H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload.
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)
Ferreira
C
C
INSERM U409 and INSERM U327, Faculté Xavier Bichat, 16 Rue Henri Huchard, 75870 Paris cedex 18, France.
Santambrogio
P
P
Martin
M E
ME
Andrieu
V
V
Feldmann
G
G
Hénin
D
D
Beaumont
C
C
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
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D005293:Ferritins