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PubMed2004

Transcobalamin polymorphism and serum holo-transcobalamin in relation to Alzheimer's disease.

Isoforms of the vitamin B(12) carrier protein transcobalamin (TC) might influence its cellular availability and contribute to the association between disrupted single-carbon metabolism and Alzheimer's disease (AD). We therefore investigated the relationships between the TC 776C>G (Pro259Arg) genetic polymorphism, total serum cobalamin and holo-TC levels, and disease onset in 70 patients with clinically diagnosed AD and 74 healthy elderly controls. TC 776C>G polymorphism was also determined for 94 histopathologically confirmed AD patients and 107 controls. Serum holo-TC levels were significantly higher in TC 776C homozygotes (p = 0.04). Kaplan-Meier survival functions differed between homozygous genotypes (Cox's F-Test F(42, 46) = 2.1; p = 0.008) and between 776C homozygotes and heterozygotes (Cox's F test F(46, 108) = 1.7; p = 0.02). Proportionately fewer TC 776C homozygotes appear to develop AD at any given age, but this will require confirmation in a longitudinal study.

Aged↗
PubMed1985

Synthesis and secretion of the human vitamin B12-binding protein, transcobalamin II, by cultured skin fibroblasts and by bone marrow cells.

Human skin fibroblasts and bone marrow cells were tested for their ability to synthesize the cobalamin-binding protein transcobalamin II. Cobalamin binders secreted in the media of cultured fibroblasts and of dextran-sedimented bone marrow cells in liquid culture could be identified as transcobalamin II on the basis of immunological, electrophoretical and chromatographical identity with serum transcobalamin II. The net secretion of transcobalamin II increased linearly with time of culture, up to 30 days after confluence. The reversible inhibition of transcobalamin II secretion by cycloheximide demonstrated that human fibroblasts are capable of de novo transcobalamin II synthesis. Addition of cyanocobalamin to the fibroblast culture medium induced a reduction of transcobalamin II net secretion, most likely due to preferred uptake of transcobalamin II saturated with cobalamin, as opposed to unsaturated protein. Addition of lysozymal enzyme inhibitors, ammonium chloride and chloroquine, resulted in a markedly increased secretion of transcobalamin II. In the culture medium of fibroblasts, obtained from two transcobalamin II-deficient patients, functionally deficient transcobalamin II was demonstrated on the basis of strongly reduced secretion of immunoreactive transcobalamin II, and the absence of apotranscobalamin II. Individual phenotypes in the culture media of the fibroblasts and bone marrow cells were identical to the corresponding serum transcobalamin II types.

Bone Marrow↗
PubMed1977

Changes in circulating transcobalamin II after injection of cyanocobalamin.

Since transcobalamin II is the plasma binder of vitamin B12(cobalamin) that mediates delivery of cobalamin to tissues, we measured circulating levels of transcobalamin II after intravenous injection unlabeled cyanocobalamin in 12 control subjects and, because the liver is a major source of transcobalamin II, in eight patients with decompensated cirrhosis. Thirty minutes after injection of cyanocobalamin (200 ng per kilogram of body weight), total transcobalamin II (unsaturated plus cobalamin bound) declined in all 20 subjects to levels that averaged (+/- S.E.) 53.5 +/- 4.6 per cent of initial values. Subsequently, unsaturated transcobalamin II rapidly increased so that by eight hours, total transcobalamin II approached preinjection levels. Rates of regeneration of transcobalamin II were similar in control subjects and patients with liver disease. Unlike total transcobalamin II, total transcobalamin I was unaltered by injection of cyanocobalamin. Moreover, addition of cyanocobalamin to plasma in vitro did not alter measurements of total transcobalamin II. The rapid response of circulating transcobalamin II to cyanocobalamin injection strongly supports a dynamic role for this polypeptide during transport of a relatively large load of cobalamin.

Adult↗
PubMed1988

Application of heparin-conjugated Sepharose for the measurement of cobalamin-saturated and unsaturated transcobalamin II.

