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PubMed2005

Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II.

BACKGROUND: Cobalamin attached to transcobalamin II (TC II), known as holo-TC II, is the active cobalamin fraction taken up by tissues. Holo-TC II is also the form in which absorbed cobalamin enters the circulation from the ileum. Therefore, holo-TC II has been proposed variously as a marker of cobalamin adequacy, cobalamin absorption, or both, including even its advocacy as a surrogate Schilling test. Such claims carry conflicting diagnostic implications because metabolic adequacy and absorption are not identical. OBJECTIVE: The objective was to examine metabolic and absorptive influences on holo-TC II. DESIGN: Treated patients with pernicious anemia (PA), who have abnormal absorption but a normal metabolic status, were chosen as the model to differentiate between the effects of the 2 cobalamin-related characteristics. Serum holo-TC II and indexes of cobalamin metabolism in 23 treated patients were compared with those of 6 untreated PA patients (abnormal absorption and metabolic status) and 33 control subjects (normal absorption and metabolic status). RESULTS: Holo-TC II, which correlated directly with cobalamin and inversely with homocysteine, was significantly higher in treated PA patients in metabolic remission than in untreated PA patients (74 +/- 59 compared with 9 +/- 6 pmol/L) and was significantly lower than in control subjects (105 +/- 58 pmol/L), although the latter difference was small and the values overlapped greatly. CONCLUSIONS: Metabolic cobalamin status is a major determinant of serum holo-TC II. Absorption status may have mild influence as well, although other explanations remain possible. Serum holo-TC II cannot be used clinically to diagnose cobalamin malabsorption because of overlap with normal values. The influences on holo-TC II are complex and require careful analysis.

Anemia, Pernicious↗
PubMed1981

Transcobalamin-binding capacities in vitamin B12-related diseases.

Abnormalities in some transcobalamin unsaturated binding capacities (TC-UBBC) were found in some patients with treated pernicious anemia who had elevated TC II-UBBC, R-UBBC, and total UBBC, in gastrectomized patients with latent vitamin B12 deficiency who had elevated R-UBBC and UBBC, and in patients with obstructive jaundice who had elevated TC II-UBBC and UBBC. No abnormalities were found in patients who had untreated pernicious anemia, folate deficiency, unclassifiable megaloblastic anemia, tobacco amblyopia, or low serum B12 level but normal capacity to absorb vitamin B12.

Anemia, Pernicious↗
PubMed1994

Identification of two mutant alleles of transcobalamin II in an affected family.

Transcobalamin II (TC II) deficiency is a rare autosomal recessive disease leading to cobalamin (Cbl; Vitamin B12) deficiency characterized by failure to thrive, megaloblastic anemia, impaired immunodefence and neurological manifestations. By means of Southern blotting and sequence analysis of TC II cDNA amplified from fibroblasts of an affected child and his parents, we have identified two mutant TC II alleles, one with a gross deletion and the other with a 4 nucleotide deletion. Both the mutations caused TC II mRNA and protein deficiency and hence defective plasma transport of Cbl and the development of Cbl deficiency in the affected child. The present study has identified molecular defects that cause TC II deficiency and lead to intracellular Cbl deficiency in humans.

Alleles↗
PubMed2002

The transcobalamin codon 259 polymorphism influences the risk of human spontaneous abortion.

BACKGROUND: The remethylation cycle of methionine is folate and vitamin B(12) (cobalamin) dependent and appears to be crucial for embryonic development, probably through effects on synthesis of DNA, proteins and polyamines. Transcobalamin (TC) transports vitamin B(12) to the tissues. The objective of the present investigation was to explore the putative association between the major TC genetic polymorphism (Pro259Arg) and human spontaneous abortion. METHODS: The prevalence of the TC Pro259Arg polymorphism was determined in DNA samples from embryos that had been spontaneously aborted between the 6th and 20th week after conception, and adult controls using solid-phase minisequencing technique. RESULTS: The 259-Pro allele was significantly less frequent in the spontaneous abortion group than in the control group (42.2 and 57.0% respectively; P = 0.005), while the frequency of 259-Arg was significantly increased. There was a lower prevalence of 259-Pro homozygotes in the spontaneous abortion group compared with the control group (9.1 and 32.2% respectively; P < 0.001). CONCLUSIONS: The 259-Pro allele seems to have beneficial influences during embryogenesis, conceivably through its positive effect on vitamin B(12) intracellular bioavailability. Our results warrant additional investigations addressing the question if vitamin B(12) supplementation in addition to folic acid supplementation may prevent spontaneous abortion in women planning a pregnancy.

