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Hemochromatosis due to mutations in transferrin receptor 2.

A rare recessive disorder which leads to iron overload and severe clinical complications similar to those reported in HFE-related hemochromatosis has been delineated and sometimes called hemochromatosis type 3. The gene responsible is Transferrin Receptor 2 (TFR2), which maps to chromosome 7q22. The TFR2 gene presents a significative homology to transferrin receptor (TFRC) gene, encodes for a transmembrane protein with a large extracellular domain, is able to bind transferrin, even if with lower affinity than TFRC. The TFR2 function is still unclear. The transcript does not contain IRE elements and is not modified by the cellular iron status. At variance with TFRC, interactions between TFR2 and HFE do not occur, at least in their soluble forms. TFR2 is spliced in two alternative forms, alfa and beta. The alfa form is strongly expressed in the liver. The beta form, codified from a start site in exon 4 of the alpha, has a low and ubiquitous expression. 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. Our results suggest a regulatory role of TFR2 in iron metabolism. Five TFR2 homozygous mutations have been documented in HFE3 patients: a nonsense mutation (Y250X); a C insertion that causes a frameshift and a premature stop codon (E60X); a missense mutation (M172K); a 12 basepair deletion in exon 16, that causes 4 aminoacid loss (AVAQ 594-597del) in the extracellular domain of TFR2; a missense mutation in exon 17 (Q690P). The mutation analysis supports the hypothesis that all are private mutations. The pathogenetic role of TFR2 in hemochromatosis has been recently further demonstrated through the targeted expression of the Y250X human mutation in mice, which develop sings of iron overload identical to the human disease. Although the rarity of TFR2 mutations limits their usefulness in diagnostic/screening programs, their study can contribute to a better understanding of the protein function.

Hemochromatosis↗

PubMed1997

The effects of anticoagulation and processing on assays of IL-6, sIL-6R, sIL-2R and soluble transferrin receptor.

Levels of plasma cytokines, their receptors or immune-related peptides, are used in experimental and clinical medicine. However, no standards are available regarding the use of anticoagulants or blood processing including the technique of blood collection or time delay between blood sampling and centrifugation. Blood was collected from 10 patients in order to assay interleukin 6, soluble interleukin 6 receptor, soluble interleukin 2 receptor and soluble transferrin receptor by enzyme-linked immunosorbent assay (ELISA). At the time of sampling, five different collecting tubes were used: allowing coagulation, in the presence of EDTA, with EDTA being administered to the serum after its separation, in citrated and in heparinized blood. Blood was centrifuged 10 min after collection and separated serum or plasma was immediately frozen at -20 degrees C. To study the effect of time delay between blood sampling and processing, blood from 11 other patients was sampled, allowing coagulation; or in EDTA tubes and stored at 4 degrees C. The blood was centrifuged 10 min, 8 h and 24 h later, and the separated serum or EDTA plasma was stored at -20 degrees C until thawed for protein determination. Plasma interleukin 6 and soluble interleukin 6 receptor concentrations did not depend on the type of anticoagulant used or the time delay between sampling and processing. Soluble interleukin 2 receptor concentrations were not influenced by time delay before centrifugation, but concentrations were increased 10-fold in EDTA plasma exclusively when EDTA had contact with blood cells. Soluble transferrin receptor concentrations rose progressively with storage time before centrifugation. Contact of EDTA to whole blood or serum resulted in the same increase of soluble transferrin receptor concentration. The results suggest that standardization of the use of anticoagulant and time delay before centrifugation and serum or plasma separation is necessary for soluble interleukin 2 receptor and soluble transferrin receptor.

Anticoagulants↗

PubMed1993

Metal-induced conformational changes in transferrins.

Recent studies on iron-loaded transferrins have revealed a conformational change upon binding iron due to a domain closure. It has been suggested that the domain closure may be the key for the receptor recognition of the metal loaded transferrin (Grossmann et al., 1992). Small angle X-ray scattering has been used to provide direct structural information on the conformational changes that may take place upon the binding and release of different metals to the transferrins in solution. The data show that In3+ and Cu2+ induce the same domain closure as Fe3+; Al3+ causes a conformational change of somewhat smaller magnitude while Hf4+ does not induce any conformational change. The results are discussed in terms of the molecular recognition of metal loaded transferrin by the receptor.

