title: Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract.
abstract: 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). 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 synthesis. Ferritin is composed of a 24-subunit protein shell surrounding an iron core. The two types of subunit, H and L, are encoded by two genes located on chromosomes 11q13 and 19q13.1, respectively. Both genes are ubiquitously expressed but transcriptional regulation mediates tissue-specific changes in the H/L mRNA ratio 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.
mesh_terms: D001483:Base Sequence; D002386:Cataract / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005293:Ferritins / Q000032:analysis / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D007501:Iron / Q000097:blood*; D035925:Iron-Regulatory Proteins; D008099:Liver / Q000737:chemistry; D008214:Lymphocytes; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D005293:Ferritins; D007501:Iron