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.
"2001 Auto dom macrophage normal high Val 162del Devalia et al.  2002 Auto dom macrophage normal high Val 162del Cazzola et al.  2002 Auto dom macrophage normal high Val 162del Wallace et al.  2002 Auto dom macrophage high Val 162del Roetto et al.  2002 Auto dom macrophage normal high Asp157Gly Hetet et al.  2003 Auto dom normal high Gln182His Hetet et al.  2003 Auto dom normal high Gly323Val Hetet et al.  2003 Auto dom normal high Asn144His Njajou et al.  2001 Auto dom Gly490Asp Jouanolle et al.  2003 Auto dom macrophage normal high Tyr64Asp Rivard et al.  2003 Auto dom elevated Asp144Thr Arden et al.  2003 Auto dom hepatocyte elevated high Gln248His Beutler et al.  2003 Unclear macrophage normal high Cys326Tyr Viprakasit et al.  2004 Auto dom elevated Cys326Ser Sham 2005 Auto dom hepatocyte elevated high a Transferrin saturation. Fig. 1. "
[Show abstract][Hide abstract] 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.
"Other mutations in the HFE gene account for the disease phenotype in approximately 2%–10% of cases (reviewed by Pointon et al. 2000). Non-HFE related forms of haemochromatosis are less common but have also been reported and include mutations in the transferrin receptor 2 gene (TFR2) (Camaschella et al. 2000; Roetto et al. 2001), the solute carrier family 40 (proton-coupled divalent metal ion transporter) member 1 gene (SLC40A1), which is also known as the solute carrier family 11 (proton-coupled divalent metal ion transporter) member 3 gene (SLC11A3), ferroportin 1 gene (FPN1), iron-regulated transporter 1 gene (IREG1) or metal transporter 1 gene (MTP1; Njajou et al. 2001; Montosi et al. 2001; Devalia et al. 2002; Roetto et al. 2002; Wallace et al. 2002; Cazzola et al. 2002; Hetet et al. 2003; Jouanolle et al. 2003; Gordeuk et al. 2003; Rivard et al. 2003) and the hepcidin antimicrobial peptide gene (HAMP), which is also known as the Nucleotide sequence data reported are available in the Genbank database under the assession numbers AJ604512, "
[Show abstract][Hide abstract] 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 · 4.82 Impact Factor
"Autosomal dominant haemochromatosis (type 4): Fe accumulation in liver and RE cells, hyperferritinaemia 2q32 Njajou et al. (2001), Montosi et al. (2001), Cazzola et al. (2002), Devalia et al. (2002), Wallace et al. (2002a), Hetet et al. (2003), Jouanolle et al. (2003) L-ferritin Light chain of ferritin: essential for core formation of ferritin (cellular Fe storage protein) "
[Show abstract][Hide abstract] 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 · 5.27 Impact Factor
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