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Gene Review

TFR2  -  transferrin receptor 2

Homo sapiens

Synonyms: HFE3, TFRC2, TfR2, Transferrin receptor protein 2
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Disease relevance of TFR2


High impact information on TFR2


Chemical compound and disease context of TFR2


Biological context of TFR2

  • Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes [9].
  • The gene responsible is Transferrin Receptor 2 (TFR2), which maps to chromosome 7q22 [10].
  • Finally, we also tested for this TFR2 mutation 20 H63D homozygotes with milder manifestations of iron overload and no acquired cause of iron overload [11].
  • A novel intronic (IVS6 (+6) T-->A) mutation of the TFR2 gene was identified in one patient, and six others were found to carry a known missense mutation (exon 5, I238M) that was also present in one normal control subject [12].
  • These 18 patients had no other HFE sequence change and were subsequently subjected to DNA sequencing of the 15 last exons and flanking sequences of the TFR2 gene [11].

Anatomical context of TFR2

  • Using anti-TFR2 monoclonal antibodies we have confirmed expression of the protein in the liver but also in duodenal epithelial cells, and studied the protein functional behaviour in cell lines, in response to iron addition, iron deprivation and olo-transferrin exposure [10].
  • Analysis of distribution in normal tissues and in representative cell lines revealed that TFR-2 displays a restricted expression pattern--it is present at high levels in hepatocytes and in the epithelial cells of the small intestine, including the duodenal crypts [13].
  • Western blot analyses showed a dominant chain of approximately 90 kDa in TFR-2 transfectants and HepG2 cell line [13].
  • TfR and TfR2 have similar cellular localizations in K562 cells and coimmunoprecipitate to only a very limited extent [14].
  • Western blots demonstrate that TfR2 protein is expressed strongest in erythroid/myeloid cell lines [14].

Associations of TFR2 with chemical compounds


Physical interactions of TFR2


Co-localisations of TFR2


Regulatory relationships of TFR2


Other interactions of TFR2

  • In summary, pathologic TfR2 mutations are present outside of Italy, accounting for a small proportion of non-C282Y HH [15].
  • Metabolic labeling studies indicate that TfR2 protein levels are approximately 20-fold lower than TfR in these cells [14].
  • A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625) [21].
  • RESULTS:: Physiological iron overload led to significantly upregulated hepcidin, HJV and ferroportin mRNA expression while TfR2 expression was not significantly different to controls [22].
  • CONCLUSIONS:: These findings suggest that patients with HH, in contrast to those with physiological iron overload, have a weakened TfR2 sensing mechanism that leads to the lack of induction of hepcidin and HJV [22].

