Question

There is a mutation in the 5’ Iron response element (IRE) of ferritin mRNA so that IRP is no longer able to bind to the IRE. What would be the outcome of this mutation on ferritin expression?

Answer 1

Ferritin is an iron storing protein. Iron has a major role in the synthesis, accumulation and translation of ferritin mRNA. If the concentration of iron is high, then it stimulates the synthesis and translation of ferritin mRNA, so that excess iron can be stored. Ferritin mRNA constitutes a conserved regulatory sequence of 28 nucleotides in the 5' non-coding region (Untranslated region-UTR) called, Iron Responsive Element (IRE). IRE is a hairpin structure, which is required for the enhanced translation of ferritin mRNA by excess cellular iron. During low iron concentration in the cells, IRE interacts with cytoplasmic regulator proteins called Iron Response Proteins (IRP) and reduces the translation of ferritin mRNA. If there is a mutation in the 5' Iron response element of ferritin mRNA so that the Iron Response Proteins is no longer able to bind to the IRE, leads to a constitutive, poorly regulated ferritin protein synthesis. This excess production of ferritin proteins in tissues leads to hyperferritinaemia and the intra-cellular accumulation of ferritin leads to cataract.

So, the need for ferritin proteins comes only when the concentration of iron is high. But in IRE mutated conditions, ferritin proteins are synthesized and accumulated excessively even in the absence of iron. Such a condition is found in hyperferritinaemia cataract syndrome patients, which is a genetic disease defined by cataracts, hyperferritinaemia, and ferritin light chain gene mutations.