The cobalamin-binding plasma protein transcobalamin II has a high affinity for the anticoagulant heparin. This phenomenon has been exploited in a new method for the quantification of cobalamin-saturated (holo-) and unsaturated (apo-) transcobalamin II in human plasma. Transcobalamin II is adsorbed from human plasma to heparin-conjugated Sepharose under suitable conditions and either cobalamin from adsorbed holo-transcobalamin II is measured by a radioisotope dilution assay or apo-transcobalamin II is determined by measuring the adsorbed unsaturated cobalamin-binding capacity with radioactive cobalamin. The assay results for apo- and holo-transcobalamin II are similar (r = 0.99 and 1.0, respectively) to those obtained with the established radioimmunosorbent assay using specific rabbit anti-human transcobalamin II-conjugated Sepharose. The assay cannot be carried out in heparin-anticoagulated plasma, because the free heparin competes with the immobilized heparin for the binding of transcobalamin II. The amount of heparin in plasma from patients being treated with subcutaneous or intravenous heparin is too low to interfere significantly with the measurement of transcobalamin II. Also the presence of circulating anti-transcobalamin II antibodies, as occur in some rare patients after frequent intramuscular injections of cobalamin, does not influence the assay.

Heparin↗
PubMed1980

Characterization of the particulate and soluble acceptor for transcobalamin II from human placenta and rabbit liver.

We describe in both human placenta and rabbit liver membranes specific acceptors which bind the human transcobalamin II-vitamin B-12 (cobalamin) complex with an affinity of 2.3 . 10(9) (placenta) and 6.7 . 10(9) (liver) M-1 and which bind the rabbit transcobalamin II-cobalamin complex with an affinity of 1.1 . 10(9) (placenta) and 1.9 . 10(9) (liver) M-1, respectively. The binding requires Ca2+ and is sensitive to both 1 M NaCl and acid pH. A new ligand binding assay, based on the ability of the acceptor, but not transcobalamin II, to bind to concanavalin A, is described and is used to characterize the solubilized acceptors. The solubilized acceptors bind human transcobalamin II-cobalamin with high affinity (about 2-9 . 10(9) M-1) but do not bind free cobalamin; unsaturated transcobalamin II is bound with an affinity approximately one-third of that for transcobalamin II saturated with cobalamin. On gel filtration, the human acceptor saturated with transcobalamin II-cobalamin exhibits a Stokes radius of 6.7 nm, whereas the free acceptor has a Stokes radius of 5.1 nm. The rabbit liver acceptor either unsaturated or saturated with transcobalamin II-cobalamin exhibits a Stokes radius of 5.7 nm. Both acceptors bind to lectins such as concanavalin A, wheat germ agglutinin and phytohemagglutinin, indicating their glycoprotein nature, and both acceptors can be purified approximately 30-fold by affinity chromatography on wheat germ agglutinin-Sepharose columns. The concanavalin A assay, combined with lectin-Sepharose and transcobalamin II-cobalamin-Sepharose affinity chromatography will provide for the isolation and study of pure acceptors from a variety of tissue sources.

Animals↗
PubMed1977

Unsaturated and cobalamin saturated transcobalamin I and II in normal human plasma.

Insolubilized antibody against human transcobalamin I has been used as a specific and precise tool for the separation of transcobalamin I (and III) from transcobalamin II. Range and mean (in parentheses) for the unsaturated binding capacity for twenty samples are 40-190 (90) pmol/l and 220-1170 (560) pmol/l for transcobalamin I (and III) and transcobalamin II, respectively. The similar figures for the cobalamin saturated transcobalamins are 200-549 (320) pmol/l and 75-475 (160 pmol/l. On analyses of the cobalamins attached to each of the transcobalamins, it is shown that methylcobalamin accounts for most of the cobalamins attached to transcobalamin I whereas transcobalamin II carries most of the 5'-deoxyadenosylcobalamin.

Antibodies↗
PubMed2000

Measurement of transcobalamin by ELISA.

BACKGROUND: Transcobalamin is essential for the cellular internalization of cobalamin. Methods to quantify the unsaturated protein are available, but few attempts have been made to develop methods to quantify the sum of unsaturated and cobalamin saturated transcobalamin. METHODS: gamma-Globulins from two polyclonal rabbit antibodies against recombinant human transcobalamin were used as capture and detection antibodies, and recombinant human transcobalamin was used as calibrator in an ELISA design. RESULTS: The ELISA is specific for transcobalamin and has a detection limit of <1.6 pmol/L. The imprecision (CV) is 4-6% for mean concentrations of 13-70 pmol/L. The central 95% interval for serum from healthy blood donors (n = 77) was approximately 600-1500 pmol/L and showed limited variation with age and sex. No correlation was observed between the marker of acute phase reaction, C-reactive protein, and transcobalamin in plasma. CONCLUSIONS: The ELISA measures total transcobalamin in serum and thus can be used for measurement of transcobalamin in patients treated with cobalamin.

Animals↗
PubMed1983

Genetic patterns of transcobalamin II and the relationships with congenital defects.