Metals↗

PubMed1994

Salt effects on the physical properties of the transferrins.

Salts are known to have a pronounced effect on the spectroscopic, thermodynamic and kinetic properties of human serum transferrin. The present study was undertaken to examine the effect of NaCl on the related proteins ovotransferrin and lactoferrin. EPR difference spectroscopy was used to probe changes in the metal site of these proteins. Sodium chloride was found to perturb the g' = 4.3 EPR spectra of both ovotransferrin and lactoferrin but in different ways. The spectrum of ovotransferrin is reduced in amplitude with a broad feature appearing at g' = 4.8 whereas there is a loss of resolution of the doublet feature at the peak of the EPR derivative spectrum for lactoferrin. The increase in the amplitude of the ovotransferrin EPR difference spectrum (spectrum without NaCl minus spectrum with NaCl) as a function of NaCl concentration is suggestive of saturation binding. A Hill plot binding isotherm gave n = 1.87 +/- 0.32 and log K = 1.49 +/- 0.03 for ovotransferrin, where n is the number of C1- ions binding to either one or both iron containing lobes of the protein and K is the overall association constant. Preliminary measurements with lactoferrin gave n = 1.95 +/- 0.34 and log K = 1.41 +/- 0.06. These results are similar to those previously reported for serum transferrin and suggest that Cl- binds to all the transferrins with strong pairwise cooperativity. This binding may reflect a functional role for chloride and other physiological anions in the uptake and release of iron by the transferrins.

Chlorides↗

PubMed1983

67Ga-transferrin and 67Ga-lactoferrin binding to tumor cells: specific versus nonspecific glycoprotein-cell interaction.

In order to evaluate the mechanisms which facilitate the transfer of 67Ga from transferrin in plasma to intracellular binding sites, lactoferrin, a glycoprotein with high affinity for 67Ga, was used as a probe to study the effect of protein binding on gallium uptake by tumor cells. The in vivo effect of transferrin and lactoferrin on the biodistribution of 67Ga was studied in nude mice bearing human malignant mesothelioma. Tumor uptake of 67Ga was reduced 30% by transferrin and 57% by lactoferrin compared with 67Ga-citrate alone. Liver uptake of 67Ga, however, was significantly increased by binding to lactoferrin. The in vitro binding of 67Ga to tumor cells (Burkitt's lymphoma) was apparently promoted by the addition of transferrin or lactoferrin to the incubation medium, but this glycoprotein enhancement of gallium uptake by the cells was dependent on the albumin level, decreasing in absolute uptake as the albumin concentration was increased, suggesting nonspecific binding of glycoproteins to cells. Because of the significant amount of nonspecific binding of 67Ga-labeled glycoprotein complexes in cell culture experiments, in vitro experiments should be used with caution in developing a hypothesis on the mechanisms of cellular uptake of radiogallium. In vivo experiments suggest different mechanisms for cellular uptake of 67Ga in neoplastic tissue and in liver.

Adult↗

PubMed1984

Effect of insulin and transferrin in the maintenance of the activated state of the T-lymphocyte induced by allo-antigen.

Insulin is an immuno-modulating molecule enhancing cytotoxic T-cell function and supporting intermediary metabolism in activated lymphocytes. Insulin also maintains the activated state of mitogen-stimulated lymphocytes. Because of the importance of allo-antigen response of diabetic patients for infections and transplant immunity, we explored the role of insulin in the allo-activated state of lymphocytes. Allo-stimulation was provided in one-way mixed lymphocyte reactions, with Balb/C mouse lymph node cells responding to irradiated spleen cells of C57BL/6 mice, in culture under conditions which permitted evaluation of hormonal modulation. Mixed lymphocyte reactions established in fetal calf serum, insulin-depleted by passage over antibody affinity columns, were of equal magnitude to those in insulin-replete serum. A weak but positive mixed lymphocyte reaction can be effected with an artificial serum substitute containing no additional hormone. Provision of insulin (10 nmol/l) restored a full mixed lymphocyte reaction response which was mimicked by addition of transferrin. The insulin-transferrin combination was not additive. In conclusion, insulin and transferrin maintain the allo-activated state of the mouse lymphocyte, transferrin alone being sufficient when full antigenic stimulation is provided. If the same applies to human lymphocytes, insulin-deficient diabetic patients will respond to full allo-antigen challenge, and so should be fully capable of mounting a transplant immune response.