Abortion, Spontaneous↗
PubMed2003

Gene-gene interaction between fetal MTHFR 677C>T and transcobalamin 776C>G polymorphisms in human spontaneous abortion.

BACKGROUND: Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and transcobalamin (TC) genes influence homocysteine metabolism which in turn may influence the risk of spontaneous abortion. It was hypothesized that there may be a significant interaction between MTHFR and TC genotypes which affects the pathogenesis of spontaneous abortion. METHODS AND RESULTS: A total of 76 fetal tissue samples from spontaneous abortions between weeks 6 and 20 of pregnancy, and 114 control samples from healthy blood donors were genotyped for the MTHFR 677C>T and 776C>G polymorphisms. Subjects with combined MTHFR 677TT/TC 776GG and combined MTHFR 677TT/TC 776CG genotypes gave an odds ratio for spontaneous abortion of 3.8 (95% confidence interval 1.4-9.9, P = 0.005). CONCLUSIONS: Embryos that have combined MTHFR 677TT and TC 776CG or 776GG genotypes; genotypes that individually are associated with impaired homocysteine metabolism in adults, are at increased risk for spontaneous abortion compared with embryos that have only one of these genotypes.

Abortion, Spontaneous↗
PubMed1975

The three transcobalamins in myeloproliferative disorders and acute leukaemia.

The unsaturated vitamin B12 binding capacity of whole serum (UBBC) and of the three transcobalamins (TC) has been studied in patients with various haematological diseases including myeloproliferative disorders (MPD) and acute leukaemia. The binding capacity of TC I and TC III was increased in MPD; TC I being particularly high in chronic granulocytic leukaemia (CGL) and TC III especially raised in polycythaemia rubra vera (PRV) and in infectious leucocytosis. The binding capacity of both TC I and TC III correlated with blood neutrophil count and the ratio TC III/TC I was low in CGL and increased in PRV. TC II was increased in acute myelogenous leukaemia, during remission and blast cell crisis of CGL and in refractory anaemia with excess of myeloblasts but not in acute lymphoblastic leukaemia (ALL). TC II correlated inversely with blood neutrophil count. There is an inverse ratio between TC II and TC I at least in myelogenous leukaemia. These abnormalities are discussed in relation to granulocyte kinetics. TC III and TC I reflect probably the total body granulocyte pool and share some biochemical and immunological properties supporting the view that they have a common origin in the more mature stages of the granulocyte cell line while TC II probably originates partly in more primitive granulocytes.

Anemia, Aplastic↗
PubMed1975

The intercellular content of the three transcobalamins at various stages of normal and leukaemic myleoid cell development.

A study of the three serum transcobalamins (TC) in myeloproliferative disorders and acute leukaemia has suggested a granulocyte origin for the three binders; the later stages of this cell line might be releasing 'TC I' and 'TC III' while 'TC II' which is increased in sera from patients with acute myelogenous leukaemia, probably originates at least in part from myeloblasts. The intracellular content of each TC has been studied in normal and leukaemic bone marrow cells after separation on a discontinuous bovine serum albumin gradient. Myeloblasts contain a TC II-like protein almost exclusively but promyelocytes contain a TC I-like protein which increases as the cells mature whilst 'TC II' decreases. A TC III-like binder parallels 'TC I' but appears later and reaches a maximum in the polymorphonuclear cells. In various types of leukaemia, abnormal TC distributions are related either to marrow replacement by the blast cells or to a disorder of the maturation process in the leukaemic cell line.

Blood Proteins↗
PubMed1975

Binding of vitamin B12--rat transcobalamin II and free vitamin B12 to plasma membranes isolated from rat liver.

When dialysed rat serum which contains a single, low molecular weight binder for vitamin B12, rat transcobalamin II (rat TC-II), was labelled in vitro with 57Co-vitamin B12 and then incubated at 30 degrees C (pH 7-5) with vesicles of highly purified plasma membranes separated from microsomal fractions of rat liver by density gradient centrifugation, the 57Co-vitamin B12-rat TC-II complex bound to high affinity sites on the vesicles via a specific (binding after correction for 'non-specific' binding in the presence of a large excess of the non-radioactive complex), saturable, and reversible interaction. The apparent affinity constant for the binding reaction was 5-5 X 10(9) M-1. Using the same incubation conditions, free vitamin B12 also bound to the vesicles of plasma membranes via a specific, saturable, but apparently irreversible interaction. Preincubation of the membranes with free vitamin B12 did not interfere with the subsequent binding of the vitamin B12-rat TC-II complex to the membranes; however, preincubation with the vitamin B12-rat TC-II complex did interfere, to some extent, with the subsequent binding of free vitamin B12. Dialysed rat serum, perhaps the free rat TC-II in the dialysed serum, also inhibited the binding of the vitamin B12-rat TC-II complex to the plasma membranes. The relationship of the binding sites identified in this report to the absorption of vitamin B12 by rat liver, and thus their physiological significance remains unknown until further work is done, perhaps using intact hepatocytes.

