Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis |
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Authors: | Wallace Daniel F Summerville Lesa Crampton Emily M Subramaniam V Nathan |
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Affiliation: | Membrane Transport Laboratory, The Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia. |
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Abstract: | 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. |
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