Animals↗

PubMed1987

Intestinal iron absorption and mucosal transferrin in rats subjected to hypoxia.

Three days hypoxia (0.5 atm) increased the haemoglobin and haematocrit values in rats paralleled by enhanced intestinal iron absorption. The destination of recently-absorbed iron was primarily the erythropoietic system, viz. bone marrow, spleen and red cells. Total plasma transferrin, was increased by 30%, but no significant changes in mucosal transferrin were found. No increase in labelling of mucosal transferrin by absorbed iron was observed. These results suggest that mucosal transferrin does not play a major role in the regulation of intestinal iron absorption in hypoxia.

Animals↗

PubMed1985

Transferrin receptors in cultured breast cancer cells.

Transferrin receptors were demonstrated on the cell membrane of breast cancer epithelial cells in primary or long-term culture. Diferric transferrin binding was saturable, specific and was not related to DNA content or clinical and histological features of the tumour. However a good correlation (p less than 0.01) was found between transferrin binding and thymidine incorporation. These results suggest the possibility of transferrin receptor measurement as a reflection of the proliferative activity of cultured breast tumour cells.

Breast Neoplasms↗

PubMed1977

Bovine serum transferrin phenotypes AA, D1D1, D2D2, EE: their carbohydrate compositions and electrophoretic multiplicity.

Samples of homozygous bovine serum transferrins have been prepared and their purity has been ascertained by immunological techniques and electrophoretic analysis in SDS. Measurements of carbohydrate composition show that no significant differences exist among the phenotype variants AA, D1D1, D2D2, and EE. Chromatography of transferrin AA on DEAE-cellulose separated four subfractions, each of which corresponded well with one band obtained by polyacrylamide gel electrophoresis. Carbohydrate analyses of the individual subfractions did not show significant differences in sialic acid, hexose, or hexosamine contents. After desialylation with neuraminidase, each subfraction was converted to a major band and a minor band on gel electrophoresis. From the relative band positions of the desialylated transferrins, it was concluded that possession of sialyl residued by bovine transferrin is not the primary cause of electrophoretic multiplicity. Rather, sialic acid masks an underlying heterogeneity which most likely resides within the polypeptide chain. Further characterization of this heterogeneity will best be undertaken with the isolated asialotransferrin subfractions.

Animals↗

PubMed1976

Polymorphism of transferrin in carp (Cyprinus carpio L.): genetic determination, isolation, and partial characterization.

Seven transferrin variants (A,B,C,D,E,F, and G) have been found in carp sera (Cyprinus carpio L.). Genetic analysis involves five variants and agrees with the hypothesis of simple codominant autosomal inheritance at one transferrin (Tf) locus in spite of the fact that the carp is a tetraploid in relation to other species of the same family. Carp populations from three regions were studied which differed in gene frequencies. Individual populations were in Hardy-Weinberg equilibrium. The polymorphism of carp transferrins can be used for the identification of offspring of single parent pairs, stocked in one pond. Transferrins have been isolated and characterized. Homozygous phenotypes comprised four iron-binding components differing in electrophoretic mobility. This heterogeneity is not caused by sialic acid, which is absent. Amino acid composition, content of hexoses (1 mole/mole of protein) and hexosamines (1 mole/mole of protein), molecualr weight (70,000), and the isoelectric point (5.0) have been determined. No N-terminal amino acid could be detected.

Amino Acids↗

PubMed1991

Transferrin is a growth factor for the bloodstream form of Trypanosoma brucei.

A method for the selective depletion of transferrin from bovine serum is presented. Bloodstream forms of Trypanosoma brucei cannot grow in medium containing transferrin-deficient serum, whereas reconstitution with transferrin restores normal growth. We conclude that transferrin is an essential growth factor for the mammalian stage of the parasite.

