MUTATION IN THE IRON-RESPONSIVE ELEMENT OF THE L-FERRITIN MESSENGER-RNA IN A FAMILY WITH DOMINANT HYPERFERRITINEMIA AND CATARACT

The synthesis of ferritin, the iron-storing molecule, is regulated at the translational level by iron through interaction between a cytoplasmic protein, iron regulatory protein (IRP), and a conserved nucleotide motif present in the 5′ non-coding region of all ferritin mRNAs — the iron responsive element (IRE)1–l3. This region forms a stem-loop structure and when the supply of iron to the cells is limited, the IRP is bound to IRE and represses ferritin synthesis4. Ferritin is composed of a 24-subunit protein shell surrounding an iron core5. The two types of subunit, H and L, are encoded by two genes located on chromosomes 11q13 and 19q13.1, respectively6. Both genes are ubiquitously expressed but trancriptional regulation mediates tissue-specific changes in the H/L mRNA ratio7 and isoferritin profiles. We now report the identification of a single point mutation in the IRE of the L-ferritin mRNA in members from a family affected with dominantly inherited hyperferritinaemia and cataract. This mutation consists of an A to G change in the highly conserved CAGUGU motif that constitutes the IRE loop and mediates the high-affinity interaction with the IRP. We show that this mutation abolishes the binding of IRP in vitro and leads to a high constitutive, poorly regulated L-ferritin synthesis in cultured lymphoblastoid cells established from affected patients. This is, to our knowledge, the first mutation affecting the IRP–IRE interaction and the iron-mediated regulation of ferritin synthesis. We suggest that excess production of ferritin in tissues is responsible for the hyperferritinaemia and that intracellular accumulation of ferritin leads to cataract. © 1995 Nature Publishing Group.