| Reduced sensitivity of the ferroportin Q248H mutant to physiologicconcentrations of hepcidin. | |
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MedLine Citation:
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PMID: 23065513 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background. Ferroportin Q248H mutation has an allele frequency of 2.2-13.4% in African populations and is associated with a mild tendency to increased serum ferritin in the general population. Other investigators reported that ferroportin Q248H is degraded after exposure to hepcidin identically to wildtype ferroportin, but supraphysiologic concentrations of hepcidin were used. The aim of our study was to determine if ferroportin Q248H may have reduced sensitivity to physiologic hepcidin concentrations. Design and Methods. Sensitivity of ferroportin Q248H to hepcidin was determined in 293T cells transiently expressing ferroportin using immunoblotting and fluorescence analysis. Ferritin concentrations were measured in these cells and also in human primary monocytes derived from humans with different ferroportin genotypes. The effect of Q248H on serum iron measures was examined in patients with sickle cell anemia. Results. Immunoblotting and fluorescence analysis showed decreased sensitivity of ferroportin Q248H to physiologic hepcidin. Lower ferritin concentrations were observed after incubation with iron and hepcidin in 293T cells expressing ferroportin Q248H and in primary monocytes from ferroportin Q248H subjects. In sickle cell anemia, ferroportin Q248H heterozygotes had lower serum ferritin concentration than wildtype subjects, consistent with enhanced iron release by macrophage ferroportin Q248H. Clinical benefit of ferroportin Q248H was suggested by lower echocardiographic estimates of pulmonary artery pressure in patients carrying mutant alleles. Conclusions. Our results suggest that ferroportin Q248H protein is resistant to physiologic hepcidin concentrations and that this mutation has discernible effects on iron metabolismrelated clinical complications of sickle cell anemia. They provide a mechanistic explanation for the effect of ferroportin Q248H on iron status in individuals of African descent and suggest these changes in iron metabolism may be beneficial under certain disease-specific circumstances. (ClinicalTrials.gov Identifier:NCT00011648). |
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Authors:
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Sergei Nekhai; Min Xu; Altreisha Foster; Ishmael Kasvosve; Sharmin Diaz; Roberto F Machado; Oswaldo L Castro; Gregory J Kato; James Taylor; Victor R Gordeuk |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-12 |
Journal Detail:
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Title: Haematologica Volume: - ISSN: 1592-8721 ISO Abbreviation: Haematologica Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0417435 Medline TA: Haematologica Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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USA; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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