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Factors influencing disease phenotype and penetrance in HFE haemochromatosis

Abstract

Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not all p.C282Y homozygotes develop clinical features of haemochromatosis, and not all p.C282Y homozygotes even present abnormal iron parameters justifying venesection therapy. This situation was not apparent from initial genotype/phenotype correlation studies as there was a selection bias of patients. Only those patients with a significant iron burden were included in these early studies. It is now largely accepted that the p.C282Y/p.C282Y genotype is necessary for the development of HFE haemochromatosis. However, this genotype provides few clues as to why certain symptoms are associated with the disease. Expression of iron overload in people with this genotype depends on the complex interplay of environmental factors and modifier genes. In this review, we restrict our discussion to work done in humans giving examples of animal models where this has helped clarify our understanding. We discuss penetrance, explaining that this concept normally does not apply to autosomal recessive disorders, and discuss the usefulness of different biochemical markers in ascertaining iron burden. Hepcidin, a peptide synthesized primarily by the liver, has been identified as the central regulator in iron homeostasis. Consequently, understanding its regulation is the key. We conclude that the main goal now is to identify important modifiers that have a significant and unambiguous effect on iron storage.

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References

  1. Adams PC, Jeffrey G, Alanen K, Chakrabarti S, Preshaw R, Howson W, Grant D (1999) Transplantation of haemochromatosis liver and intestine into a normal recipient. Gut 45:783

  2. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P (2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352:1769–1778

  3. Aguilar-Martinez P, Bismuth M, Blanc F, Blanc P, Cunat S, Dereure O, Giansily-Blaizot M, Jorgensen C, Konate A, Larrey D, Le Quellec A, Mura T, Raingeard I, Ramos J, Renard EFR, Schved JF, Picot MC (2010) The Southern French registry of genetic hemochromatosis: a tool for determining clinical prevalence of the disorder and genotype penetrance. Hematologica 95:551–556

  4. Aigner E, Theurl I, Haufe H, Seifert M, Hohla F, Scharinger L, Stickel F, Moulane F, Weiss G, Datz C (2008) Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology 135:680–688

  5. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, McLaren CE, Bahlo M, Nisselle AE, Vulpe CD, Anderson GJ, Southey MC, Giles GG, English DR, Hopper JL, Olynyk JK, Powell LW, Gertig DM (2008) Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 358:221–230

  6. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG (2004) Hemochromatosis mutations in the general population: iron overload progression rate. Blood 103:2914–2919

  7. Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL (2009) BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41:482–487

  8. Asberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelonning K, Fjosne U, Halvorsen TB, Smethurst HB, Sagen E, Bjerve KS (2001) Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol 36:1108–1115

  9. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY (2006) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38:531–539

  10. Bacon BR, Britton RS (2008) Clinical penetrance of hereditary hemochromatosis. N Engl J Med 358:291–292

  11. Bahram S, Gilfillan S, Kühn LC, Moret R, Schulze JB, Lebeau A, Schümann K (1999) Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc Natl Acad Sci USA 96:13312–13317

  12. Beaton MD, Adams PC (2006) Prognostic factors and survival in patients with hereditary hemochromatosis and cirrhosis. Can J Gastroenterol 20:257–260

  13. Bennett MJ, Lébron JA, Bjorkman PJ (2000) Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403:46–53

  14. Bensaid M, Fruchon S, Mazeres C, Bahram S, Roth MP, Coppin H (2004) Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology 126:1400–1408

  15. Benyamin B, McRae AF, Zhu G, Gordon S, Henders AK, Palotie A, Peltonen L, Martin NG, Montgomery GW, Whitfield JB, Visscher PM (2009) Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 84:60–65

  16. Beutler E, Gelbart T (2002) Tumor necrosis factor alpha promoter polymorphisms and liver abnormalities of homozygotes for the 845 G>A (C282Y) hereditary hemochromatosis mutation. Blood 100:2268–2269

  17. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T (2002a) Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359:211–218

  18. Beutler E, Felitti V, Koziol JA, Gelbart T (2002b) Clinical haemochromatosis in HFE mutation carriers. Lancet 360:411–412

