Hemochromatosis protein HFE C282Y conformational considerations


  • Potential conflict of interest: Nothing to report.

Hemochromatosis Protein HFE C282Y Conformational Considerations

To the Editor:

I read with interest the results of the recent study by Vecchi et al.on HFE C282Y mutation impairing protein traffic to the plasma membrane, which is associated with lower hepcidin expression.1 Indeed, hepcidin suppression has been consistently linked to iron overload. Furthermore, the homozygous Cys-to-Tyr mutation at residue 282 (C282Y) of the hemochromatosis protein HFE (the most common form of iron overload) is recognized to induce the formation of aggregates that are retained in the endoplasmic reticulum (ER).2, 3

The report by Vecchi et al. importantly suggests that the abnormal protein trafficking of the mutant HFE C282Y protein directly results in the suppression of hepcidin expression. Viewing HFE C282Y hereditary hemochromatosis in the context of aberrant protein trafficking that leads to the suppression of hepcidin has important implications for iron overload regulation, thus highlighting the conformational aspects of HFE C282Y protein in the onset and variable pathogenesis of this conditions.4

A close relationship exists between abnormal protein trafficking and clinical consequences, evidence of which can be observed in a range of disorders.5 This emphasis of the study by Vecchi et al. is that investigations of the misfolding protein (HFE C282Y) may provide further intriguing possibilities for the understanding of this condition.

Thus, the recognition of HFE C282Y hereditary hemochromatosis aberrant protein trafficking as an important consideration for this condition may reveal new and more-effective approaches to diagnosis and treatment of iron overload.

Matthew W. Lawless*, * Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland.