title: H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload.
abstract: Ferritin, the iron-storing molecule, is made by the assembly of various proportions of 2 different H and L subunits into a 24-mer protein shell. These heteropolymers have distinct physicochemical properties, owing to the ferroxidase activity of the H subunit, which is necessary for iron uptake by the ferritin molecule, and the ability of the L subunit to facilitate iron core formation inside the protein shell. It has previously been shown that H ferritin is indispensable for normal development, since inactivation of the H ferritin gene by homologous recombination in mice is lethal at an early stage during embryonic development. Here the phenotypic analysis of the mice heterozygous for the H ferritin gene (Fth(+/-) mice) is reported, and differences in gene regulation between the 2 subunits are shown. The heterozygous Fth(+/-) mice were healthy and fertile and did not present any apparent abnormalities. Although they had iron-overloaded spleens at the adult stage, this is identical to what is observed in normal Fth(+/+) mice. However, these heterozygous mice had slightly elevated tissue L ferritin content and 7- to 10-fold more L ferritin in the serum than normal mice, but their serum iron remained unchanged. H ferritin synthesis from the remaining allele was not up-regulated. This probably results from subtle changes in the intracellular labile iron pool, which would stimulate L ferritin but not H ferritin synthesis. These results raise the possibility that reduced H ferritin expression might be responsible for unexplained human cases of hyperferritinemia in the absence of iron overload where the hereditary hyperferritinemia-cataract syndrome has been excluded. (Blood. 2001;98:525-532)
authors.affiliation: INSERM U409 and INSERM U327, Faculté Xavier Bichat, 16 Rue Henri Huchard, 75870 Paris cedex 18, France.
authors.forename: C
authors.initials: C
authors.lastname: Ferreira
authors.forename: P
authors.initials: P
authors.lastname: Santambrogio
authors.forename: M E
authors.initials: ME
authors.lastname: Martin
authors.forename: V
authors.initials: V
authors.lastname: Andrieu
authors.forename: G
authors.initials: G
authors.lastname: Feldmann
authors.forename: D
authors.initials: D
authors.lastname: Hénin
authors.forename: C
authors.initials: C
authors.lastname: Beaumont
mesh_terms: D000483:Alleles; D018798:Anemia, Iron-Deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005293:Ferritins / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007150:Immunohistochemistry; D019190:Iron Overload / Q000097:blood; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D016601:RNA-Binding Proteins / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D005293:Ferritins