Reduced sensitivity of the ferroportin Q248H mutant to physiologic concentrations of hepcidin
Sergei Nekhai, Min Xu, Altreisha Foster, Ishmael Kasvosve, Sharmin Diaz, Roberto F. Machado, Oswaldo L. Castro, Gregory J. Kato, James Taylor, Victor R. Gordeuk

Author Affiliations

  1. Sergei Nekhai1,*,
  2. Min Xu1,
  3. Altreisha Foster1,
  4. Ishmael Kasvosve2,
  5. Sharmin Diaz1,
  6. Roberto F. Machado3,
  7. Oswaldo L. Castro1,
  8. Gregory J. Kato4,
  9. James Taylor4 and
  10. Victor R. Gordeuk3
  1. 1 Howard University, USA;
  2. 2 University of Botswana, Gaborone, Botswana;
  3. 3 University of Illinois at Chicago, USA;
  4. 4 NHLBI, USA
  1. * Corresponding author; email: snekhai{at}howard.edu

Abstract

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)

  • Received March 21, 2012.
  • Accepted September 24, 2012.