Iron-deficiency anemia secondary to mutations in genes controlling hepcidin

Expert Review of Hematology

Volumn 3, Issue 2, 2010, Pages 205-216

  Cau, Milena ^a   Melis, Maria Antonietta ^a   Congiu, Rita ^a   Galanello, Renzo ^a  

^a UNIVERSITY OF CAGLIARI   (Italy)

Author keywords

Hepcidin; IRIDA; Iron homeostasis; Iron deficiency anemia; Matriptase 2; TMPRSS6

Indexed keywords

APOTRANSFERRIN; BONE MORPHOGENETIC PROTEIN; CARRIER PROTEIN; FERROPORTIN; FERROUS GLUCONATE; GROWTH DIFFERENTIATION FACTOR 15; HEME CARRIER PROTEIN 1; HEMOGLOBIN; HEMOJUVELIN; HEPCIDIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 1BETA; INTERLEUKIN 1BETA; INTERLEUKIN 6; IRON; MATRIPTASE; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; RECEPTOR; SMAD1 PROTEIN; SMAD5 PROTEIN; SMAD8 PROTEIN; STAT3 PROTEIN; TF RECEPTOR 1; TF RECEPTOR 2; TRANSFERRIN; TRANSMEMBRANE PROTEASE SERINE 6; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ERYTHROPOIESIS; GENE CONTROL; GENE EXPRESSION REGULATION; GENE MUTATION; GENE OVEREXPRESSION; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; GENOME ANALYSIS; HEART PROTECTION; HEMATOLOGICAL PARAMETERS; HEMOGLOBIN BLOOD LEVEL; HOMEOSTASIS; HORMONE BLOOD LEVEL; HORMONE SYNTHESIS; HORMONE URINE LEVEL; HUMAN; HYPOXIA; IMMUNOPRECIPITATION; IRON ABSORPTION; IRON BLOOD LEVEL; IRON DEFICIENCY ANEMIA; IRON INTAKE; IRON METABOLISM; IRON OVERLOAD; IRON STORAGE; MEAN CORPUSCULAR HEMOGLOBIN; MEAN CORPUSCULAR VOLUME; PHENOTYPE; POINT MUTATION; PRIORITY JOURNAL; PROTEIN BINDING; REVIEW; SPLICING DEFECT; TRANSFERRIN BLOOD LEVEL;

ANEMIA, IRON-DEFICIENCY; ANTIMICROBIAL CATIONIC PEPTIDES; HOMEOSTASIS; HUMANS; IRON; MEMBRANE PROTEINS; MUTATION; SERINE ENDOPEPTIDASES;

EID: 77953379428     PISSN: 17474086     EISSN: None     Source Type: Journal    
DOI: 10.1586/ehm.10.2     Document Type: Review

References (107)

