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Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin.

Publication ,  Journal Article
Schmidt, PJ; Andrews, NC; Fleming, MD
Published in: Blood
December 16, 2010

Mutations in HFE cause the most common form of hereditary hemochromatosis (HH). We previously showed that liver-specific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin. We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human disease-causing mutation (murine C294Y) did not cause iron deficiency. Furthermore, hepcidin induction by transgenes encoding both WT Hfe and Hfe lacking its cytoplasmic domain is greatly attenuated in the absence of hemojuvelin (Hjv). Our observations indicate that the extracellular and transmembrane domains of Hfe are sufficient, and Hjv is essential, for Hfe-mediated induction of hepcidin expression.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 16, 2010

Volume

116

Issue

25

Start / End Page

5679 / 5687

Location

United States

Related Subject Headings

  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Prealbumin
  • Mutation, Missense
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Membrane Proteins
  • Male
 

Citation

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Schmidt, P. J., Andrews, N. C., & Fleming, M. D. (2010). Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin. Blood, 116(25), 5679–5687. https://doi.org/10.1182/blood-2010-04-277954
Schmidt, Paul J., Nancy C. Andrews, and Mark D. Fleming. “Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin.Blood 116, no. 25 (December 16, 2010): 5679–87. https://doi.org/10.1182/blood-2010-04-277954.
Schmidt, Paul J., et al. “Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin.Blood, vol. 116, no. 25, Dec. 2010, pp. 5679–87. Pubmed, doi:10.1182/blood-2010-04-277954.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 16, 2010

Volume

116

Issue

25

Start / End Page

5679 / 5687

Location

United States

Related Subject Headings

  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Prealbumin
  • Mutation, Missense
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Membrane Proteins
  • Male