  19. Beutler E, Gelbart T, Lee P (2002c) Haptoglobin polymorphism in iron homeostasis. Clin Chem 48:2232–2235

  20. Bonekamp NA, Volkl A, Fahimi HD, Schrader M (2009) Reactive oxygen species and peroxisomes: struggling for balance. Biofactors 35:346–355

  21. Bothwell TH, MacPhail AP (1998) Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects. Semin Hematol 35:55–71

  22. Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH, Subramaniam VN, Powell LW, Anderson GJ, Ramm GA (2003) Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361:669–673

  23. Brissot P, de Bels F (2006) Current approaches to the management of hemochromatosis. Hematol Soc Hematol Educ Program 2006:36–41

  24. Cadet E, Capron D, Perez AS, Crépin SN, Arlot S, Ducroix JP, Dautréaux M, Fardellone P, Leflon P, Merryweather-Clarke AT, Livesey KJ, Pointon JJ, Rose P, Harcourt J, Emery J, Sueur JM, Feyt R, Robson KJ, Rochette J (2003) A targeted approach significantly increases the identification rate of patients with undiagnosed haemochromatosis. J Intern Med 253(2):217–224

  25. 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

  26. Carter K, Bowen DJ, McCune CA, Worwood M (2003) Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis. Br J Haematol 122:326–332

  27. Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler M (2009) 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 87:471–480

  28. Chua AC, Delima RD, Morgan EH, Herbison CE, Tirinitz-Parker JE, graham RM, Fleming RE, Britton RS, Bacon BR, Olynyk JK, Trinder D (2010) Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of hemochromatosis. J Hepatol 52:425–431

  29. Constantine CC, Anderson GJ, Vulpe CD, McLaren CE, Bahlo M, Yeap HL, Gertig DM, Osborne NJ, Bertalli NA, Beckman KB, Chen V, Matak P, McKie AT, Delatycki MB, Olynyk JK, English DR, Southey MC, Giles GG, Hopper JL, Allen KJ, Gurrin LC (2009) A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis. Br J Haematol 147:140–149

  30. Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B Jr, Lin HY, Pietrangelo A, Babitt JL (2009) Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology 137:1489–1497

  31. Cox T, Rochette J, Camaschella C, Walker A, Robson K (2002) Clinical haemochromatosis in HFE carriers. Lancet 360:412–413

  32. Crawford DH, Powell LW, Leggett BA, Francis JS, Fletcher LM, Webb SI, Halliday JW, Jazwinska EC (1995) Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene. Am J Hum Genet 57:362–367

  33. Crawford DH, Fletcher LM, Hubscher SG, Stuart KA, Gane E, Angus PW, Jeffrey GP, McCaughan GW, Kerlin P, Powell LW, Elias EE (2004) Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis. Hepatology 39:1655–1662

  34. Cruz E, Whittington C, Krikler SH, Mascarenhas C, Lacerda R, Vieira J, Porto G (2008) A new 500 kb haplotype associated with high CD8+T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis. BMC Med Genet 9:97

  35. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, Ganz T, Musci G, Kaplan J (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 18:2569–2578

  36. de Sousa M, Reimão R, Lacerda R, Hugo P, Kaufmann SHE, Porto G (1994) Iron overload in β2-microglobulin-deficient mice. Immunol Lett 39:105–111

  37. Deugnier Y, Mosser J (2008) Modifying factors of the HFE hemochromatosis phenotype. Expert Rev Gastroenterol Hepatol 2:531–540

  38. Deugnier Y, Jouanolle A-M, Chaperon J, Moirand R, Pithois C, Meyer J-F, Pouchard M, Lafraise B, Brigand A, Caserio-Schoenemann C, Adams P, Le-Gall J-Y, David V (2002) Gender-specific phenotypic expression, screening strategies in C282Y-linked haemochromatosis. A study of 9396 French people. Br J Haematol 118:1170–1178

  39. Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M (2004) The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 115(4):269–779

  40. 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, Palls J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781

  41. Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR (2005) Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 106(3):1092–1097

