Skip to main content
SpringerLink
Log in

Hemojuvelin: a supposed role in iron metabolism one year after its discovery

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The discovery of hemojuvelin and its association with juvenile hemochromatosis are important not only for the diagnostics of this rare severe disease but also for the understanding of the complex mechanism of iron metabolism regulation. Currently, the physiological role of hemojuvelin is obscure. Recent experimental and clinical studies indicate that hemojuvelin will probably be a regulator of hepcidin, similar to HFE and transferrin receptor 2. However, in contrast to transferrin receptor 2, which is relevant in the hepcidin response to changes in transferrin saturation, HFE and especially hemojuvelin seem to be involved in the inflammation-induced hepcidin expression. Hepcidin, generally accepted as a hormone targeting enterocytes and macrophages, decreases iron absorption from the intestinal lumen and iron release from phagocytes. This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease. Further basic and clinical research is needed to uncover the details of hemojuvelin pathophysiology required for potential pharmacological interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM, Gasparini P, Cazzola M, Camaschella C (2002) Natural history of juvenile haemochromatosis. Br J Haematol 117:973–979

    PubMed  Google Scholar 

  2. Pietrangelo A (2004) Non-HFE hemochromatosis. Hepatology 39:21–29

    PubMed  Google Scholar 

  3. Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D’Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C (1999) Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet 64:1388–1393

    CAS  PubMed  Google Scholar 

  4. Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R, Simard R, D’Adamo AP, Ferec C, Camaschella C, Mura C, Roetto A, De Braekeleer M, Bechner L, Gasparini P (2003) Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur J Hum Genet 11:585–589

    CAS  PubMed  Google Scholar 

  5. Roetto A, Alberti F, Daraio F, Cali A, Cazzola M, Totaro A, Gasparini P, Camaschella C (2000) Exclusion of ZIRTL as candidate gene of juvenile hemochromatosis and refinement of the critical interval on 1q21. Blood Cells Mol Dis 26:205–210

    CAS  PubMed  Google Scholar 

  6. 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

    CAS  PubMed  Google Scholar 

  7. Brissot P, Troadec MB, Loreal O (2004) The clinical relevance of new insights in iron transport and metabolism. Curr Hematol Rep 3:107–115

    PubMed  Google Scholar 

  8. Griffiths W, Cox T (2000) Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. Hum Mol Genet 9:2377–2382

    CAS  PubMed  Google Scholar 

  9. 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, Wolff RK et al (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  11. 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 U S A 95:2492–2497

    CAS  PubMed  Google Scholar 

  12. 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

    CAS  PubMed  Google Scholar 

  13. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276:7806–7810

    CAS  PubMed  Google Scholar 

  14. Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S (2002) Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 29:327–335

    CAS  PubMed  Google Scholar 

  15. 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

    CAS  PubMed  Google Scholar 

  16. 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

    CAS  PubMed  Google Scholar 

  17. 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

    CAS  PubMed  Google Scholar 

  18. 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

    CAS  PubMed  Google Scholar 

  19. Rodriguez Martinez A, Niemela O, Parkkila S (2004) Hepatic and extrahepatic expression of the new iron regulatory protein hemojuvelin. Haematologica 89:1441–1445

    PubMed  Google Scholar 

  20. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C (2005) Hepcidin is decreased in TFR2 hemochromatosis. Blood 105:1803–1806

    CAS  PubMed  Google Scholar 

  21. Robson KJ, Merryweather-Clarke AT, Cadet E, Viprakasit V, Zaahl MG, Pointon JJ, Weatherall DJ, Rochette J (2004) Recent advances in understanding haemochromatosis: a transition state. J Med Genet 41:721–730

    CAS  PubMed  Google Scholar 

  22. Camaschella C, Roetto A, De Gobbi M (2002) Juvenile hemochromatosis. Semin Hematol 39:242–248

    PubMed  Google Scholar 

  23. Lee PL, Barton JC, Brandhagen D, Beutler E (2004) Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Br J Haematol 127:224–229

    CAS  PubMed  Google Scholar 

  24. Biasiotto G, Roetto A, Daraio F, Polotti A, Gerardi GM, Girelli D, Cremonesi L, Arosio P, Camaschella C (2004) Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood Cells Mol Dis 33:338–343

    CAS  PubMed  Google Scholar 

  25. 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

    CAS  PubMed  Google Scholar 

  26. 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

    CAS  PubMed  Google Scholar 

  27. Barton JC, Rivers CA, Niyongere S, Bohannon SB, Acton RT (2004) Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population. BMC Med Genet 5:29

    PubMed  Google Scholar 

  28. Huang FW, Rubio-Aliaga I, Kushner JP, Andrews NC, Fleming MD (2004) Identification of a novel mutation (C321X) in HJV. Blood 104:2176–2177

    CAS  PubMed  Google Scholar 

  29. 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

    CAS  PubMed  Google Scholar 

  30. de Sousa M, Porto G (1998) The immunological system in hemochromatosis. J Hepatol 28(Suppl 1):1–7

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C (2005) Hepcidin is decreased in TFR2-hemochromatosis. Blood 105:1803–1806

    CAS  PubMed  Google Scholar 

  33. 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 down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105:376–381

    CAS  PubMed  Google Scholar 

  34. Nisbet-Brown E (2004) Hemojuvelin and hepcidin: the keys to JH? Blood 104:1918–1919

    CAS  Google Scholar 

  35. Ajioka R, Kushner J (2004) Another link in the chain. Blood 103:2439–2440

    CAS  Google Scholar 

  36. 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

    CAS  PubMed  Google Scholar 

  37. Ludwiczek S, Aigner E, Theurl I, Weiss G (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101:4148–4154

    CAS  PubMed  Google Scholar 

  38. 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

    CAS  PubMed  Google Scholar 

  39. 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

    CAS  PubMed  Google Scholar 

  40. Gasparini P, Camaschella C (2004) Hereditary hemochromatosis: is the gene race over? Eur J Hum Genet 12:341–342

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author would like to thank Assoc. Prof. Ĺubomír Tomáška, Ph.D., for the stimulus to write this article and for his critical reading of the manuscript. The anonymous reviewers and their comments should be acknowledged. The author is supported by grants 116/2004 and 117/2004 from the Comenius University and by the Agency for Science and Technology grant APVT-20-003-104.

Author information

Authors and Affiliations

  1. BiomeD Research and Publishing Group, Bratislava, Slovakia

    Peter Celec

  2. Institute of Pathophysiology, Comenius University, Bratislava, Slovakia

    Peter Celec

  3. Department of Molecular Biology, Comenius University, Bratislava, Slovakia

    Peter Celec

  4. Galbavého 3, 841 01, Bratislava, Slovakia

    Peter Celec

Authors
  1. Peter Celec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Celec.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Celec, P. Hemojuvelin: a supposed role in iron metabolism one year after its discovery. J Mol Med 83, 521–525 (2005). https://doi.org/10.1007/s00109-005-0668-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-005-0668-y

Keywords

Search

Navigation