CALL FOR PAPERS Protein and Vesicle Trafficking, Cytoskeleton Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

Wallace DF, Summerville L, Crampton EM, Subramaniam VN. Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis. Am J Physiol Cell Physiol 294: C383–C390, 2008. First published December 19, 2007; doi:10.1152/ajpcell.00492.2007.—Transferrin receptor 2 (TfR2), a homologue of transferrin receptor 1 (TfR1), is a key molecule involved in the regulation of iron homeostasis. Mutations in TfR2 result in iron overload with similar features to HFE-associated hereditary hemochromatosis. The precise role of TfR2 in iron metabolism and the functional consequences of disease-causing mutations have not been fully determined. We have expressed wild-type and various mutant forms of TfR2 that are associated with human disease in a mouse liver cell line. Intracellular and surface analysis shows that all the TfR2 mutations analyzed cause the intracellular retention of the protein in the endoplasmic reticulum, whereas the wild-type protein is expressed in endocytic structures and at the cell surface. Our results indicate that the majority of mutations that cause type 3 hereditary hemochromatosis are a consequence of the defective localization of the protein.