1. Andrews N. Iron deficiency and related disorders. In: Wintrobe's Clinical Hematology (Volume 1). Greer JP, Means RT, Arbor D et al. (Eds). Lippincott Williams & Wilkins, PA, USA, 810-834 (2009).
2. Means RT, Glader B. Anemia: general considerations. In: Wintrobe's Clinical Hematology (Volume 1). Greer JP, Means RT, Arbor D et al. (Ed). Lippincott Williams & Wilkins, PA, USA, 779-809 (2009).
3. Iolascon A, De Falco L, Beaumont C. Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematologica 94(3), 395-408 (2009).
4. Piperno A, Mariani R, Trombini P, Girelli D. Hepcidin modulation in human diseases: from research to clinic. World J. Gastroenterol. 15(5), 538-551 (2009).
5. Fleming MD. The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology Am. Soc. Hematol. Educ. Program 151-158 (2008).
6. Kemna EH, Tjalsma H, Podust VN, Swinkels DW. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin. Chem. 53(4), 620-628 (2007).
7. Finberg KE, Heeney MM, Campagna DR et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat. Genet. 40(5), 569-571 (2008).
8. Melis MA, Cau M, Congiu R 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 93(10), 1473-14799 (2008).
9. 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 112(5), 2089-2091 (2008).
10. Ramsay AJ, Quesada V, Sanchez M et al. Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Hum. Mol. Genet. 18(19), 3673-3683 (2009).
11. Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol. Appl. Pharmacol. 202(2), 199-211 (2005).
12. Wrighting DM, Andrews NC. Iron homeostasis and erythropoiesis. In: Current Topics in Developmental Biology (Volume 82). Bieker JJ (Eds). Elsevier Inc., San Diego, CA, USA, 141-167 (2008).
13. Nemeth E. Iron regulation and erythropoiesis. Curr. Opin. Hematol. 15(3), 169-175 (2008).
14. Anderson GJ. Mechanisms of iron loading and toxicity. Am. J. Hematol. 82(12 Suppl.), 1128-1131 (2007).
15. McKie AT, Barrow D, Latunde-Dada GO et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291(5509), 1755-1759 (2001).
16. Gunshin H, Starr CN, Direnzo C et al. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 106(8), 2879-2883 (2005).
17. 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 98(13), 3823-3830 (2001).
18. Shayeghi M, Latunde-Dada GO, Oakhill JS et al. Identification of an intestinal heme transporter. Cell 122(5), 789-801 (2005).
19. Qiu A, Jansen M, Sakaris A et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127(5), 917-928 (2006).
20. Vulpe CD, Kuo YM, Murphy T et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet. 21(2), 195-199 (1999).
21. Anderson GJ, Frazer DM, McLaren GD. Iron absorption and metabolism. Curr. Opin. Gastroenterol. 25(2), 129-135 (2009).
22. Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol. Rev. 67(2), 520-582 (1987).
23. Darshan D, Anderson GJ. Interacting signals in the control of hepcidin expression. Biometals 22(1), 77-87 (2009).
24. Ohgami RS, Campagna DR, Greer EL et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat. Genet. 37(11), 1264-1269 (2005).
25. Gruenheid S, Canonne-Hergaux F, Gauthier S, Hackam DJ, Grinstein S, Gros P. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med. 189(5), 831-841 (1999).
26. Breuer W, Shvartsman M, Cabantchik ZI. Intracellular labile iron. Int. J. Biochem. Cell Biol. 40(3), 350-354 (2008).
27. Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P. Comparative studies of duodenal and macrophage ferroportin proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 290(1), G156-G163 (2006).
28. Donovan A, Lima CA, Pinkus JL et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell. Metab. 1(3), 155-157 (2005).
29. De Domenico I, Ward DM, di Patti MC et al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 26(12), 2823-2831 (2007).
30. De Domenico I, McVey Ward D, Kaplan J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat. Rev. Mol. Cell. Biol. 9(1), 72-81 (2008).
31. Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol. Dis. 30(3), 288-297 (2003).
32. Nemeth E, Tuttle MS, Powelson J et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704), 2090-2093 (2004).
33. Anderson GJ, Frazer DM, Wilkins SJ et al. Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochem. Soc. Trans. 30(4), 724-726 (2002).
34. Muckenthaler MU. Fine tuning of hepcidin expression by positive and negative regulators. Cell. Metab. 8(1), 1-3 (2008).
35. Viatte L, Vaulont S. Hepcidin. The iron watcher. Biochimie 91(10), 1223-1228 (2009).
36. Krause A, Neitz S, Mägert HJ et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480(2-3), 147-150 (2000).
37. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276(11), 7806-7810 (2001).
