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TRANSFERRIN; TF

TRANSFERRIN; TF

HGNC Approved Gene Symbol: TFCytogenetic location: 3q22.1 Genomic coordinates (GRCh38): 3:133,661,997-133,796,640 (from NCBI)▼ DescriptionThe TF gene encodes...

HGNC Approved Gene Symbol: TF

Cytogenetic location: 3q22.1 Genomic coordinates (GRCh38): 3:133,661,997-133,796,640 (from NCBI)

▼ Description
The TF gene encodes transferrin, a circulating serum protein responsible for delivering iron to cells (Hershberger et al., 1991).

▼ Cloning and Expression
Uzan et al. (1984) isolated a clone corresponding to the human transferrin gene from a human liver cDNA library. A single major 2.4-kb mRNA species was identified.

Yang et al. (1984) isolated recombinant plasmids containing human cDNA encoding TF by screening an adult human liver library with a mixed oligonucleotide probe. Sequence analysis indicated that 3 areas of the homologous amino and carboxyl domains were strongly conserved in evolution.

Bost et al. (1985) identified short regions in the nucleotide and amino acid sequences of epidermal growth factor (EGF; 131530), interleukin-2 (IL2; 147680), and transferrin that matched short regions in their respective receptor complements (antisense strand) and their deduced amino acid sequences. In each case, the region of homology of the receptor was in sequences external to the cytoplasmic membrane that might qualify for the ligand binding site.

Hershberger et al. (1991) cloned the human TF gene and determined that the deduced protein contains 678 residues and 19 disulfide bonds, with a molecular mass of about 80 kD.

▼ Mapping
Robson et al. (1966) presented evidence of linkage between the transferrin locus and the pseudocholinesterase locus E1 (CHE1, BCHE; 177400). Naylor et al. (1980) suggested that the TF-CHE1 linkage group may be on chromosome 3 in man because aminoacylase (ACY1; 104620) and beta-galactosidase-1 (GLB1; 611458) are on chromosome 3 in man and on chromosome 9 in the mouse, and because Tf is closely linked to Acy1 and Glb1 in the mouse.

By somatic cell hybridization, using a monoclonal antibody to demonstrate the synthesis of transferrin, Bodmer (1981) assigned the TF gene to chromosome 3. Lactotransferrin (LTF; 150210), found in milk of many mammals including man, is structurally similar to serum transferrin and is coded by a gene on chromosome 3p. Interestingly and perhaps significantly, the gene for the transferrin receptor (TFRC; 190010) is on chromosome 3q29. Eiberg et al. (1984) found a low positive lod score at a recombination fraction of about 0.23 for linkage of TF to heteromorphism at the centromere of chromosome 3. Since CHE1 and A2HS (104210) showed negative lod scores, these are possibly distal to TF on chromosome 3.

Yang et al. (1984) mapped the TF gene to chromosome 3q21-q25 by in situ hybridization and analysis of somatic cell hybrids. Huerre et al. (1984) confirmed these findings.

Through linkage studies in a large Newfoundland kindred segregating for an inversion, inv(3)(p25q21), McAlpine et al. (1987) determined the order to be cen--3q21--TF--CHE1--AHSG (138680)--qter.

By in situ hybridization, Baranov et al. (1987) assigned the TF gene to 3q21. They mapped both the CP (117700) and TF genes to chromosome 9 in the mouse and chromosome 7 in rats. In rats, they also observed a concentration of silver grains over chromosome 15 after hybridization with both CP and TF probes, suggesting the presence of a related pseudogene cluster on rat chromosome 15 and favoring partial homeology to rat chromosome 7. Use of a rat CP DNA probe appeared to contradict synteny of CP and TF in man and suggested the existence of a related DNA sequence on 15q11-q13.

▼ Gene Function
Transferrin is the product of an ancient intragenic duplication that led to homologous carboxyl and amino domains, each of which binds 1 ion of ferric iron. Transferrin carries iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. It carries iron into cells by receptor-mediated endocytosis. Iron is dissociated from transferrin in a nonlysosomal acidic compartment of the cell. Provision of intracellular iron is required for cell division. After dissociation of iron, transferrin and its receptor return undegraded to the extracellular environment and the cell membrane, respectively (Yang et al., 1984; Park et al., 1985; Bowman et al., 1988).

Sass-Kuhn et al. (1984) identified a heat-stable protein in normal human serum that promoted the binding of granulocytes to timothy grass pollen. They concluded that this granulocyte/pollen-binding protein (GPBP) was identical to transferrin. This novel property of transferrin was unrelated to iron transport. The authors concluded that transferrin may have a physiologic role in the removal of certain organic matter.

IGFBP3 (146732) possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP3-binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. Weinzimer et al. (2001) characterized TF as one of these IGFBP3-binding proteins. Human serum was fractionated over an IGFBP3 affinity column, and a 70-kD protein was eluted, sequenced, and identified (through database searching and Western immunoblot) as human TF. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to that of IGF1 (147440), and suggested that binding occurs in the vicinity of the IGFBP3 nuclear localization site. TF treatment blocked IGFBP3-induced cell proliferation in bladder smooth muscle cells and IGFBP3-induced apoptosis in prostate cancer cells.