Animals↗
PubMed1978

Formation of transcobalamin II--vitamin B12 complex by guinea-pig ileal mucosa in organ culture after in vivo incubation with intrinsic factor--vitamin B12.

The in vivo incubation of intrinsic factor--[57Co]vitamin B12 in an ileal loop of a guinea-pig followed by in vitro culturing of segments of the ileum for 180 min has been used to study the transepithelial transport of vitamin B12. Analysis of the solubilized supernate of mucosa following the in vivo phase demonstrated that 44% of the [57Co]vitamin B12 was bound to intrinsic factor (IF), 26% was free, and 16% was bound to transcobalamin II (TCII). Following culture, similar analysis demonstrated that 18% of the vitamin was now bound to IF, 49% was free, and 35% ws bound to TCII. In the culture medium, 54% of the [57Co]vitamin B12 was free and 37% was bound to TCII. The formation of TCII-[57Co]vitamin B12 did not occur if homogenized mucosa was incubated with free[57Co]vitamin B12, but it did form in cultures of ileal segments from animals given an excess of unlabelled vitamin to saturate all circulating TCH, and in the medium containing puromycin. Indirect immunofluorescence using chicken anti-TCII demonstrated that TCII was associated with the mucosal cells of both the ileum and jejunum. These studies demonstrate that following transepithelial flux of vitamin B12 through the ileal mucosa, the vitamin becomes coupled to TCII. This coupling requires a structurally intact mucosa and the source of the TCII appears to be the ileal mucosal cell rather than unsaturated TCII circulating in the blood.

Animals↗
PubMed1979

Transplacental transport in the rabbit of vitamin B12 bound to human transcobalamin I, II and III.

Transcobalamins I, II and III (TCI, TCII, TCIII) were purified from human serum, saturated with 57Co-vitamin B12 (57Co-B12), and injected into pregnant rabbits. Whole body retention of the 57Co-B12 averaged 91% and was similar for each of the three vitamin B12 binders. A maximum of 62% of the injected 57Co-B12 was found in fetal tissues when the vitamin was injected bound to TCII, but only 6--7% when bound to TCI or TCIII. Thus TCII is responsible for the delivery of vitamin B12 to the fetus.

Animals↗
PubMed1982

Atypical cobalamin binding in the serum of congenital deficiency of transcobalamin II.

The serum cobalamin (Cb 1) binding patterns were described in nine children with congenital deficiency of transcobalamin II (TC II). Immunoreactive TC II was less than 100 pg/ml TC II-Cb 1 equivalent in eight and 150 pg/ml in the ninth. There was neither endogenous TC II-Cb 1 (holo TC II) nor apo TC II. Thus, the defect was characterized by the absence of any binding of Cb 1 to TC II either in vivo or in vitro and either non-detectable or much reduced immunoreactive TC II. Only the serum from an untreated infant bound any added Cb 1 at all, but in every sera there was binding of endogenous Cb 1 to a substance of the molecular size of albumin. Native Cb 1 was also bound to R binder and in some instances was incorporated into large complexes. The precise nature, cause and consequences of this atypical binding are unknown.

Adolescent↗
PubMed1983

Serum transcobalamin levels as an early indicator of bone marrow engraftment following transplantation.

Three B12 binding proteins, the transcobalamins TCI, TCII and TCIII, were determined serially in the serum of five patients who underwent bone marrow transplantation. The increase in TCII, followed by the increase in TCI, proved to be an early indicator of bone marrow regeneration, reaching a peak of up to twice its normal levels at least 5 d prior to the rise of the peripheral white blood cell count.

Adolescent↗
PubMed1992

The neurologic aspects of transcobalamin II deficiency.

Thirty-four symptomatic cases of inherited transcobalamin II (TCII) deficiency were analysed in order to determine the frequency and nature of neurologic manifestations. In no instance was there definite evidence of a neurologic disorder at the time of presentation as a young infant. One child of 2 1/2 years transiently lost deep tendon reflexes at a time of suboptimal treatment. A syndrome of mental retardation and other neurologic manifestations was observed in three cases, all with the following in common: (1) an extended duration of illness of 2-17 years; (2) inadequate or not treatment with Cbl; (3) treatment with folic of folinic acid. TCII deficiency rarely if ever presents with neurologic manifestations. However, neurologic disorders can be produced subsequently by improper treatment.

