Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload
ABSTRACT We report a family affected with dominant autosomal iron overload related to a new mutation in ferroportin 1, a transmembrane protein involved in the export of iron from duodenal enterocytes and likely from macrophages. The originality of this family is represented by the nature of the mutation consisting in the replacement of glycine 490 with aspartate. Clinicians should be aware of this novel iron overload entity, which corresponds to a particular phenotypic expression (high serum ferritin values contrasting with relatively low transferring saturation, and important Kupffer cell iron deposition as compared to hepatocytic iron excess) with poor tolerance of venesection therapy and a dominant pattern of inheritance. Given this dominant transmission, the mixed Causasian-Asian origin of our Asian proband leaves open the issue of the ethnic origin of the new mutation.
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ABSTRACT: Hereditary hemochromatosis is a common disorder of iron metabolism most frequently associated with mutations in the HFE gene. Hereditary hemochromatosis may be caused by other less common genetic mutations including those in the ferroportin gene. Whereas hereditary hemochromatosis associated with HFE mutations is an autosomal recessive disorder, essentially all cases of hereditary hemochromatosis associated with ferroportin mutations follow an autosomal dominant pattern of inheritance, and most cases are notable for the lack of an elevated transferrin saturation and presence of iron deposition in Kupffer cells. This report describes the clinical and laboratory features of a family with hereditary hemochromatosis associated with a previously unrecognized ferroportin mutation (Cys326Ser). Three generations of the family are described. The disease in this family is notable for young age at onset, elevated transferrin saturation values, and hepatocyte iron deposition. The distinct molecular and clinical features reflect the heterogeneous nature of this disease.Blood Cells Molecules and Diseases 03/2005; 34(2):157-61. DOI:10.1016/j.bcmd.2004.12.002 · 2.33 Impact Factor
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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.Human Genetics 11/2004; 115(5):409-17. DOI:10.1007/s00439-004-1166-y · 4.52 Impact Factor
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ABSTRACT: Fe homeostasis is maintained by regulation of Fe absorption to balance largely unregulated body Fe losses. The majority of human subjects maintain relatively constant Fe stores; however, Fe deficiency and Fe overload are common conditions. Fe overload is frequently associated with mutations in genes of Fe metabolism. The present paper summarises present knowledge of these mutations as well as indicating other genes that animal studies have implicated as candidates for influencing body Fe stores.Proceedings of The Nutrition Society 03/2004; 63(1):11-20. DOI:10.1079/PNS2003312 · 4.94 Impact Factor