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Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload

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Abstract

Extensive investigation into the molecular basis of iron overload disorders has provided new insights into the complexity of iron metabolism and related cellular pathways. The possible involvement of genes affecting iron homeostasis, including HFE, SLC40A1, HAMP and CYBRD1, was investigated in individuals who were referred for confirmation or exclusion of a diagnosis of haemochromatosis, but who tested negative or were heterozygous for the causative HFE mutation, C282Y. Denaturing high performance liquid chromatography analysis of these genes revealed a unique spectrum of mutations in the South African study population, including 67 unrelated patients and 70 population-matched controls. Two novel CYBRD1 gene mutations, R226H and IVS1-4C→G, were identified in 11% of South African Caucasian patient referrals. We identified a novel D270V mutation in the SLC40A1 gene in a Black South African female with iron overload. These mutations were absent in the control population. In Africans with iron overload not related to the HFE gene, the possible involvement of the SLC40A1 and CYBRD1 genes was demonstrated for the first time. This study confirms the genetic heterogeneity of haemochromatosis and highlights the significance of CYBRD1 mutations in relation to iron overload.

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Acknowledgements

This work was supported by the South African Medical Research Council, the Universities of Stellenbosch, South Africa and Oxford, United Kingdom, the Medical Research Council and the British Association of Commonwealth scholarships. This work was also supported by EC contract QLRT 1999-02237.

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Authors and Affiliations

  1. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

    Monique G. Zaahl, Alison T. Merryweather-Clarke & Kathryn J. H. Robson

  2. Department of Genetics, University of Stellenbosch, Stellenbosch, South Africa

    Monique G. Zaahl & Louise Warnich

  3. Genecare Molecular Genetics (Pty) Ltd., Christiaan Barnard Memorial Hospital, Cape Town, South Africa

    Maritha J. Kotze

  4. Department of Internal Medicine, University of Pretoria, South Africa

    Schalk van der Merwe

  5. Department of Genetics, Private Bag X1, Matieland, 7602, South Africa

    Monique G. Zaahl

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  1. Monique G. Zaahl
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  2. Alison T. Merryweather-Clarke
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  3. Maritha J. Kotze
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  4. Schalk van der Merwe
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  6. Kathryn J. H. Robson
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Correspondence to Monique G. Zaahl.

Additional information

Nucleotide sequence data reported are available in the Genbank database under the assession numbers AJ604512, AJ609539, AJ616848, AJ616847, AJ609540, AJ715523, AJ715524 and AJ715525.

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Zaahl, M.G., Merryweather-Clarke, A.T., Kotze, M.J. et al. Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload. Hum Genet 115, 409–417 (2004). https://doi.org/10.1007/s00439-004-1166-y

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