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Blood, 1 August 2001, Vol. 98, No. 3, pp. 525-532
PLENARY PAPER
H ferritin knockout mice: a model of hyperferritinemia in the
absence of iron overload
Chrystophe Ferreira,
Paolo Santambrogio,
Marie-Elise Martin,
Valérie Andrieu,
Gérard Feldmann,
Dominique Hénin, and
Carole Beaumont
From INSERM U409 and INSERM U327, Faculté Xavier
Bichat; and Service d'Hématologie et d'Immunologie Biologiques,
and Service d'Anatomo- Pathologie, CHU Bichat, Paris, France; and
DIBIT, Department of Biological and Technological Research, IRCCS, San
Raffaele, Milan, Italy.
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.
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