Seminars in Hematology
Volume 46, Issue 4 , Pages 378-386 , October 2009

Iron-Refractory Iron Deficiency Anemia

  • Karin E. Finberg

      Affiliations

    • Corresponding Author InformationAddress correspondence to Karin E. Finberg, MD, PhD, Duke University Medical Center, Department of Pharmacology & Cancer Biology, Levine Science Research Center C-127, Research Drive, Box 3813, Durham, NC 27710

References 

  1. Buchanan GR, Sheehan RG. Malabsorption and defective utilization of iron in three siblings. J Pediatr. 1981;98:723–728
  2. Brown AC, Lutton JD, Pearson HA, Nelson JC, Levere RD, Abraham NG. Heme metabolism and in vitro erythropoiesis in anemia associated with hypochromic microcytosis. Am J Hematol. 1988;27:1–6
  3. Hartman KR, Barker JA. Microcytic anemia with iron malabsorption: an inherited disorder of iron metabolism. Am J Hematol. 1996;51:269–275
  4. Pearson HA, Lukens JN. Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J Pediatr Hematol Oncol. 1999;21:412–417
  5. Andrews NC. Iron deficiency: lessons from anemic mice. Yale J Biol Med. 1997;70:219–226
  6. Galanello R, Cau M, Melis MA, Deidda F, Cao A, Cazzola M. Studies of NRAMP2, transferrin receptor and transferrin genes as candidate genes for human hereditary microcytic anemia due to defective iron absorption and utilization [abstract]. ASH Annual Meeting Abstracts. 1998;92S:669a
  7. Mayo MM, Samuel SM. Iron deficiency anemia due to a defect in iron metabolism: a case report. Clin Lab Sci. 2001;14:135–138
  8. 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;40:569–571
  9. 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;93:1473–1479
  10. Hartman KR, Finberg KE, Merino ME. Iron resistant iron deficiency anemia: long term follow-up of 5 patients [abstract]. ASPHO Annual Meeting Abstracts. 2009;
  11. Melis MA, Cau M, Congiu R, Sole G, Cao A, Galanello R. Identification of a gene involve in hereditary microcytic anemia due to defective iron absorption in a Sardinian family [abstract]. ESHG Annual Meeting Abstracts. 2007;15 S1:261
  12. Velasco G, Cal S, Quesada V, Sanchez LM, Lopez-Otin C. Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J Biol Chem. 2002;277:37637–37646
  13. 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;320:1088–1092
  14. Beutler E, Lee P, Gelbart T, Du X, Beutler B. The mask mutation identifies Tmprss6 as an essential suppressor of hepcidin [abstract]. ASH Annual Meeting Abstracts. 2007;110:9a
  15. Netzel-Arnett S, Hooper JD, Szabo R, Madison EL, Quigley JP, Bugge TH, et al. Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Rev. 2003;22:237–258
  16. 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;112:2089–2091
  17. Finberg KE, Heeney MM, Campagna D, Fleming MD, Andrews NC. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia [abstract]. ASHG Annual Meeting Abstracts. 2008;317
  18. The International HapMap Consortium. The International HapMap Project. Nature. 2003;426:789–796
  19. Lin CY, Anders J, Johnson M, Sang QA, Dickson RB. Molecular cloning of cDNA for matriptase, a matrix-degrading serine protease with trypsin-like activity. J Biol Chem. 1999;274:18231–18236
  20. Parr C, Sanders AJ, Davies G, Martin T, Lane J, Mason MD, et al. Matriptase-2 inhibits breast tumor growth and invasion and correlates with favorable prognosis for breast cancer patients. Clin Cancer Res. 2007;13:3568–3576
  21. Sanders AJ, Parr C, Martin TA, Lane J, Mason MD, Jiang WG. Genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. J Cell Physiol. 2008;216:780–789
  22. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 2006;26:323–342
  23. 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
  24. Kemna EH, Tjalsma H, Podust VN, Swinkels DW. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 2007;53:620–628
  25. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008;112:4292–4297
  26. 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;306:2090–2093
  27. Nemeth E, Preza GC, Jung CL, Kaplan J, Waring AJ, Ganz T. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood. 2006;107:328–333
  28. 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;18:2569–2578
  29. De Domenico I, Nemeth E, Nelson JM, Phillips JD, Ajioka RS, Kay MS, et al. The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab. 2008;8:146–156
  30. Folgueras AR, Martin de Lara F, Pendas AM, Garabaya C, Rodriguez F, Astudillo A, et al. The membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood. 2008;112:2539–2545
  31. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8:502–511
  32. 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
  33. 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;38:531–539
  34. Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev. 2005;16:251–263
  35. Iolascon A, De Falco L, Beaumont C. Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematologica. 2009;94:395–408
  36. 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;105:1337–1342
  37. Iolascon A, d'Apolito M, Servedio V, Cimmino F, Piga A, Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006;107:349–354
  38. Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood. 2006;107:4168–4170
  39. 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
  40. Canonne-Hergaux F, Zhang AS, Ponka P, Gros P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood. 2001;98:3823–3830
  41. Bannerman RM, Edwards JA, Kreimer-Birnbaum M, McFarland E, Russell ES. Hereditary microcytic anaemia in the mouse; studies in iron distribution and metabolism. Br J Haematol. 1972;23:235–245
  42. Edwards JA, Hoke JE. Red cell iron uptake in hereditary microcytic anemia. Blood. 1975;46:381–388
  43. Fleming MD, Trenor 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;16:383–386
  44. Craven CM, Alexander J, Eldridge M, Kushner JP, Bernstein S, Kaplan J. Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proc Natl Acad Sci U S A. 1987;84:3457–3461
  45. Trenor CC, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood. 2000;96:1113–1118
  46. Goldwurm S, Casati C, Venturi N, Strada S, Santambrogio P, Indraccolo S, et al. Biochemical and genetic defects underlying human congenital hypotransferrinemia. Hematol J. 2000;1:390–398
  47. Aslan D, Crain K, Beutler E. A new case of human atransferrinemia with a previously undescribed mutation in the transferrin gene. Acta Haematol. 2007;118:244–247
  48. 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
  49. Chung A, Leo K, Wong G, Chuah K, Ren J, Lee C. Giant hepatocellular adenoma presenting with chronic iron deficiency anemia. Am J Gastroenterol. 2006;101:2160–2162
  50. 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
  51. 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;113:1271–1276
  52. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–1023

 Supported by a grant from the Cooley's Anemia Foundation.

PII: S0037-1963(09)00103-6

doi: 10.1053/j.seminhematol.2009.06.006

Seminars in Hematology
Volume 46, Issue 4 , Pages 378-386 , October 2009

Article Tools

* Image Usage & Resolution