  42. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, Khovananth K, Mudd S, Mann N, Moresco EM, Beutler E, Beutler B (2008) The serine protease TMPRSS6 is required to sense iron deficiency. Science 320:1088–1092

  43. Dupic F, Fruchon S, Bensaid M, Borot N, Radosaljevic M, Loreal O, Brissot P, Gilfillan S, Bahram S, Coppin H, Roth M-P (2002) Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains. Gastroenterology 122:745–751

  44. Fargion S, Valenti L, Dongiovanni P, Scaccabarozzi A, Fracanzani AL, Taioli E, Mattioli M, Sampietro M, Fiorelli G (2001) Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood 97:3707–3712

  45. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, 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, Prass 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

  46. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, Andrews NC, Fleming MD (2008) Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 40:569–571

  47. Flanagan JM, Peng H, Beutler E (2007) Effects of alcohol consumption on iron metabolism in mice with hemochromatosis mutations. Alcohol Clin Exp Res 31:138–143

  48. Fleming RE (2009) Iron sensing as a partnership: HFE and transferrin receptor 2. Cell Metab 9:211–212

  49. Fleming RE, Holden CC, Tomatsu S, Waheed A, brunt EM, Britton RS, Bacon BR, Roopenian DC, Sly WS (2001) Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc Natl Acad Sci USA 98:2707–2711

  50. 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

  51. Gable CB (1992) Hemochromatosis and dietary iron supplementation: implications from US mortality, morbidity, and health survey data. J Am Diet Assoc 92:208–212

  52. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA (2009) Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 9:217–227

  53. Garuti C, Tian Y, Montosi G, Sabelli M, Corradini E, Graf R, Ventura P, Vegetti A, Clavien PA, Pietrangelo A (2010) Hepcidin expression does not rescue the iron-poor phenotype of Kuppfer cells in Hfe-null mice after liver transplantation. Gastroenterology (in press)

  54. Gerolami V, Le Gac G, Mercier L, Nezri M, Berge-Lefranc JL, Ferec C (2008) Early-onset haemochromatosis caused by a novel combination of TFR2 mutations(p.R396X/c.1538–2 A>G) in a woman of Italian descent. Haematologica 93:e45–e46

  55. Goswami T, Andrews NC (2006) Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 281:28494–28498

  56. Gouya L, Muzeau F, Robreau AM, Letteron P, Couchi E, Lyoumi S, Deybach JC, Puy H, Fleming R, Demant P, Beaumont C, Grandchamp B (2007) Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFE-hemochromatosis modifier gene. Gastroenterology 132:679–686

  57. Guillem F, Lawson S, Kannengiesser C, Westerman M, Beaumont C, Grandchamp B (2008) Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood 112:2089–2091

  58. Guyader D, Jacquelinet C, Moirand R, Turlin B, Mendler MH, Chaperon J, David V, Brissot B, Adams P, Deugnier Y (1998) Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 115:929–936

  59. 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

  60. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, Fein E, Andriopoulos B, Pantopoulos K, Gollan J (2006) Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 281:22974–22982

  61. Harrison-Findik DD, Klein E, Evans J, Gollan J (2009) Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-alpha signaling. Am J Physiol Gastrointest Liver Physiol 296:G112–G118

  62. Heritage ML, Murphy TL, Bridle KR, Anderson GJ, Crawford DH, Fletcher LM (2009) Hepcidin regulation in wild-type and Hfe knockout mice in response to alcohol consumption: evidence for an alcohol-induced hypoxic response. Alcohol Clin Exp Res 33:1391–1400

  63. Hofmann WK, Tong XJ, Ajioka RS, Kushner JP, Koeffler HP (2002) Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. Blood 100:1099–1100

  64. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC (2005) A mouse model of juvenile hemochromatosis. J Clin Invest 115:2187–2191

  65. Hutchinson C, Geissler CA, Powell JJ, Bomford A (2007) Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 56:1291–1295

  66. Island ML, Jouanolle AM, Mosser A, Deugnier Y, David V, Brissot P, Loreal O (2009) A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis. Haematologica 94:720–724