38. Kemna EH, Tjalsma H, Willems HL, Swinkels DW. Hepcidin: from discovery to differential diagnosis. Haematologica 93(1), 90-97 (2008).
39. Atanasiu V, Manolescu B, Stoian I. Hepcidin - central regulator of iron metabolism. Eur. J. Haematol. 78(1), 1-10 (2007).
40. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323-342 (2006).
41. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol. Dis. 40(1), 132-138 (2008).
42. Scamuffa N, Basak A, Lalou C et al. Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7. Gut 57(11), 1573-1582 (2008).
43. Kartikasari AE, Roelofs R, Schaeps RM et al. Secretion of bioactive hepcidin-25 by liver cells correlates with its gene transcription and points towards synergism between iron and inflammation signaling pathways. Biochim. Biophys. Acta 1784(12), 2029-2037 (2008).
44. Bekri S, Gual P, Anty R et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology 131(3), 788-796 (2006).
45. Gnana-Prakasam JP, Martin PM, Mysona BA, Roon P, Smith SB, Ganapathy V. Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/ toll-like receptor-4 pathway independent of Hfe. Biochem. J. 411(1), 79-88 (2008).
46. Theurl M, Theurl I, Hochegger K et al. Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression. J. Mol. Med. 86(7), 825-835 (2008).
47. Nicolas G, Bennoun M, Devaux I 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 98(15), 8780-8785 (2001).
48. Roetto A, Papanikolaou G, Politou M et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat. Genet. 33(1), 21-22 (2003).
49. Nicolas G, Bennoun M, Porteu A et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc. Natl Acad. Sci. USA 99(7), 4596-4601 (2002).
50. 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 100(10), 3776-3781 (2002).
51. Nicolas G, Chauvet C, Viatte L et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110(7), 1037-1044 (2002).
52. Babitt JL, Huang FW, Wrighting DM et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38(5), 531-539 (2006).
53. Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler MU. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J. Mol. Med. 87(5), 471-480 (2009).
54. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117(7), 1933-1939 (2007).
55. Wang RH, Li C, Xu X et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell. Metab. 2(6), 399-409 (2005).
56. Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc. Natl Acad. Sci. USA 103(27), 10289-10293 (2006).
57. Yu PB, Hong CC, Sachidanandan C et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4(1), 33-41 (2008).
58. Kautz L, Meynard D, Monnier A et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112(4), 1503-1509 (2008).
59. Andriopoulos B Jr, Corradini E, Xia Y et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41(4), 482-487 (2009).
60. 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. 41(4), 478-481 (2009).
61. Xia Y, Babitt JL, Sidis Y, Chung RT, Lin HY. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111(10), 5195-5204 (2008).
62. Papanikolaou G, Samuels ME, Ludwig EH et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36(1), 77-82 (2004).
63. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 106(8), 2884-2889 (2005).
64. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J. Clin. Invest. 115(8), 2187-2191 (2005).
65. Bridle KR, Frazer DM, Wilkins SJ et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361(9358), 669-673 (2003).
66. Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 110(6), 2182-2189 (2007).
67. Giannetti AM, Björkman PJ. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J. Biol. Chem. 279(24), 25866-25875 (2004).
68. Lebrón JA, West AP Jr, Bjorkman PJ. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J. Mol. Biol. 294(1), 239-245 (1999).
69. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell. Metab. 9(3), 217-227 (2009).
70. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell. Metab. 7(3), 205-214 (2008).
71. Ramey G, Deschemin JC, Vaulont S. Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 94(6), 765-772 (2009).
72. 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 50(6), 1992-2000 (2009).
73. Lee P, Peng H, Gelbart T, Beutler E. The IL-6- and lipopolysaccharide- induced transcription of hepcidin in HFE-, transferrin receptor 2-, and b2- microglobulin-deficient hepatocytes. Proc. Natl Acad. Sci. USA 101(25), 9263-9265 (2004).
74. Inamura J, Ikuta K, Jimbo J et al. Upregulation of hepcidin by interleukin-1b in human hepatoma cell lines. Hepatol. Res. 33(3), 198-205 (2005).
75. Fleming RE. Iron and inflammation: cross-talk between pathways regulating hepcidin. J. Mol. Med. 86(5), 491-494 (2008).
76. Verga Falzacappa MV, Casanovas G, Hentze MW, Muckenthaler MU. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J. Mol. Med. 86(5), 531-540 (2008).
