Alternative titles; symbols
HGNC Approved Gene Symbol: TFRC
SNOMEDCT: 1179288008;
Cytogenetic location: 3q29 Genomic coordinates (GRCh38): 3:196,049,284-196,082,090 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q29 | Immunodeficiency 46 | 616740 | Autosomal recessive | 3 |
The TFRC gene encodes the transferrin receptor, which is important for cellular iron uptake. Circulating apotransferrin (TF; 190000) binds 2 Fe(3+) ions to form holotransferrin, which binds to TFRC. The TFRC-holotransferrin complex is internalized by receptor-mediated endocytosis (summary by Jabara et al., 2016).
A monoclonal antibody, OKT-9, recognizes an antigen ubiquitously distributed on the cell surface of actively growing human cells. It is a glycoprotein composed of disulfide-linked polypeptide chains, each of 90,000 daltons molecular weight. Immunoprecipitation of the OKT-9 antigen in the presence of labeled transferrin results in specific precipitation of transferrin (Sutherland et al., 1981); thus, the OKT-9 antigen is presumably transferrin receptor. Nikinmaa and Schroder (1987) concluded that p90 and TFRC are the same protein: studies using monoclonal antibodies indicated that exhaustive precipitation of radioactively labeled lysates with one antibody removed all activity of lysates with the other. Peptide maps of antigens recognized with both antibodies showed great similarity and indicated that both antibodies react with the same antigen, the human transferrin receptor, but with different antigenic sites of the molecule.
Casey et al. (1988) analyzed the regulation by iron of the TFRC gene by examining mouse cells transformed with chimeric constructs containing the human transferrin receptor gene's promoter and either the structural gene for bacterial chloramphenicol acetyltransferase or the human TFRC cDNA. They concluded that at least 2 genetic elements, one 5-prime and one 3-prime to the gene, are involved in the regulation of the TFRC gene by iron.
Radoshitzky et al. (2007) demonstrated a specific high-affinity association between TFR1 and the entry glycoprotein of Machupo virus (a New World arenavirus). Expression of human TFR1, but not human TFR2 (604720), in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the glycoprotein of Machupo, Guanarito, and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TFR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin, and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. Radoshitzky et al. (2007) concluded that TFR1 is a cellular receptor for New World hemorrhagic fever arenaviruses.
Ishii et al. (2009) found that knockdown of Ppargc1b (608886) in primary mouse osteoclasts impaired their differentiation and mitochondrial biogenesis. Transferrin receptor expression was induced in osteoclasts via iron regulatory protein-2 (IREB2; 147582), and Tfrc-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, which was associated with the induction of mitochondrial respiration, production of reactive oxygen species, and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected female mice against bone loss following estrogen deficiency resulting from ovariectomy. Ishii et al. (2009) concluded that mitochondrial biogenesis, which is induced by PPARGC1B and supported by TFRC-mediated iron uptake for utilization by mitochondrial respiratory proteins, is fundamental to osteoclast activation and bone metabolism.
Elahi et al. (2013) showed that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after coculture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2 (ARG2; 107830), and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with L-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses, parallels the loss of suppression and restored resistance to the perinatal pathogens Listeria monocytogenes and E. coli. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition. Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Elahi et al. (2013) thus concluded that CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. The authors further suggested that this finding challenged the idea that the susceptibility of neonates to infection reflects immune cell-intrinsic defects and instead highlights processes that are developmentally more essential and that inadvertently mitigate innate immune protection.
Senyilmaz et al. (2015) identified the metabolite stearic acid (C18:0) and human TFR1 as mitochondrial regulators. Senyilmaz et al. (2015) elucidated a signaling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK (601158) signaling. This leads to reduced ubiquitination of mitofusin via HUWE1 (300697), thereby promoting mitochondrial fusion and function. Senyilmaz et al. (2015) found that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink (608309) or Parkin (602544) in Drosophila. Senyilmaz et al. (2015) concluded that their work identified the metabolite C18:0 as a signaling molecule regulating mitochondrial function in response to diet.
Gruszczyk et al. (2018) identified TFR1 as the receptor for P. vivax reticulocyte-binding protein 2b (PvRB2b) and determined the structure of the N-terminal domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TFR1 recognition. Gruszczyk et al. (2018) validated TFR1 as the biologic target of PvRBP2b engagement by means of TFR1 expression knockdown analysis. TFR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of P. vivax but not to invasion of P. falciparum.
By somatic cell hybrid studies, Goodfellow et al. (1982) assigned the TFR locus to chromosome 3. Miller et al. (1983) confirmed the assignment to chromosome 3, specifically 3q22-qter. By in situ hybridization, Rabin et al. (1985) narrowed the assignment to 3q26.2-qter. Adriaansen et al. (1990) confirmed the assignment to chromosome 3 by study of somatic cell hybrids. Using linkage analysis, somatic cell hybrid and radiation hybrid mapping panels, and fluorescence in situ hybridization, Kashuba et al. (1997) refined the localization of the TFRC gene to 3q29.
Valenzuela et al. (1991) found highly significant association between Rh (111700) phenotypes and total iron binding capacity, i.e., transferrin. Children with the C Rh specificity had higher values than non-C or c individuals. Valenzuela et al. (1991) suggested that this finding may be significant in relation to maintenance of the Rh polymorphism and fetomaternal incompatibility.
