title: A mouse model of juvenile hemochromatosis.
abstract: Hereditary hemochromatosis is an iron-overload disorder resulting from mutations in proteins presumed to be involved in the maintenance of iron homeostasis. Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis. The normal function of HJV is unknown. Juvenile hemochromatosis patients have decreased urinary levels of hepcidin, a peptide hormone that binds to the cellular iron exporter ferroportin, causing its internalization and degradation. We have disrupted the murine Hjv gene and shown that Hjv-/- mice have markedly increased iron deposition in liver, pancreas, and heart but decreased iron levels in tissue macrophages. Hepcidin mRNA expression was decreased in Hjv-/- mice. Accordingly, ferroportin expression detected by immunohistochemistry was markedly increased in both intestinal epithelial cells and macrophages. We propose that excess, unregulated ferroportin activity in these cell types leads to the increased intestinal iron absorption and plasma iron levels characteristic of the juvenile hemochromatosis phenotype.
authors.affiliation: Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115-5737, USA.
authors.forename: Franklin W
authors.initials: FW
authors.lastname: Huang
authors.forename: Jack L
authors.initials: JL
authors.lastname: Pinkus
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071020:Hemochromatosis Protein; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D019190:Iron Overload / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D000098742:Ferroportin