  67. Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, Napier JA, Worwood M (2001) HFE mutations, iron deficiency and overload in 10, 500 blood donors. Br J Haematol 114:474–484

  68. Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C (2004) HAMP as a modifier gene that increase the phenotypic expression of the HFE p.C282Y homozygous genotype. Blood 103:2835–2840

  69. Jazwinska EC, Cullen LM, Busfield F, Pyper WR, Webb SI, Powell LP, Morris CP, Walsh TP (1996) Haemochromatosis and HLA-H. Nat Genet 14:249–251

  70. Johnson MB, Enns CA (2004) Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104:4287–4293

  71. Jouanolle AM, Gandon G, Blayau M, Campion ML, Yaouanq J, Mosser J, Fergelot P, Chauvel B, Bouric P, Carn G, Andrieux N, Le Gall J-Y, David V (1996) Haemochromatosis and HLA-H. Nat Genet 14:251–252

  72. Ka C, Le Gac G, Letocart E, Gourlaouen I, Martin BJ, Ferec C (2007) Phenotypic and functional data confirm causality of the recently identified p.R176C missense mutation. Hematologica 92:1262–1263

  73. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H, Roth MP (2008) Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112:1503–1509

  74. Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J (2007) Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance. World J Gastroenterol 13:4699–4706

  75. Krayenbuehl PA, Maly FE, Hersberger M, Wiesli P, Himmelmann A, Eid K, Greminger P, Vetter PA, Schulthess G (2006) Tumor necrosis factor alpha −308 G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis. Clin Chem 52:1552–1558

  76. Le Gac G, Férec C (2005) The molecular genetics of haemochromatosis. Eur J Hum Genet 13:1172–1185

  77. Le Gac G, Mons F, Jacolot S, Scotet V, Ferec C, Frebourg T (2004a) 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

  78. Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, Mura C, Ferec C (2004b) The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 13:1913–1918

  79. Le Gac G, Gourlaouen I, Ronsin C, Geromel V, Bourgarit A, Parquet N, Quemener S, Le Marechal C, Chen JM, Ferec C (2008) Homozygous deletion of HFE produces a phenotype similar to the HFE p.C282Y/p.C282Y genotype. Blood 112:5238–5240

  80. Le Gac G, Ka C, Gourlaouen I, Bryckaert L, Mercier AY, Chanu B, Scotet V, Ferec C (2009) HFE-related hemochromatosis: the haptoglobin 2–2 type has a significant but limited influence on phenotypic expression of the predominant p.C282Y homozygous genotype. Adv Hematol 2009:251701

  81. Le Gac G, Congiu R, Gourlaouen I, Cau M, Ferec C, Melis MA (2010) Homozygous deletion of HFE is the common cause of hemochromatosis in Sardinia. Haematologica 95:685–687

  82. Lee P, Gelbart T, West C, Halloran C, Beutler E (2002) Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol Dis 29:471–487

  83. Lee PL, Beutler E, Rao SV, Barton JC (2004) Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 103:4669–4671

  84. Levy JE, Montross LK, Cohen DE, Fleming MD, Andrews NC (1999) The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94:9–11

  85. Levy JE, Montross LK, Andrewes NC (2000) Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 105:1209–1216

  86. Livesey KJ, Wimhurst VL, Carter K, Worwood M, Cadet E, Rochette J, Roberts AG, Pointon JJ, Merryweather-Clarke AT, Bassett ML, Jouanolle AM, Mosser A, David V, Poulton J, Robson KJ (2004) The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading. J Med Genet 41:6–10

  87. Makui H, Soares RJ, Jiang W, Constante M, Santos MM (2005) Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading. Blood 106(6):2189–2195

  88. 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

  89. McCune A, Worwood M (2003) Penetrance in hereditary hemochromatosis. Blood 102:2696; author reply 2696–2697

  90. McCune CA, Al-Jader LN, May A, Hayes SL, Jackson HA, Worwood M (2002) Hereditary haemochromatosis: only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum Genet 111:538–543