Analytical, diagnostic and therapeutic context of TFR2


  1. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Calì, A., De Gobbi, M., Gasparini, P., Camaschella, C. Blood (2001) [Pubmed]
  2. Hepcidin is decreased in TFR2 hemochromatosis. Nemeth, E., Roetto, A., Garozzo, G., Ganz, T., Camaschella, C. Blood (2005) [Pubmed]
  3. Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer. Abraham, B.K., Justenhoven, C., Pesch, B., Harth, V., Weirich, G., Baisch, C., Rabstein, S., Ko, Y.D., Brüning, T., Fischer, H.P., Haas, S., Brod, S., Oberkanins, C., Hamann, U., Brauch, H. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  4. Diferric transferrin regulates transferrin receptor 2 protein stability. Johnson, M.B., Enns, C.A. Blood (2004) [Pubmed]
  5. Iron overload in acute myeloid leukemia patients is not related to HFE and TFR2 gene mutations. Veneri, D., Franchini, M., Zanetti, F., Krampera, M., de Matteis, G., Pizzolo, G. Haematologica (2003) [Pubmed]
  6. Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Wallace, D.F., Summerville, L., Subramaniam, V.N. Gastroenterology (2007) [Pubmed]
  7. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Pietrangelo, A., Caleffi, A., Henrion, J., Ferrara, F., Corradini, E., Kulaksiz, H., Stremmel, W., Andreone, P., Garuti, C. Gastroenterology (2005) [Pubmed]
  8. Regulation of expression of murine transferrin receptor 2. Kawabata, H., Germain, R.S., Ikezoe, T., Tong, X., Green, E.M., Gombart, A.F., Koeffler, H.P. Blood (2001) [Pubmed]
  9. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Le Gac, G., Mons, F., Jacolot, S., Scotet, V., Férec, C., Frébourg, T. Br. J. Haematol. (2004) [Pubmed]
  10. Hemochromatosis due to mutations in transferrin receptor 2. Roetto, A., Daraio, F., Alberti, F., Porporato, P., Calì, A., De Gobbi, M., Camaschella, C. Blood Cells Mol. Dis. (2002) [Pubmed]
  11. Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis. Aguilar-Martinez, P., Esculié-Coste, C., Bismuth, M., Giansily-Blaizot, M., Larrey, D., Schved, J.F. Blood Cells Mol. Dis. (2001) [Pubmed]
  12. Can defects in transferrin receptor 2 and hereditary hemochromatosis genes account for iron overload in HbH disease? Chan, V., Wong, M.S., Ooi, C., Chen, F.E., Chim, C.S., Liang, R.H., Todd, D., Chan, T.K. Blood Cells Mol. Dis. (2003) [Pubmed]
  13. Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and a polyclonal antiserum. Deaglio, S., Capobianco, A., Calì, A., Bellora, F., Alberti, F., Righi, L., Sapino, A., Camaschella, C., Malavasi, F. Blood (2002) [Pubmed]
  14. Heterotypic interactions between transferrin receptor and transferrin receptor 2. Vogt, T.M., Blackwell, A.D., Giannetti, A.M., Bjorkman, P.J., Enns, C.A. Blood (2003) [Pubmed]
  15. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G. Blood (2002) [Pubmed]
  16. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. Kawabata, H., Germain, R.S., Vuong, P.T., Nakamaki, T., Said, J.W., Koeffler, H.P. J. Biol. Chem. (2000) [Pubmed]
  17. Regulatory effects of tumor necrosis factor-alpha and interleukin-6 on HAMP expression in iron loaded rat hepatocytes. Dzikaite, V., Holmström, P., Stål, P., Eckes, K., Hagen, K., Eggertsen, G., Gåfvels, M., Melefors, O., Hultcrantz, R. J. Hepatol. (2006) [Pubmed]
  18. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Kawabata, H., Fleming, R.E., Gui, D., Moon, S.Y., Saitoh, T., O'Kelly, J., Umehara, Y., Wano, Y., Said, J.W., Koeffler, H.P. Blood (2005) [Pubmed]
  19. Analyses for binding of the transferrin family of proteins to the transferrin receptor 2. Kawabata, H., Tong, X., Kawanami, T., Wano, Y., Hirose, Y., Sugai, S., Koeffler, H.P. Br. J. Haematol. (2004) [Pubmed]
  20. Interaction of human Ku70 with TRF2. Song, K., Jung, D., Jung, Y., Lee, S.G., Lee, I. FEBS Lett. (2000) [Pubmed]
  21. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. West, A.P., Bennett, M.J., Sellers, V.M., Andrews, N.C., Enns, C.A., Bjorkman, P.J. J. Biol. Chem. (2000) [Pubmed]
  22. Hepatic iron metabolism gene expression profiles in HFE associated Hereditary Hemochromatosis. Gleeson, F., Ryan, E., Barrett, S., Russell, J., Crowe, J. Blood Cells Mol. Dis. (2007) [Pubmed]
  23. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. Kawabata, H., Yang, R., Hirama, T., Vuong, P.T., Kawano, S., Gombart, A.F., Koeffler, H.P. J. Biol. Chem. (1999) [Pubmed]
  24. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. Calzolari, A., Raggi, C., Deaglio, S., Sposi, N.M., Stafsnes, M., Fecchi, K., Parolini, I., Malavasi, F., Peschle, C., Sargiacomo, M., Testa, U. J. Cell. Sci. (2006) [Pubmed]
  25. Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload. Biasiotto, G., Belloli, S., Ruggeri, G., Zanella, I., Gerardi, G., Corrado, M., Gobbi, E., Albertini, A., Arosio, P. Clin. Chem. (2003) [Pubmed]
  26. Localization of the iron-regulatory proteins hemojuvelin and transferrin receptor 2 to the basolateral membrane domain of hepatocytes. Merle, U., Theilig, F., Fein, E., Gehrke, S., Kallinowski, B., Riedel, H.D., Bachmann, S., Stremmel, W., Kulaksiz, H. Histochem. Cell Biol. (2007) [Pubmed]
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