Skip to main content
SpringerLink
Log in

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype–genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

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

Similar content being viewed by others

References

  1. 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, Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators (2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352:1769–1778 doi:10.1056/NEJMoa041534

    Article  PubMed  CAS  Google Scholar 

  2. Altes A, Ruiz A, Barceló MJ, Remacha AF, Puig T, Maya AJ, Castell C, Amate JM, Saz Z, Baiget M (2004) Prevalence of C282Y, H63D and S65C mutations of HFE gene in 1146 newborns from a region of Northern Spain. Genet Test 8:407–410 doi:10.1089/gte.2004.8.407

    Article  PubMed  CAS  Google Scholar 

  3. Altes A, Ruiz A, Martinez C, Esteve A, Vela MD, Remacha AF, Sarda P, Bach V, Baiget M (2007) The relationship between iron overload and clinical characteristics in a Spanish cohort of 100 C282Y homozygous hemochromatosis patients. Ann Hematol 86:831–835 doi:10.1007/s00277-007-0336-0

    Article  PubMed  Google Scholar 

  4. Barry M, Sherlock SA (1971) Measurements of liver-iron concentration in needle-biopsy specimens. Lancet 1:100–103 doi:10.1016/S0140-6736(71)90838-5

    Article  PubMed  CAS  Google Scholar 

  5. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T (2002) Penetrance of 845-A (C282Y) HFE hereditary haemochromatosis mutations in USA. Lancet 359:211–218 doi:10.1016/S0140-6736(02)07447-0

    Article  PubMed  Google Scholar 

  6. Biasiotto G, Belloli S, Ruggeri G, Zanella I, Gerardi G, Corrado M, Gobbi E, Albertini A, Arosio P (2003) Identification of new mutations of the HFE hepcidin, and transferring receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload. Clin Chem 49:1981–1988 doi:10.1373/clinchem.2003.023440

    Article  PubMed  CAS  Google Scholar 

  7. 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 doi:10.1016/j.bcmd.2004.08.002

    Article  PubMed  CAS  Google Scholar 

  8. 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 doi:10.1038/75534

    Article  PubMed  CAS  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, 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 doi:10.1038/ng0896-399

    Article  PubMed  CAS  Google Scholar 

  10. Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C (2004) HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 103:2835–2840 doi:10.1182/blood-2003-10-3366

    Article  PubMed  CAS  Google Scholar 

  11. Lanzara C, Roetto A, Daraio F, Rivard S, Ficarella R, Simard H, Cox TM, Cazzola M, Piperno A, Gimenez-Roqueplo AP, Grammatico P, Bolina S, Gasparini P, Camaschella C (2004) Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 103:4317–4321 doi:10.1182/blood-2004-01-0192

    Article  PubMed  CAS  Google Scholar 

  12. Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, Mura C, Férec C (2004) The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 13:1913–1918 doi:10.1093/hmg/ddh206

    Article  PubMed  Google Scholar 

  13. 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 doi:10.1182/blood-2004-01-0072

    Article  PubMed  CAS  Google Scholar 

  14. Majore S, Binni F, Ricerca BM, Brioli G, Grammatico P (2002) Absence of hepcidin gene mutations in 10 Italian patients with primary iron overload. Haematologica 87:221–222

    PubMed  Google Scholar 

  15. Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, McHugh PJ, Chapman RW, Pointon JJ, Wimhurst VL, 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 doi:10.1093/hmg/ddg225

    Article  PubMed  CAS  Google Scholar 

  16. 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

    PubMed  CAS  Google Scholar 

  17. Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, vanDuijn CM, Heutink P (2001) A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28:213–214 doi:10.1038/90038

    Article  PubMed  CAS  Google Scholar 

  18. Papanikolaou G, Sauels ME, Ludwig EH, MacDonald MLE, Franchini PL, Dubé 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) Mutation in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82 doi:10.1038/ng1274

    Article  PubMed  CAS  Google Scholar 

  19. Pietrangelo A (2004) Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383–2397 doi:10.1056/NEJMra031573

    Article  PubMed  CAS  Google Scholar 

  20. Pietrangelo A (2004) The ferroportin disease. Blood Cells Mol Dis 32:131–138 doi:10.1016/j.bcmd.2003.08.003

    Article  PubMed  CAS  Google Scholar 

  21. Roetto A, Papanikolau 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 doi:10.1038/ng1053

    Article  PubMed  CAS  Google Scholar 

  22. 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 doi:10.1182/blood-2003-10-3390

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was partially supported by grants from Fondo de Investigaciones Sanitarias (PI-04/1120) and Agencia d’Avaluació de Tecnología i Recerca Mèdica (005/29/2004).

Author information

Authors and Affiliations

  1. Hematology Department, Althaia Foundation, Flor de Lis 33, 08242, Manresa, Spain

    Albert Altès

  2. Laboratori Hospital de l’Esperit Sant, Santa Coloma de Gramenet, Spain

    Angels Ruiz & Anna Esteve

  3. ABS Canaletes, Cerdanyola del Vallés, SPAIN

    Jordi Felez

  4. Hematology and Genetics Departments, Hospital de Sant Pau, Barcelona, Spain

    Vanessa Bach, Angel F. Remacha, M. Pilar Sardà & Montserrat Baiget

Authors
  1. Albert Altès
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vanessa Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angels Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Esteve
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jordi Felez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angel F. Remacha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Pilar Sardà
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Montserrat Baiget
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert Altès.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Altès, A., Bach, V., Ruiz, A. et al. Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene. Ann Hematol 88, 951–955 (2009). https://doi.org/10.1007/s00277-009-0705-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-009-0705-y

Keywords

Search

Navigation