  91. McCune CA, Ravine D, Carter K, Jackson HA, Hutton D, Hedderich J, Krawczak M, Worwood M (2006) Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients. Gut 55:554–562

  92. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzeneh 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

  93. McLaren GD, McLaren CE, Adams PC, Barton JC, Reboussin DM, Gordeuk VR, Acton RT, Harris EL, Speechley MR, Sholinsky P, Dawkins FW, Snively BM, Vogt TM, Eckfeldt JH (2008) Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening. Can J Gastroenterol 22:923–930

  94. Melis MA, Cau M, Congiu R, Sole G, Barella S, Cao A, Westerman M, Cazzola M, Galanello R (2008) 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 93:1473–1479

  95. Merryweather-Clarke AT, Worwood M, Parkinson L, Mattock C, Pointon JJ, Shearman JD, Robson KJH (1998) The effect of HFE mutations on serum ferritin and transferrin saturation in the Jersey population. Br J Haematol 101:369–373

  96. Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, McHugh PJ, Chapman RW, Pointon JJ, Wimhurst VLC, Livesey KJ, Tanphaichitr V, Rochette J, Robson KJ (2003) Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet 12:2241–2247

  97. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP (2009) Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41:478–481

  98. Milet J, Dehais V, Bourgain C, Jouanolle AM, Mosser A, Perrin M, Morcet J, Brissot P, David V, Deugnier Y, Mosser J (2007) Common variants on the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet 81:799–807

  99. Milet J, Le Gac G, Scotet V, Gourlouen I, Theze C, Mosser J, Bourgain C, Deugnier Y, Ferec C (2010) A common SNP near BMP2 is associated with severity of iron burden in HFE p.C282Y homozygous patients: a follow-up study. Blood Cells Mol Dis 44:34–37

  100. Milward EA, Baines SK, Knuiman MW, Bartholomew HC, Divitini ML, Bruce DG, Olynyk JK (2008) Noncitrus fruits as novel dietary environmental modifiers in people with or without HFE gene mutations. Mayo Clin Proc 83:543–549

  101. Mleczko-Sanecka K, Casanovas G, Ragab A, Breitkopf K, Müller A, Boutros M, Dooley S, Hentze MW, Muckenthaler M (2010) SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 115:2657–2665

  102. Morrison ED, Brandhagen DJ, Phatak PD, Barton JC, Krawitt EL, El-Serag HB, Gordon SC, Galan MV, Tung BY, Ioannou GN, Kowdley KV (2003) Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 138:627–633

  103. Mura C, Le Gac G, Scotet V, Raguenes O, Mercier AY, Ferec C (2001) Variation of iron loading expression in C282Y homozygous haemochromatosis probands and sib pairs. J Med Genet 38:632–636

  104. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093

  105. Nielsen P, Gunther U, Durken M, Fischer R, Dullmann J (2000) Serum ferritin iron in iron overload and liver damage: correlation to body iron stores and diagnostic relevance. J Lab Clin Med 135:413–418

  106. Njajou OT, Houwing-Duistermaat JJ, Osborne RH, Vaessen N, Vergeer J, Heeringa J, Pols HA, Hofman A, van Duijn CM (2003) A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism. Eur J Hum Genet 11:225–231

  107. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW (1999) A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 341:718–724

  108. Österreicher CH, Datz C, Stickel F, Hellerbrand C, Penz M, Hofer H, Wrba F, Penner E, Schuppan D, Ferenci P (2005a) Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis. J Hepatol 42:914–919

  109. Österreicher CH, Datz C, Stickel F, Hellerbrand C, Penz M, Hofer H, Wrba F, Penner E, Schuppan D, Ferenci P (2005b) TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis. Cytokine 31:142–148

  110. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald MLE, Franchini PL, Dubé M-P, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson KJ, 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

  111. Pedersen P, Milman N (2009) Genetic screening for HFE hemochromatosis in 6, 020 Danish men: penetrance of C282Y, H63D, and S65C variants. Ann Hematol 88:775–784

