HFE: An Iron Uptake Regulation Molecule

Accumulation of excess iron results in a common hereditary disease, Hereditary Haemochromatosis (HH). There are various genetic mutations that lead to different forms of the disease. HH‐I is a form of this disease in which iron accumulates in hepatocytes and intestinal epithelial cells and is associated with a mutation in the HFE (high iron protein) gene. The Brookfield Central SMART Team (Students Modeling A Research Topic) developed a model of HFE using 3D printing technology. The HFE gene encodes for a non‐classical MHC class I protein. In physiological conditions, HFE is expressed and translocated to the cell surface where it may interact with a transferrin receptor (Tfr). The binding of the α1/β2 domains of HFE to the Tfr allows for controlled release of iron bound to transferrin‐transferrin receptor complex. A mutation (845G>A) causes the replacement of a cysteine with a tyrosine (C282Y). This replacement prevents the α3 subunit of HFE from folding properly and from interacting with β2 microglobulin, abrogating the translocation of the HFE‐microglobulin complex to the cell membrane and promoting its rapid degradation. This defect hinders the regulatory capability of HFE. Current treatments include phlebotomy to prevent organ damage from accumulated iron. Further study to increase understanding of the regulatory mechanism may lead to improved treatment design. Supported by a grant from NIH‐NCRR‐SEPA.