Animals↗

PubMed1986

Transferrin binding by mammalian cortical cells.

Predominantly neuronal (neuronal) or non-neuronal (glial) cerebral cortical cell cultures were employed to study the kinetics and changes with maturation of 125I-diferric-transferrin uptake. The diferric-transferrin association curve of neuronal cultures at 37 degrees C was nonphasic and indicated equilibrium at 90 minutes. Dissociation was completed by 70 minutes. Diferric-transferrin specific uptake (80% of total) in neuronal cells (evaluated at days 6, 9, 13, 16, and 23 in culture) increased with maturation. Scatchard transformation of the data revealed increasing Bmax from day 6 to day 16 in culture (1626 to 2740 fmoles/mg protein). However, the K uptake was statistically unchanged over time and equaled 48.7 +/- 13.9 nM (mean +/- SD). In contrast, association studies of glial cultures documented equilibrium by 45 minutes and dissociation by 40 minutes. The concentration curves for diferric-transferrin uptake in glial cells, evaluated at days 11, 15, and 18 in culture, revealed virtually identical uptake at the three ages studied, but the percent specific uptake (58%) was less than for neurons (88%). Scatchard transformation of the data revealed no statistical alteration of Bmax or K uptake from days 11 to 18 in culture. Bmax ranged from 595 to 751 fmol/mg protein; overall K uptake was 48.3 +/- 13.2 nM (mean +/- SD).

Animals↗

PubMed1989

Iron release from transferrin induced by mixed ligand complexes of copper(II).

Copper(II) complexes CuL1L2 with the ligand pairs 3-phosphoglycerate (PG)/ethylenediamine (en), phosphoserine (PS)/ethylenediamine, phosphoserine/malonate (mal) are shown to be effective in inducing the release of both iron atoms from di-ferric transferrin (Fe2Tf; human serum transferrin) at pH 7.3 in 1 M NaCl at 25 degrees C. Half-times of the reaction with Cu(PG)(en)- were less than 1 min at 0.02 M concentration. The iron(III) products are polynuclear hydroxo complexes. There is weaker interaction with Cu(PS)4-2 and virtually none with Cu(serine)(en) nor Cu(PS)(2,2'-bipyridyl)-, revealing crucial effects of the combined ligand sphere including the phosphomonoester group. The results suggest that the release of iron from Fe2Tf, or from either monoferric transferrins, occurred due to the breakdown of the stability of iron binding in conjunction with the expulsion of the synergistic anion carbonate (or oxalate). The active copper(II) complexes are postulated to be models of membrane components that could liberate iron from transferrin succeeding its uptake at the receptor sites of cells.

Apoproteins↗

PubMed1981

Properties and hepatic metabolism of non-transferrin-bound iron.

These experiments have examined the physical properties and the hepatic uptake of non-transferrin-bound iron, a fraction found in the serum of untreated primary hemochromatosis patients. Ultrafiltration, polyacrylamide gel electrophoresis, and TLC have demonstrated the non-transferrin-bound iron complex to have a molecular weight less than 1000 and to be distinct from free iron and amino acid iron complexes. Hepatic iron uptake from serum containing non-transferrin-bound iron was significantly higher than from the same serum sample from which the abnormal iron had been removed. Non-transferrin-bound iron entering the liver was localized to the lysosomal fraction in the first hour and was subsequently incompletely incorporated into ferritin. The results demonstrated an abnormal uptake of this iron fraction by the liver and suggest that the abnormal serum fraction may contribute to tissue damage by entering the lysosomes.

Animals↗

PubMed1982

Expression of human transferrin receptor is controlled by a gene on chromosome 3: assignment using species specificity of a monoclonal antibody.

The monoclonal antibody OKT-9 has been shown to recognize the human transferrin receptor. We have exploited the species specificity of OKT-9 to map a gene controlling human transferrin receptor expression to chromosome 3, using human-mouse somatic cell hybrids. The gene for the human transferrin receptor and the gene controlling transferrin expression may be linked in humans.

Animals↗

PubMed1989

Comparative effects of fagaronine, adriamycin and aclacinomycin on K562 cell sensitivity to natural-killer-mediated lysis. Lack of agreement between alteration of transferrin receptor and CD15 antigen expressions and induction of resistance to natural killer.

