Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract

Nat Genet. 1995 Dec;11(4):444-6. doi: 10.1038/ng1295-444.


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

  • Base Sequence
  • Cataract / genetics*
  • Cataract / metabolism
  • Cells, Cultured
  • Female
  • Ferritins / analysis
  • Ferritins / biosynthesis
  • Ferritins / blood*
  • Ferritins / genetics*
  • Ferritins / metabolism
  • Genes, Dominant
  • Humans
  • Iron / blood*
  • Iron-Regulatory Proteins
  • Liver / chemistry
  • Lymphocytes
  • Male
  • Molecular Sequence Data
  • Point Mutation*
  • RNA, Messenger / genetics*
  • RNA-Binding Proteins / metabolism


  • Iron-Regulatory Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Ferritins
  • Iron