77. Frazer DM, Wilkins SJ, Millard KN, McKie AT, Vulpe CD, Anderson GJ. Increased hepcidin expression and hypoferraemia associated with an acute owing response are not affected by inactivation of HFE. Br. J. Haematol. 126(3), 434-436 (2004).
78. Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle 7(1), 28-32 (2008).
79. Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA. Molecular characterization and chromosomal localization of a third a-class hypoxia inducible factor subunit, HIF3a. Gene Expr. 7(3), 205-213 (1998).
80. Peyssonnaux C, Zinkernagel AS, Schuepbach RA et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest. 117(7), 1926-1932 (2007).
81. Semenza GL. Life with oxygen. Science 318(5847), 62-64 (2007).
82. Braliou GG, Verga Falzacappa MV, Chachami G, Casanovas G, Muckenthaler MU, Simos G. 2-oxoglutarate-dependent oxygenases control hepcidin gene expression. J. Hepatol. 48(5), 801-810 (2008).
83. Choi SO, Cho YS, Kim HL, Park JW. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPa and STAT-3. Biochem. Biophys. Res. Commun. 356(1), 312-317 (2007).
84. 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. 9(2), 152-164 (2009).
85. Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2a, but not HIF-1a, promotes iron absorption in mice. J. Clin. Invest. 119(5), 1159-1166 (2009).
86. Tanno T, Bhanu NV, Oneal PA et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat. Med. 13(9), 1096-1101 (2007).
87. Tanno T, Porayette P, Sripichai O et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114(1), 181-186 (2009).
88. Kanda J, Mizumoto C, Kawabata H et al. Serum hepcidin level and erythropoietic activity after hematopoietic stem cell transplantation. Haematologica 93(10), 1550-1554 (2008).
89. Pinto JP, Ribeiro S, Pontes H et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPa. Blood 111(12), 5727-5733 (2008).
90. Velasco G, Cal S, Quesada V, Sánchez LM, López-Otín 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. 277(40), 37637-37646 (2002).
91. Ramsay AJ, Hooper JD, Folgueras AR, Velasco G, Lope-Otin C. Matriptase-2 (TMPRSS6): a protelytic regulator of iron homeostasis. Haematologica 94(6), 840-849 (2009).
92. Hooper JD, Campagnolo L, Goodarzi G, Truong TN, Stuhlmann H, Quigley JP. Mouse matriptase-2: identification, characterization and comparative mRNA expression analysis with mouse hepsin in adult and embryonic tissues. Biochem. J. 373(Pt 3), 689-702 (2003).
93. Du X, She E, Gelbart T et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320(5879), 1088-1092 (2008).
94. Folgueras AR, de Lara FM, Pendás AM et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112(6), 2539-2545 (2008).
95. Knutson MD. Into the matrix: regulation of the iron regulatory hormone hepcidin by matriptase-2. Nutr. Rev. 67(5), 284-288 (2009).
96. 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. 8(6), 502-511 (2008).
97. Truksa J, Gelbart T, Peng H, Beutler E, Beutler B, Lee P. Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. Br. J. Haematol. 147(4), 571-581 (2009).
98. Melis MA, Cau M, Congiu R, Sole G, Cao A, Galanello R. Identification of a gene involved in hereditary microcytic anemia due to detective iron absorption in a Sardinian family. Presented at: European Human Genetics Conference 2007. Nice, France, June 16-19 (2007).
99. Tchou I, Diepold M, Pilotto PA et al. Haematologic data, iron parameters and molecular findings in two new cases of iron-refractory iron deficiency anaemia. Eur. J. Haematol. 83(6), 595-602 (2009).
100. 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. 147(5), 766-769 (2009).
101. Beutler E, Van Geet C, Te Loo DM et al. Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia. Blood Cells Mol. Dis. 44(1), 16-21 (2009).
102. Silvestri L, Guillem F, Pagani A et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood 113(22), 5605-5608 (2009).
103. Chambers JC, Zhang W, Li Y et al. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat. Genet. 41(11), 1170-1172 (2009).
104. Benyamin B, Ferreira MA, Willemsen G et al. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat. Genet. 41(11), 1173-1175 (2009).
105. Tanaka T, Roy CN, Yao W et al. A genome-wide association analysis of serum iron concentrations. Blood 115(1), 94-96 (2009).
106. Finberg KE. Iron-refractory iron deficiency anemia. Semin Hematol. 46(4), 378-386 (2009).
107. Castoldi M, Vujic-Spasic M, Stolte J et al. The liver specific microRNA 122a regulates the expression of HFE, HFE2, and Hepcidin and controls systemic iron homeostasis. Presented at: 2009 International BioIron Society Meeting. Porto, Portugal, 7-11 June 2009