  112. Pietrangelo A (1996) Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis 16:13–30

  113. Pietrangelo A (2007) The penetrance of hemochromatosis: mice to the rescue. Gastroenterology 132:805–808

  114. 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

  115. Piperno A, Sampietro M, Pietrangelo A, Arosio A, Lupica L, Montosi G, Vergani A, Fraquelli M, Girelli D, Pasquero P, Roetto A, Gasparini P, Fargion S, Conte D, Camaschella C (1998a) Heterogeneity of hemochromatosis in Italy. Gastroenterology 114:996–1002

  116. Piperno A, Vergani A, Malosio I, Parma L, Fossati L, Ricci A, Bovo G, Boari G, Mancia G (1998b) Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations. Hepatology 28:1105–1109

  117. Piperno A, Roetto A, Mariani R, Pelucchi S, Corengia C, Daraio F, Piga A, Garozzo G, Camaschella C (2004) Homozygosity for transferrin receptor-2 Y250X mutation induces early iron overload. Haematologica 89:359–360

  118. Poullis A, Moodie SJ, Maxwell JD (2002) Clinical hameochromatosis in HFE mutation carriers. Lancet 360:412

  119. Powell LW, Subramaniam VN, Yapp TR (1999) Hemochromatosis in the new millennium. J Hepatol 32:48–62

  120. Ramey G, Deschemin JC, Vaulont S (2009) 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 94:765–772

  121. Ramsay AJ, Quesada V, Sanchez M, Garabaya C, Sarda MP, Baiget M, Remacha A, Velasco G, Lopez-Otin C (2009) Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Hum Mol Genet 18:3673–3683

  122. Robb A, Wessling-Resnick M (2004) Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104:4294–4299

  123. Rochette J, Cadet E, Capron D (2007) The therapeutic penetrance of haemochromatosis: what is and what is not haemochromatosis. Haematology Australian Association, Broadbeach, Australia, p A44

  124. Roetto A, Papanikoloau G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile haemochromatosis. Nat Genet 33:21–22

  125. Rossi E, Jeffrey GP (2004) Clinical penetrance of C282Y homozygous HFE haemochromatosis. Clin Biochem Rev 25:183–190

  126. Rothenberg BE, Voland JR (1996) β2 knockout mice develop parenchymal iron overload: a putative role for class I genes of the major histocompatibilty complex in iron metabolism. Proc Natl Acad Sci USA 93:1529–1524

  127. Sachot S, Moirand R, Jouanolle AM, Fergelot P, Deugnier Y, Brissot P, J-Y LG, David V (2001) Low penetrant hemochromatosis phenotype in eight families: no evidence for modifiers in the MHC region. Blood Cells Mol Dis 27:518–529

  128. Scheen AJ (2005) Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion? Diabetes Metab 31(2):5S27–5S34

  129. 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

  130. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC (2008) The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 7:205–214

  131. Schmidt PJ, Fleming M, Andrews NC (2009) Investigation of HFE-dependent regulation of hepcidin expression. International BioIron Society, Porto, p 72

  132. Silvestri L, Pagani A, Camaschella C (2008) Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 111:924–931

  133. Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE, Rossant J, Mak TW (1998) The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 12:107–119

  134. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13:1096–2101

  135. Tanno T, Porayette P, Sripichai O, Noh SJ, Byrnes C, Bhupatiraju A, Lee YT, Goodnough JB, Harandi O, Ganz T, Paulson RF, Miller JL (2009) Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114:181–186

  136. Tchou I, Diepold M, Pilotto PA, Swinkels D, Neerman-Arbez M, Beris P (2009) Haematologic data, iron parameters and molecular findings in two new cases of iron-refractory iron deficiency anaemia. Eur J Haematol 83(6):595–602

  137. Tolosano E, Fagoonee S, Garuti C, Valli L, Andrews NC, Altruda F, Pietrangelo A (2005) Haptoglobin modifies the hemochromatosis phenotype in mice. Blood 105:3353–3355

  138. Truksa J, Lee PEB (2009) Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD, and HJV responsiveness. Blood 113:688–695