The vitamin B12-binding protein, transcobalamin II, is a trace component of plasma with a rapid turnover. This protein is essential for absorption, transport, cellular uptake and for recycling of vitamin B12 (cobalamin). Congenital transcobalamin II deficiency, an inborn error of metabolism is inherited as a recessive trait. The homozygous form of the deficiency is accompanied by severe clinical, hematological and immunological disturbances in the first months of life. Analytical, genetic, biochemical and clinical aspects of transcobalamin II in man and in vertebrates have been reviewed here. A genetic polymorphism for the protein has been found in man, rabbits and mice. Family studies revealed that the genetic patterns in man are determined by four polymorphic and several rare alleles. This genetic variability has been applied in paternity testing and in population studies. Transcobalamin II typing in families of patients with the inherited functional deficiency has led to identification of various deficient alleles in heterozygous carriers of the defects. Applying transcobalamin II typing after bone marrow transplantation demonstrated that this protein originates partly in the bone marrow. Subsequent investigations in cell culture have shown that human skin fibroblasts and cultured bone marrow synthesize and secret isotypes of a transport protein corresponding to the genetic isotypes observed in plasma. Comparison of transcobalamin II types in umbilical cord serum with the maternal types, has proven that the transcobalamin II activity in the cord serum is derived from the fetus. This finding will be of crucial importance in the early diagnosis of the deficiency syndrome.

Alleles↗
PubMed1977

The forms of vitamin B12 on the transcobalamins.

1. The transcobalamins from normal serum were obtained in two fractions. One contained transcobalamin I and transcobalamin III: the other contained transcobalamin II. The forms of vitamin B12 in the two fractions were then examined. 2. Methylcobalamin and adenosylcobalamin were found in both fractions. Hydroxocobalamin was found in the fraction containing transcobalamin I and transcobalamin III. Cyanocobalamin was found in both fractions in two cases, in the transcobalamin III fraction only in one case and was absent in one case.

Blood Proteins↗
PubMed1985

Cobalamin binding proteins (haptocorrin and transcobalamin) in human cerebrospinal fluid.

The unsaturated cobalamin binding capacity of transcobalamin and haptocorrin was studied in cerebrospinal fluid (CSF) and plasma (P) from 37 reference individuals. These comprised 27 males and 10 females who underwent minor surgery in spinal anaesthesia. The 5th and 95th percentiles were as follows: P-Transcobalamin 300-870 pmol/l (median 550 pmol/l); CSF-Transcobalamin 90-540 pmol/l (median 194 pmol/l); P-Haptocorrin 75-290 pmol/l (median 159 pmol/l); CSF-Haptocorrin 10-41 pmol/l (median 21 pmol/l). No sex difference was found between the levels of haptocorrin or transcobalamin in plasma or cerebrospinal fluid. A positive correlation between P-Transcobalamin and CSF-Transcobalamin was found, whereas no correlation between P-Haptocorrin and CSF-Haptocorrin values was found. The plasma/CSF ratios of transcobalamin, haptocorrin, albumin and IgG indicated that the binders may be synthetized into the cerebrospinal fluid or are actively being transported into the cerebrospinal fluid.

Female↗
PubMed1985

Transcobalamin II: a marker for macrophage/histiocyte proliferation.

Increased blood levels of (apo-)transcobalamin II have been observed in several clinical conditions, but persistent inability to find a common denominator for this plasma protein aberration has hampered its introduction as a clinically useful laboratory parameter. Because several observations suggested a relationship between reticuloendothelial cell activity and transcobalamin II, the finding of an extreme transcobalamin II elevation in a patient with malignant histiocytosis was taken seriously. Of 14 consecutive patients with proliferative histiocytosis (8 malignant, 6 reactive), all revealed marked to extreme elevations of transcobalamin II. Macrophage/histiocyte origin of this protein is supported by a close parallelism to increased serum angiotensin-converting enzyme activity. Comparative pre- and postoperative measurements of transcobalamin II and angiotensin-converting enzyme in four patients with histiocytic proliferation who underwent splenectomy, an intervention that led to immediate reduction of the macrophage/histiocyte cell pool, revealed a parallel and impressive drop of both parameters, further corroborating the histiocytic origin of transcobalamin II. It is suggested that transcobalamin II determination provides useful information on activity and size of the macrophage/histiocyte system, and supplements measurements of the traditional acute phase reactants (e.g., C-reactive protein, red blood cell sedimentation rate).

Adult↗