005) Hepcidin is decreased in TFR2 hemochromatosis. Blood 105:1803-1806
110. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004b) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090-2093
111. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T (2003) Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461-2463
112. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98:8780-8785
113. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S (2002a) Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 99:4596-4601
114. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002b) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037-1044
115. Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S (2002c) Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 29:327-335
116. Nicolas G, Viatte L, Lou DQ, Bennoun M, Beaumont C, Kahn A, Andrews NC, Vaulont S (2003) Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 34:97-101
117. Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P (2001) A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28:213-214
118. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77-82
119. Papanikolaou G, Tzilianos M, Christakis JI, Bogdanos D, Tsimirika K, Macfarlane J, Goldberg YP, Sakellaropoulos N, Ganz T, Nemeth E (2005) Hepcidin in iron overload disorders. Blood 105:4103-4105
120. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276:7806-7810
121. Parkkila S, Waheed A, Britton RS, Bacon BR, Zhou XY, Tomatsu S, Fleming RE, Sly WS (1997a) Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA 94:13198-13202
122. Parkkila S, Waheed A, Britton RS, Feder JN, Tsuchihashi Z, Schatzman RC, Bacon BR, Sly WS (1997b) 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 94:2534-2539
123. Pietrangelo A (2002) Physiology of iron transport and the hemochromatosis gene. Am J Physiol Gastrointest Liver Physiol 282:G403-414
124. Pietrangelo A, Caleffi A, Henrion J, Ferrara F, Corradini E, Kulaksiz H, Stremmel W, Andreone P, Garuti C (2005) Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128:470-479
125. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811-7819
126. Piperno A, Mariani R, Arosio C, Vergani A, Bosio S, Fargion S, Sampietro M, Girelli D, Fraquelli M, Conte D, Fiorelli G, Camaschella C (2000) Haemochromatosis in patients with beta-thalassaemia trait. Br J Haematol 111:908-914
127. Ponka P (1997) Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 89:1-25
128. Ponka P, Wilczynska A, Schulman HM (1982) Iron utilization in rabbit reticulocytes. A study using succinylacetone as an inhibitor or heme synthesis. Biochim Biophys Acta 720:96-105
129. Priwitzerova M, Pospisilova D, Prchal JT, Indrak K, Hlobilkova A, Mihal V, Ponka P, Divoky V (2004) Severe hypochromic microcytic anemia caused by a congenital defect of the iron transport pathway in erythroid cells. Blood 103:3991-3992
130. Raskind W, Wijsman E, Pagon RA, Cox TC, Bawden MJ, May BK, Bird TD (1991) X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am J Hum Genet 48:335-341
131. Richardson D, Ponka P, Vyoral D (1996) Distribution of iron in reticulocytes after inhibition of heme synthesis with succinylacetone: examination of the intermediates involved in iron metabolism. Blood 87:3477-3488
132. Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R, Simard R, D'Adamo AP, De Braekeleer M, Gasparini P (2003) Autosomal dominant reticuloendothelial iron overload (HFE type 4) due to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a large French-Canadian family. Haematologica 88:824-826
133. Rivera S, Liu L, Nemeth E, Gabayan V, Sorensen OE, Ganz T (2005) Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood 105:1797-1802
134. Robb A, Wessling-Resnick M (2004) Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104:4294-4299
135. Robb AD, Ericsson M, Wessling-Resnick M (2004) Transferrin receptor-2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies. Am J Physiol Cell Physiol 287:C1769-C1775
136. Rodriguez Martinez A, Niemela O, Parkkila S (2004) Hepatic and extrahepatic expression of the new iron regulatory protein hemojuvelin. Haematologica 89:1441-1445
137. Roetto A, Daraio F, Porporato P, Caruso R, Cox TM, Cazzola M, Gasparini P, Piperno A, Camaschella C (2004) Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). Blood 103:2407-2409
138. Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G, Piga A, Mackie PH, Robson KJ, Camaschella C (2002) A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4. Blood 100:733-734
139. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21-22
140. Roetto A, Totaro A, Piperno A, Piga A, Longo F, Garozzo G, Cali A, De Gobbi M, Gasparini P, Camaschella C (2001) New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 97:2555-2560