Iron is essential to life, but poses severe problems because of its toxicity and the insolubility of hydrated ferric ions at neutral pH. In animals, transferrins are responsible for the sequestration, transport, and distribution of free iron. Baker et al. (2003) compared the structure and function of transferrins with hemopexin (HPX; 142290), a completely unrelated protein that carries out the same function for heme. They identified molecular features that contribute to a successful protein system for iron acquisition, transport, and release. These include a 2-domain protein structure with flexible hinges that allow these domains to enclose the bound ligand and provide suitable chemistry for stable binding and an appropriate trigger for release.

▼ Molecular Genetics
TF Polymorphisms

Transferrin polymorphisms were first demonstrated by Oliver Smithies (1957, 1958) using starch gel electrophoresis. Welch and Langmead (1990) stated that more than 30 different genetic TF variants had been described. TF C (190000.0004), especially TF C1 (Kamboh and Ferrell, 1987), is the predominant form in all investigated populations.

Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).

Evans et al. (1982) described a transferrin variant that was abnormal in its iron-binding properties. It was able to bind 2 atoms of iron, but the iron in the C-terminal binding site was bound abnormally, as judged by its spectral properties, and dissociated from the protein under certain conditions. Furthermore, the iron-free C-terminal domain was relatively unstable. Young et al. (1984) described a variant transferrin that showed both abnormal iron-binding properties and an abnormal interaction with the transferrin receptor.

Weidinger et al. (1984) identified and characterized several TF variants, including a null allele, in a German population.

Pang et al. (1998) showed that peripheral blood cells can be used as a source for preparation of TF cDNA, as an alternative to human liver, in the molecular analysis of TF polymorphism.

Atransferrinemia

In a patient with atransferrinemia (209300), Beutler et al. (2000) identified compound heterozygosity for 2 mutations in the TF gene (190000.0006 and 190000.0007).

Associations Pending Confirmation

For discussion of a possible relationship between variation in the TF gene and serum transferrin as a quantitative trait, see 614193.

▼ Evolution
Barber and Elde (2014) showed that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism (P589S; 190000.0004) in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. Barber and Elde (2014) concluded that these findings identified a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens.

▼ History
Chautard-Freire-Maia (1976) presented evidence that the TF locus was on chromosome 1 and linked to Rh (111700). However, King et al. (1979) were unable to confirm these findings. Linkage of HLA and TF was excluded by Jenkins et al. (1982).

▼ ALLELIC VARIANTS ( 10 Selected Examples):

.0001 TRANSFERRIN VARIANT D1
TF, GLY277ASP
Yang et al. (1984) identified the amino acid change in 3 genetic variants of transferrin: D1 (Wang and Sutton, 1965), D(chi) (Wang et al., 1967), and B2 (Wang et al., 1966). The variants differed at the following amino acids: 277 (gly-to-asp), 300 (his-to-arg; 190000.0002), and 652 (gly-to-glu; 190000.0003). All could be explained by mutational transitions, G-to-A, A-to-G, and G-to-A, respectively, in the second nucleotide of each of the 3 codons.

Yang et al. (1984) originally reported this mutation as ASP277GLY, caused by an A-to-G nucleotide change.

.0002 TRANSFERRIN VARIANT D(CHI)
TF, HIS300ARG
Yang et al. (1984) determined that transferrin variant D(Chi) (Wang et al., 1967) has an A-to-G transition resulting in a his300-to-arg (H300R) substitution.

.0003 TRANSFERRIN VARIANT B2
TF, GLY652GLU
Yang et al. (1984) determined that transferrin variant B2 (Wang et al., 1966) has a G-to-A transition resulting in a gly652-to-glu (G652E) substitution.

.0004 TRANSFERRIN VARIANT C1/C2
ALZHEIMER DISEASE, SUSCEPTIBILITY TO, INCLUDED
TF, PRO589SER (rs1049296)
Kauwe et al. (2010) noted that the C2 variant of TF is a pro589-to-ser (P589S; rs1049296) substitution.

As the basis of the C1/C2 variation in transferrin as revealed by isoelectric focusing, Namekata et al. (1997) identified a single base change in exon 15 of the TF gene. A C-to-T substitution at codon 570 replaced proline (in C1) with serine (in C2) (PRO570SER). Based on this nucleotide substitution, Namekata et al. (1997) established PCR-based genotyping for the TFC1 and TFC2 alleles.

Robson et al. (2004) noted that there is evidence that iron may play a role in the pathology of Alzheimer disease (104300). Thus, genetic factors that contribute to iron deposition resulting in tissue damage might exacerbate AD. The authors examined the interaction between the C2 variant of the TF gene and the C282Y allele of the HFE gene (613609.0001), the most common basis of hemochromatosis, as risk factors for developing AD. The results showed that each of the 2 variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. Furthermore, carriers of these 2 alleles plus APOE4 (see 107741) were at still higher risk of AD: of the 14 carriers of the 3 variants identified in this study, 12 had AD and 2 had mild cognitive impairment. Robson et al. (2004) concluded that their results indicated that the combination of TF*C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurons, which is exacerbated in carriers of APOE4. They noted that 4% of northern Europeans carry the 2 iron-related variants and that iron overload is a treatable condition.

