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: Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends </=6 Mb, suggesting that this mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </=700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.The American Journal of Human Genetics 05/1999; 64(4):1056-62. · 11.20 Impact Factor
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ABSTRACT: The HFE gene is a crucial candidate gene for hemochromatosis. The aims of this study were to assess the HFE genotypic profile in a large series of unrelated probands diagnosed as having phenotypic hemochromatosis, to characterize the sub-group of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE-identical siblings. In 217 patients, the phenotypic diagnosis of hemochromatosis was based on strict bioclinical and/or histological criteria, and their genotypic profile (C282Y and H63D mutations) was determined. 1) 209 of the 217 probands were C282Y +/+. In 33 cases, an HFE-identical sibling was identified. Two of them had neither a clinical nor a biochemical phenotypic profile of hemochromatosis in the absence of any external factor which might have attenuated this expression. 2) Eight patients (seven males) were not C282Y +/+. Their genotypic profiles were: (C282Y +/-): six cases (four were H63D +/- and two H63D -/-); (C282Y -/-): two cases (one was H63D +/+, one H63D +/-). Phenotypic expression consisted of six cases of mild liver siderosis (among whom were the four compound heterozygotes and one case of alcoholic cirrhosis) and two severe cases of hepatic iron overload (one with alcoholic cirrhosis). Three HFE-identical siblings were identified, none of them presenting with iron excess. In our population: 1) The classical phenotypic criteria fitted, in 96.3% of cases, with a homogeneous genotypic entity defined by homozygosity for the C282Y mutation. Incomplete penetrance of the homozygous status was shown by the absence of the hemochromatosis phenotypic profile in 6% of the HFE-identical siblings. 2) A minority (3.7%) were not homozygous for C282Y. These were essentially men with mild iron overload, and might present with distinct iron overload entity(ies) as suggested by the presence in three of an HFE-identical sibling with absence of iron overload.Journal of Hepatology 05/1999; 30(4):588-93. · 9.86 Impact Factor
- Blood 01/2002; 100(2):733-734. · 9.06 Impact Factor