141. Rothenberg BE, Voland JR (1996) beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc Natl Acad Sci USA 93:1529-1534
142. Roy CN, Carlson EJ, Anderson EL, Basava A, Starnes SM, Feder JN, Enns CA (2000) Interactions of the ectodomain of HFE with the transferrin receptor are critical for iron homeostasis in cells. FEBS Lett 484:271-274
143. Roy CN, Custodio AO, de Graaf J, Schneider S, Akpan I, Montross LK, Sanchez M, Gaudino A, Hentze MW, Andrews NC, Muckenthaler MU (2004) An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nat Genet 36:481-485
144. Roy CN, Penny DM, Feder JN, Enns CA (1999) The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J Biol Chem 274:9022-9028
145. Salter-Cid L, Brunmark A, Li Y, Leturcq D, Peterson PA, Jackson MR, Yang Y (1999) Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci USA 96:5434-5439
146. Santos M, Schilham MW, Rademakers LH, Marx JJ, de SM, Clevers H (1996) Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med 184:1975-1985
147. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR (2005) In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood 105:4096-4102
148. Schrier S, Angelucci E (2005) New strategies in the treatment of the thalassemias. Annu Rev Med 56:157-171
149. Taketani S, Kakimoto K, Ueta H, Masaki R, Furukawa T (2003) Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase. Blood 101:3274-3280
150. Touret N, Martin-Orozco N, Paroutis P, Furuya W, Lam-Yuk-Tseung S, Forbes J, Gros P, Grinstein S (2004) Molecular and cellular mechanisms underlying iron transport deficiency in microcytic anemia. Blood 104:1526-1533
151. Townsend A, Drakesmith H (2002) Role of HFE in iron metabolism, hereditary haemochromatosis, anaemia of chronic disease, and secondary iron overload. Lancet 359:786-790
152. Vogt TM, Blackwell AD, Giannetti AM, Bjorkman PJ, Enns CA (2003) Heterotypic interactions between transferrin receptor and transferrin receptor 2. Blood 101:2008-2014
153. Vulpe CD, Kuo YM, Murphy TL, Cowley L, Askwith C, Libina N, Gitschier J, Anderson GJ (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21:195-199
154. Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, Feder JN, Schatzman RC, Britton RS, Bacon BR, Sly WS (1997) 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 94:12384-12389
155. Wallace DF, Clark RM, Harley HA, Subramaniam VN (2004a) Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis. J Hepatol 40:710-713
156. Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, Subramaniam VN (2002) Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 100:692-694
157. Wallace DF, Tonks ID, Zournazi A, Kay GF, Subramaniam VN (2004b) Inactivation of the murine Transferrin Receptor 2 gene using the Cre recombinase: loxP system. Genesis 39:38-41
158. Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304-4308
159. Weatherall D (2001) Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet 2:245-255
160. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC (2002) Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 100:3776-3781
161. West AP Jr, Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ (2000) Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem 275:38135-38138
162. West AP Jr, Giannetti AM, Herr AB, Bennett MJ, Nangiana JS, Pierce JR, Weiner LP, Snow PM, Bjorkman PJ (2001) Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. J Mol Biol 313:385-397
163. Yang F, Liu XB, Quinones M, Melby PC, Ghio A, Haile DJ (2002) Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem 277:39786-39791
164. Zhang A, Sheftel D, Ponka P (2005) Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria. Blood 105:368-375
165. Zhang AS, Davies PS, Carlson HL, Enns CA (2003) Mechanisms of HFE-induced regulation of iron homeostasis: Insights from the W81A HFE mutation. Proc Natl Acad Sci USA 100:9500-9505
166. Zhang AS, Xiong S, Tsukamoto H, Enns CA (2004) Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes. Blood 103:1509-1514
167. Zhou XY, Tomatsu S, Fleming RE, Parkkila S, Waheed A, Jiang J, Fei Y, Brunt EM, Ruddy DA, Prass CE, Schatzman RC, O'Neill R, Britton RS, Bacon BR, Sly WS (1998) HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 95:2492-2497
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Johnson, M.B., Enns, C.A., Zhang, AS. (2005). Iron in mammals: pathophysiological mechanisms of overload and deficiency in relation to disease. In: Tamas, M.J., Martinoia, E. (eds) Molecular Biology of Metal Homeostasis and Detoxification. Topics in Current Genetics, vol 14. Springer, Berlin, Heidelberg. https://doi.org/10.1007/4735_99
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