  139. Valore EV, Ganz T (2008) Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis 40:132–138

  140. Van Vlierberghe H, Langlois M, Delanghe JR, Horsmans Y, Michielsen P, Henrion J, Cartuyvels R, Billet J, DV M, Leroux-Roels G (2001) Haptoglobin phenotype 2–2 overrepresentation in Cys282Tyr hemochromatotic patients. J Hepatol 35:707–711

  141. Viatte L, Vaulont S (2009) Hepcidin, the iron watcher. Biochimie 91:1223–1228

  142. Viatte L, Lesbordes-Brion JC, Lou DQ, Bennoun M, Nicolas G, Kahn A, Canonne-Hergaux F, Vaulont S (2005) Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood 105:4861–4864

  143. Vujic Spasic M, Kiss J, Herrmann T, Kessler R, Stolte J, Galy B, Rathkolb B, Wolf E, Stremmel W, Hentze MW, Muckenthaler MU (2007) Physiologic systemic iron metabolism in mice deficient for duodenal Hfe. Blood 109:4511–4517

  144. Vujic Spasic M, Kiss J, Herrmann T, Galy B, Martinache S, Stolte J, Grone HJ, Stremmel W, Hentze MW, Muckenthaler MU (2008) Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab 7:173–178

  145. Waalen J, Felitti V, Gelbart T, Ho NJ, Beutler E (2002) Penetrance of hemochromatosis. Blood Cells Mol Dis 29:418–432

  146. Waalen J, Nordestgaard BG, Beutler E (2005) The penetrance of hereditary hemochromatosis. Best Pract Res Clin Haematol 18:203–220

  147. Waalen J, Felitti V, Gelbart T, Beutler E (2008) Screening for hemochromatosis by measuring ferritin levels: amore effective approach. Blood 111:3373–3376

  148. Wallace DF, Summerville L, Lusby PE, Subramaniam VN (2005) First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin. Gut 54:980–986

  149. Wallace DF, Summerville L, Subramaniam VN (2007) Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology 132:301–310

  150. Wallace DF, Summerville L, Crampton EM, Frazer DM, Anderson GJ, Subramaniam VN (2009) Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 50:1992–2000

  151. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2:399–409

  152. Wang F, Paradkar PN, Custodio AO, McVey Ward D, Fleming MD, Campagna D, Roberts KA, Boyartchuk V, Dietrich WF, Kaplan J, Andrews NC (2007) Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet 39:1025–1032

  153. Weinstein M, Yang X, Li C, Xu X, Gotay J, Deng CX (1998) Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. Proc Natl Acad Sci USA 95:9378–9383

  154. Whitfield JB, Cullen LM, Jazwinska EC, Powell L, Heath AC, Zhu G, Duffy DL, Martin NG (2000) Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins. Am J Hum Genet 66:1246–1258

  155. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR (2006) Screening for hereditary hemochromatosis: a systematic review for the US Preventive Services Task Force. Ann Intern Med 145:209–223

  156. Worwood M, Shearman JD, Wallace DF, Dooley JS, Merryweather-Clarke AT, Pointon JJ, Rosenberg WMC, Bowen DJ, Burnett AK, Jackson HA, Lawless S, Raha-Chowdhury R, Partridge J, Williams R, Bomford A, Walker AP, Robson KJH (1997) A simple genetic test identifies 90% of UK patients with haemochromatosis. Gut 41:841–844

  157. 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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Acknowledgments

The Conseil Régional de Picardie and INSERM supported the work of JR and KL. The Etablissement Français du Sang, Bretagne and INSERM supported the work of GLG. The Université de Bretagne Occidentale, Centre Hospitalier Universitaire de Brest, Etablissement Français du Sang, Bretagne and INSERM supported the work of CF. The Haemochromatosis Society supported the work of KJHR.

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Correspondence to G. Le Gac.

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Rochette, J., Le Gac, G., Lassoued, K. et al. Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet 128, 233–248 (2010). https://doi.org/10.1007/s00439-010-0852-1

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Keywords

  • Genetic Modifier
  • Serum Ferritin
  • Iron Overload
  • Transferrin Saturation
  • Hepcidin Level