Document Detail


Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin.
MedLine Citation:
PMID:  23065513     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. Some investigators have reported that ferroportin Q248H is degraded after exposure to hepcidin in exactly the same manner as wild-type ferroportin, but supraphysiological concentrations of hepcidin were used. The aim of our study was to determine whether ferroportin Q248H may have reduced sensitivity to physiological concentrations of hepcidin. The 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. Immunoblotting and fluorescence analysis showed decreased sensitivity of ferroportin Q248H to physiological concentrations of 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 concentrations than wild-type subjects, consistent with enhanced iron release by macrophage ferroportin Q248H. A clinical benefit of ferroportin Q248H was suggested by lower echocardiographic estimates of pulmonary artery pressure in patients carrying mutant alleles. In conclusion, our results suggest that ferroportin Q248H protein is resistant to physiological concentrations of hepcidin and that this mutation has discernible effects on iron metabolism-related 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 that these changes in iron metabolism may be beneficial under certain disease-specific circumstances. (ClinicalTrials.gov Identifier:NCT00011648).
Authors:
Sergei Nekhai; Min Xu; Altreisha Foster; Ishmael Kasvosve; Sharmin Diaz; Roberto F Machado; Oswaldo L Castro; Gregory J Kato; James G Taylor; Victor R Gordeuk
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-10-12
Journal Detail:
Title:  Haematologica     Volume:  98     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-11-26     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  455-63     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00011648
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MeSH Terms
Descriptor/Qualifier:
African Continental Ancestry Group / genetics
Anemia, Sickle Cell / genetics,  metabolism,  therapy
Blood Transfusion
Cation Transport Proteins / chemistry,  genetics,  metabolism*
Cell Line
Gene Expression
Gene Frequency
Genotype
Hepcidins / metabolism*
Humans
Iron / metabolism
Macrophages / metabolism
Mutant Proteins*
Mutation
Polymorphism, Single Nucleotide
Protein Interaction Domains and Motifs / genetics
Recombinant Fusion Proteins / chemistry,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
1SC1GM082325/GM/NIGMS NIH HHS; 1ZIAHL006012-03//PHS HHS; 2G12RR003048/RR/NCRR NIH HHS; 2MOI RR10284/RR/NCRR NIH HHS; G12 RR003048/RR/NCRR NIH HHS; P30AI087714/AI/NIAID NIH HHS; P30HL107253/HL/NHLBI NIH HHS; R01 HL079912/HL/NHLBI NIH HHS; R21 AI056973/AI/NIAID NIH HHS; R25 HL003679/HL/NHLBI NIH HHS; R25 HL003679/HL/NHLBI NIH HHS; SC1 GM082325/GM/NIGMS NIH HHS; UL1 TR000101/TR/NCATS NIH HHS; ZIA HL005116-06/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cation Transport Proteins; 0/Hepcidins; 0/Mutant Proteins; 0/Recombinant Fusion Proteins; 0/metal transporting protein 1; E1UOL152H7/Iron
Comments/Corrections

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