.0005 TRANSFERRIN VARIANT Bv
TF, LYS627GLU
Pang et al. (1998) used peripheral blood cells to prepare cDNA for TF. They found that the TF B variant allele (TF Bv) contains an A-to-G transition at nucleotide 1879 in the coding region that was predicted to result in a lys627-to-glu substitution in exon 16.

.0006 ATRANSFERRINEMIA
TF, 10-BP DEL AND 9-BP DUP
In the first reported case of hereditary atransferrinemia (209300) in the U.S., Beutler et al. (2000) found compound heterozygosity for mutations in the TF gene: the patient had hypothyroidism, which was ascribed to iron overload, and was treated monthly with removal of blood followed by infusion of 500 ml of normal human plasma. The patient's DNA demonstrated heterozygosity for a 10-bp deletion followed by a 9-bp insertion of a duplicated sequence; and a G-to-C transversion at cDNA nucleotide 1429, resulting in an ala477-to-pro substitution (190000.0007). The latter mutation occurred at a highly conserved site.

.0007 ATRANSFERRINEMIA
TF, ALA477PRO
For discussion of the ala477-to-pro (A477P) substitution in the TF gene that was found in compound heterozygous state in a patient with atransferrinemia by Beutler et al. (2000), see 190000.0006.

.0008 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
TF, GLY277SER
This variant, formerly titled IRON DEFICIENCY ANEMIA, SUSCEPTIBILITY TO, has been reclassified based on the findings of Aisen (2003) and Delanghe et al. (2006).

In the course of a study to determine whether polymorphisms in transferrin may affect the severity of hemochromatosis in persons carrying mutations in the HFE gene (613609), Lee et al. (2001) found that a common polymorphism in exon 7 of the transferrin gene, a G-to-A transition at nucleotide 829, resulting in a gly277-to-ser (G277S) amino acid change, was associated with a reduction in total iron-binding capacity (TIBC). Although the loss of TIBC did not compromise the iron status of men and postmenopausal women, it predisposed menstruating women to iron deficiency anemia. In menstruating white women, iron deficiency anemia was present in 27% of homozygous ser277 women, 10% of heterozygous gly277/ser277 women, and 5% of homozygous wildtype gly277/gly277 women.

To explore the suggestion that the glycine in amino acid position 277 is important for the maintenance of the biologic activity and/or structure of transferrin, Aisen (2003) constructed the mutation in the human transferrin expression vector, verified the construct by DNA sequencing, and expressed the mutant in the nonglycosylated form of BHK21 cells. He could demonstrate no difference between the mutant and native transferrins and concluded that the cause of the iron deficiency observed in the subjects studied by Lee et al. (2001) should be sought elsewhere.

In a study of 92 pregnant women followed longitudinally during pregnancy, Delanghe et al. (2006) found no relationship between transferrin concentration, iron status, and the G277S variant of the transferrin gene. They concluded that the G277S polymorphism does not significantly alter iron metabolism.

.0009 ATRANSFERRINEMIA
TF, GLU375LYS
Hayashi et al. (1993) analyzed transferrin in a family with atransferrinemia (209300) reported by Goya et al. (1972) and concluded that the patient and his 2 healthy sibs were compound heterozygotes with a paternal 'variant' TF allele and a maternal 'null' TF allele. Asada-Senju et al. (2002) investigated the TF gene of the patient and his family. They showed that the patient and his father shared a variant TF gene bearing a G-to-A transition, resulting in a glu375-to-lys (E375K) substitution in the mature protein. As for the maternal null allele, no mutation was found in either the coding region or the exon-intron boundaries, suggesting an abnormality in the transcription or stability of mRNA of maternal allele origin.

.0010 ATRANSFERRINEMIA
TF, ASP77ASN
In lymphoblastoid cell lines from a patient with atransferrinemia (209300), her parents, and her healthy brothers, first reported by Cap et al. (1968), Knisely et al. (2004) identified a 229G-A transition in exon 3 of the TF gene, resulting in a nonconservative amino acid substitution, asp77 to asn (D77N). The proband was homozygous for the D77N mutation; both parents and 1 brother were heterozygous. The proband came to medical attention at the age of 2 months with severe hypochromic, microcytic anemia. Atransferrinemia was diagnosed by means of serum electrophoresis. Serum transferrin concentrations in her parents, a brother, and a grandfather were approximately half normal values. Periodic infusions of purified transferrin led to improved erythropoiesis, although complications attributed to siderosis developed. The proband, aged 34 years at the time of report, came from a town of 7,000 inhabitants in a relatively isolated region of west Slovakia. The disease in this patient was more severe than either of the 2 previously reported cases (Goya et al., 1972; Beutler et al., 2000).

Tags: 3q22.1

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