Early embryonic lethality of H ferritin gene deletion in mice

Ferritin molecules play an important role in the control of intracellular i ron distribution and in the constitution of long term iron stores. In vitro studies on recombinant ferritin subunits have shown that the ferroxidase a ctivity associated with the H subunit is necessary for iron uptake by the f erritin molecule, whereas the L subunit facilitates iron core formation ins ide the protein shell. However, plant and bacterial ferritins have only a s ingle type of subunit which probably fulfills both functions. To assess the biological significance of the ferroxidase activity associated with the H subunit, we disrupted the H ferritin gene (Fth) in mice by homologous recom bination. Fth(+/-) mice are healthy, fertile, and do not differ significant ly from their control littermates, However, Fth(-/-) embryos die between 3. 5 and 9.5 days of development, suggesting that there is no functional redun dancy between the two ferritin subunits and that, in the absence of H subun its, L ferritin homopolymers are not able to maintain iron in a bioavailabl e and nontoxic form. The pattern of expression of the wild type Fth gene in 9.5-day embryos is suggestive of an important function of the H ferritin g ene in the heart.