Disease relevance of TFR2

• The identification of new mutations of TFR2 confirms that this gene is associated with iron overload and offers a tool for molecular diagnosis in patients without HFE mutations [1].
• Hepcidin is decreased in TFR2 hemochromatosis [2].
• No rare variants at 15 more loci at HFE, TFR2, and FPN1 were observed in breast cancer patients [3].
• Mutations in TfR2 cause one form of hereditary hemochromatosis, a disease in which excessive absorption of dietary iron can lead to liver cirrhosis, diabetes, arthritis, and heart failure [4].
• Iron overload in acute myeloid leukemia patients is not related to HFE and TFR2 gene mutations [5].

High impact information on TFR2

• Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload [6].
• To determine the contribution of liver expressed TfR2 in iron homeostasis, we have generated and characterized a liver-specific TfR2-knockout (KO) mouse [6].
• A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2 [7].
• A 21-year-old brother with a milder phenotype resembling classic adult-onset hereditary hemochromatosis carried only the Q317X serum transferrin receptor 2 homozygote mutation [7].
• We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation [2].

Chemical compound and disease context of TFR2

• During erythrocytic differentiation of murine erythroleukemia (MEL) cells induced by dimethylsulfoxide, expression of TfR1 increased, whereas TfR2 decreased [8].

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

• Several sequence variants were identified within the TfR2 gene, including a homozygous missense change in exon 17, c2069 A-->C, which changes a glutamine to a proline residue at position 690 [15].
• Interestingly, in contrast to TfR1, expression of TfR2 mRNA in K562 cells was not up-regulated by desferrioxamine (DFO), a cell membrane-permeable iron chelator [16].
• Tumor necrosis factor-alpha significantly increased mRNA levels of TfR2 and decreased those of DMT1 and IREG1 [17].
• Transferrin receptor 2 (TfR2) is a membrane glycoprotein that mediates cellular iron uptake from holotransferrin [18].
• In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA [18].

Physical interactions of TFR2

• Neither human TfR1 nor TfR2 alpha interacted with either lactoferrin or melanotransferrin [19].

Co-localisations of TFR2

• The transfected TFR2 colocalized with Ku70 [20].

Regulatory relationships of TFR2

• Diferric transferrin regulates transferrin receptor 2 protein stability [4].
• TfR2-alpha-expressing cells had considerably lower affinity for holotransferrin when compared with TfR1-expressing CHO cells [16].

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

• We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay [21].
• Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family [23].
• Raft biochemical dissection showed that TfR2 is a component of the low-density Triton-insoluble (LDTI) plasma membrane domain, able to co-immunoprecipitate with caveolin-1 and CD81, two structural raft proteins [24].
• 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 [25].
• Their cellular localization was studied by immunofluorescence with antibodies raised against Hjv and TfR2 [26].

References