Detection of Erythropoietin Misuse
Athletes such as racing cyclists sometimes use erythropoietin, which has been officially included in the International Olympic Committee list of banned substances since 1990, as a booster drug. Gareau et al. (1994) presented evidence that the level of transferrin receptor in the blood can be used as a means of detecting Epo misuse.
Cryoelectron Microscopy
Gruszczyk et al. (2018) reported a high-resolution cryoelectron microscopy structure of a ternary complex of P. vivax reticulocyte-binding protein 2b (PvRBP2b) bound to human TFR1 and transferrin (TF; 190000) at 3.7-angstrom resolution. Mutational analyses showed that PvRBP2b residues involved in complex formation are conserved; this suggested that antigens could be designed that act across P. vivax strains. Functional analyses of TFR1 highlighted how P. vivax hijacks TFR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron. Crystal and solution structures of PvRBP2b in complex with antibody fragments characterized the inhibitory epitopes. Gruszczyk et al. (2018) concluded that their results established a structural framework for understanding how P. vivax reticulocyte-binding protein engages its receptor and the molecular mechanism of inhibitory monoclonal antibodies.
In affected members of a large consanguineous Kuwaiti family with immunodeficiency-46 (IMD46; 616740), Jabara et al. (2016) identified a homozygous missense mutation in the TFRC gene (Y20H; 190010.0001). The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. An unrelated patient with a similar disorder carried the same homozygous mutation. Patient lymphocytes showed increased surface expression of TFRC (up to 13-fold higher than controls) and impaired TFRC internalization. Transduction of patient cells with wildtype TFRC corrected cell surface expression and corrected B- and T-cell function in vitro. Addition of iron citrate also corrected the lymphocyte proliferation defect in vitro, suggesting that insufficient iron uptake is the cause of defective B- and T-cell activation in affected individuals. Patient erythrocyte precursors showed lesser increases in TFRC membrane expression (up to 2.5-fold higher than controls) than the lymphocytes, suggesting that erythrocytes have a compensatory mechanism for TFRC internalization, which could also explain the mild anemia found in patients. STEAP3 (609671), which is expressed in erythroblasts and associates with TFRC, partially rescued the transferrin uptake defect in patient-derived fibroblasts. The overall findings demonstrated the importance of TFRC in adaptive immunity.
Levy et al. (1999) disrupted the transferrin receptor gene, which they termed Trfr, in mice. Homozygous mutant mice were not viable beyond embryonic day 12.5 and had severe anemia with hydrops as well as diffuse neurologic abnormalities. There was some variation of onset of severe anemia, and in nonanemic embryos without tissue edema and necrosis (E9.5), both stressed erythropoiesis and neurologic abnormalities were apparent. The authors concluded that inadequate iron led to neuronal apoptosis, but that tissues other than erythrocytes and neurons can obtain sufficient iron for growth and development through mechanisms independent of the transferrin cycle. Haploinsufficiency for the transferrin receptor resulted in microcytic, hypochromic erythrocytes; normal hemoglobin and hematocrit values were due to compensatory increase in red cell numbers. Although iron saturation of serum transferrin was indistinguishable from that of wildtype, heterozygotes had significantly less tissue iron.
In an N-ethyl-N-nitrosourea screen, Lelliott et al. (2015) identified a mouse line with a ser161-to-pro (S161P) mutation in the Tfr1 gene. Mutant heterozygotes exhibited reduced erythrocyte volume and density, as seen in iron deficiency anemia. However, unlike in dietary deficiency, erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Furthermore, system iron bioavailability was unchanged in mutants. Infection of mutant mice with the rodent malaria parasite, P. chabaudi, resulted in increased parasitemia and more rapid lethality compared with wildtype. Transfusion of fluorescently labeled red cells demonstrated erythrocyte-autonomous enhanced parasite survival within mutant erythrocytes. Lelliott et al. (2015) concluded that Tfr1 deficiency alters erythrocyte physiology similar to dietary iron deficiency, but to a lesser degree, and thereby promotes intraerythrocytic parasite survival and increased malaria susceptibility in mice.
Jabara et al. (2016) found that transgenic mice homozygous for the human TFRC mutation Y20H were viable, indicating that the mutation resulted in a hypomorphic allele. Mutant mice had decreased serum IgG, hemoglobin, and MCV compared to controls, but normal percentages of splenic T and B cells, naive and memory T cells, and NK cells. However, mutant T cells showed impaired proliferative responses, which was improved by the addition of iron citrate, and B cells showed impaired immunoglobulin secretion in response to stimulation. Tfrc surface expression on mutant T and B cells was significantly increased, reflecting impaired internalization.
In affected members of a large, highly consanguineous Kuwaiti family with immunodeficiency-46 (IMD46; 616740), Jabara et al. (2016) identified a homozygous c.58T-C transition (c.58T-C, NM_003234.2) in the TFRC gene, resulting in a tyr20-to-his (Y20H) substitution at a highly conserved residue in the intracellular internalization motif. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family, and was not found in multiple variant databases or in 731 controls. An unrelated patient from Saudi Arabia with a similar disorder carried the same homozygous mutation, and haplotype analysis suggested a founder effect. Patient lymphocytes showed increased surface expression of TFRC (up to 13-fold higher than controls) and impaired TFRC internalization. Transduction of patient cells with wildtype TFRC corrected cell surface expression and corrected B- and T-cell function in vitro.
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