Little is known about membrane target antigens for natural killer (NK) cells. Transferrin receptor and CD15 antigen might be two of these target structures. A novel antileukemic alkaloid, fagaronine, is able to induce hemoglobin synthesis in the K562 cell line. Numerous reports suggest relations between the expression of natural killer target structures and the differentiation stage of malignant cells. Effects of fagaronine on the expression of glycophorin A, transferrin receptor and CD15 antigen and susceptibility to NK-mediated lysis have been investigated in K562 cells and compared to those of two anthracyclines (Adriamycin and aclacinomycin A) known to be erythroid-differentiation inducers. When comparing the balance of differentiating effect and toxicity, the dose and time-dependent effects of the drugs, fagaronine and aclacinomycin, are equivalent on K562 cells. In experimental conditions where fagaronine (3500 nM), Adriamycin (40 nM) and aclacinomycin (15 nM) recruit the same percentage of hemoglobin-containing cells (40%-50%), glycophorin A expression increases and transferrin receptor expression decreases. Only Adriamycin treatment decreases CD15 antigen expression. In addition, Adriamycin and aclacinomycin, but not fagaronine, induce resistance to NK-mediated lysis. These data suggest that (a) it is unlikely that CD15 antigen and transferrin receptor, separately considered, can be unique target structures for NK cells; and (b) fagaronine is a potent erythroid inducer which, in our system, has similar effects to aclacinomycin without induced resistance to NK attack.

Aclarubicin↗

PubMed1979

Binding of copper to mucosal transferrin and inhibition of intestinal iron absorption in rats.

1. The chromatographic elution patterns on Sepharose 6B of the supernatant from mucosal homogenates prepared 10 min after administration of copper into duodenal segments in vivo, indicate that copper is bound preferentially in the fraction of mucosal transferrin. 2. In iron deficiency the amount of 64Cu-copper taken up into the duodenal mucosa is more than two times higher and the amount bound to proteins of the supernatant is also increased to approximately the same degree whereas the amount transferred into the body is diminished to one fourth. 3. In the iron deficient group 64Cu-copper was also bound to a fraction which contains probably metallothionein. 4. The distribution of copper in the supernatant was changed due to a simultaneous administration of iron; the amount of copper bound in the transferrin fraction decreased in favor of the metallothionein fraction and another copper binding fraction was eluted between the transferrin and the metallothionein fraction. 5. Copper in a tenfold molar excess inhibited the iron absorption; simultaneously, the iron bound in the iron binding fractions of the supernatant was remarkably diminished. 6. The results suggest that the affinity of copper to two mucosal iron binding proteins, transferrin and metallothionein, is at least partly responsible for the inhibitory effect of copper on iron absorption in iron deficiency.

Animals↗

PubMed1977

Mucosal transferrin and ferritin factors in the regulation of iron absorption.

1. A standardized decompensation and recompensation of iron homeostasis has been produced by a change-over from normal to iron deficiency and back. 2. Under these conditions the 59Fe uptake into transferrin and ferritin of the mucosal "cytosol" and SDS treated "membrane" fraction has been measured together with the 59Fe amount transferred into the body. 3. The increase of the intestinal 59Fe absorption due to a progressive iron deficiency is associated with an increase of the 59Fe uptake into the mucosal transferrin of the "cytosol" and the "membrane" fraction; the reverse is observed with regard to mucosal ferritin. 4. Three days after the re-establishment of normal conditions the 59Fe absorption was lowered to normal values, while the 59Fe uptake into mucosal ferritin achieved again normally high values. 5. The high apparent rate of absorption in iron deficient animals decreased during the last 50 min after injection of the 59Fe labelled test dose. The 59Fe content in the ferritin fraction increased simultaneously, whereas the 59Fe content in the transferrin fraction remained the same. 6. The conclusion is drawn that the intestinal iron absorption is regulated by both mucosal iron binding proteins. Mucosal transferrin is responsible for the increase of absorption in iron deficiency while mucosal ferritin is responsible for the inhibition of iron absorption when the iron homeostasis recompensats.

Animals↗