title: Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload.
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.
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. mjulies@sun.ac.za
authors.forename: Monique G
authors.initials: MG
authors.lastname: Zaahl
authors.forename: Alison T
authors.initials: AT
authors.lastname: Merryweather-Clarke
authors.forename: Maritha J
authors.initials: MJ
authors.lastname: Kotze
authors.forename: Schalk
authors.initials: S
authors.lastname: van der Merwe
authors.forename: Louise
authors.initials: L
authors.lastname: Warnich
authors.forename: Kathryn J H
authors.initials: KJ
authors.lastname: Robson
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics; D003573:Cytochrome b Group / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D003573:Cytochrome b Group; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D000098742:Ferroportin; D007501:Iron; D010088:Oxidoreductases; C422926:CYBRD1 protein, human