Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a novel genetic di sorder characterized by elevated serum ferritin and early onset cataract fo rmation. The excessive ferritin production in HHCS patients arises from abe rrant regulation of L-ferritin translation caused by mutations within the i ron-responsive element (IRE) of the L-ferritin transcript. IREs serve as bi nding sites for iron regulatory proteins (IRPs), iron-sensing proteins that regulate ferritin translation. Previous observations suggested that each u nique HHCS mutation conferred a characteristic degree of hyperferritinemia and cataract severity in affected individuals. Here we have measured the in vitro affinity of the IRPs for the mutant IREs and correlated decreases in binding affinity with clinical severity. Thermodynamic analysis of these I REs has also revealed that although some HHCS mutations lead to changes in the stability and secondary structure of the IRE, others appear to disrupt IRP-IRE recognition with minimal effect on IRE stability. HHCS is a notewor thy example of a human genetic disorder that arises from mutations within a protein-binding site of an mRNA cis-acting element. Analysis of the effect s of these mutations on the energetics of the RNA-protein interaction expla ins the phenotypic variabilities of the disease state.