Central Nervous System Diseases↗
PubMed1992

Elevated serum transcobalamin levels in anaemia of rheumatoid arthritis: correlation with disease activity but not with serum tumour necrosis factor alpha and interleukin 6.

Transcobalamin (TCII) and haptocorrins (TCI and III), tumour necrosis factor alpha (TNF), interleukin-6 (IL6) and parameters of disease activity were assessed in 20 rheumatoid arthritis (RA) patients without anaemia and 19 subjects with anaemia of chronic disease (ACD) in order to determine if there was a possible correlation between these parameters. TCII, TNF and IL6 correlated positively with RA disease activity parameters, whereas their serum levels were higher in the ACD patients. TC levels were not correlated with cytokine levels. Vitamin B12 serum levels were lower in ACD. We conclude that in RA, elevated serum TCII levels are possibly mediated by increased RA disease activity, but probably not by actions of TNF or IL6. Increased TCII levels found in ACD may be explained by the higher degree of RA activity in these patients, and could also be viewed as a compensatory reaction to anaemia or reduced vitamin B12 levels. However, these preliminary findings require further confirmation.

Adult↗
PubMed1986

Linkage of transcobalamin II (TC2) to the P blood group system and assignment to chromosome 22.

The linkage relationships of transcobalamin II (TC2) against 64 other marker systems are studied in a Danish family material (families 604-1505). A strong indication of linkage between TC2 and the blood group system P was discovered (z = 7.91 at theta = 0.14 for males and theta = 0.20 for females combined). Accordingly, TC2 could be assigned to chromosome 22 (since blood group P has earlier been assigned to this chromosome).

Blood Group Antigens↗
PubMed1976

The failure of granulocytes to produce transcobalamin I TC I.

The hypothesis that transcobalamin I (TC I) originates from granulocytes was tested by comparing the isoelectric focusing (IEF) patterns of the R-type binder (cobalophilin) of vitamin B12 of: 1) lysed granulocytes, 2) 24 h granulocyte output, and 3) plasma. The preparations came from the blood of 5 normal subjects and 4 with myeloproliferative states. The cobalophilin released into a culture of granulocytes resembled the binder in the granulocytes initially. TC I, defined as the alpha1 cobalophilin with components isoelectric between pH 2.9-3.35 and as a carrier of native plasma B12, was not released by granulocytes. The granulocyte binder of leukaemic granulocytes did not differ from the normal in content per cell or amount released.

Blood Proteins↗
PubMed1977

The transcobalamins in polycythaemia vera.

The unsaturated B12 binding capacity (UBBC) of the serum and the binding capacity of each of the 3 vitamin B12 binders--the transcobalamins (TC) I, II and III were determined in 21 patients with polycythaemia vera (PV) during the course of the disease and following treatment, using the recently described charged cellulose filter technique. High serum UBBC due to elevated serum TCIII was found in all patients. TCI was moderately elevated in patients who had leucocytosis with a shift to the left. The changes in serum TCIII and UBBC correlated with the activity of the disease. Chemotherapy resulted in a decrease in TCIII and UBBC. The decrease in TCIII and UBBC folowing chemotherapy may be observed before a decrease in the haematocrit and the leucocyte count occurs. Activation of the disease may be assessed by the elevation of TCIII and UBBC. The onset of acute myeloblastic crisis in 1 patient was associated with a decrease in TCIII and TCI levels and a rise in serum TCII. The determination of TCIII and UBBC may be helpful in differentiating true from secondary polycythaemia.

Blood Proteins↗
PubMed1984

Evidence for genetic effects on variation in plasma unsaturated transcobalamin II and cobalamin (vitamin B12).

Unsaturated plasma transcobalamin II (UTC II) and cobalamin were measured in two selected age-groups of like-sexed mono- and dizygotic twins. For UTC II, a higher mean level was found in women than in men, and in the older (57 to 61 years) than in the younger (33 to 39 years) age group. Testing of genetic-environmental models revealed that variation in plasma levels of UTC II is almost exclusively genetically determined. More than 50% of the variation in cobalamin levels was accounted for by genes, the remainder being due to person-specific environmental factors (for older males no model gave a good fit). A negative correlation was noted between UTC II and cobalamin levels. The correlation coefficient was low, and the variation in UTC II accounted for only about 4% of the variation in the cobalamin level. This finding suggests that a pathologically high value of one of the variables may have clinical significance, regardless of the value of the other variable. For 22 patients studied longitudinally, a clear tendency to maintain plasma levels at constant levels over long periods of time was found, suggesting that certain degrees of deviation from these levels may have clinical relevance.

Adult↗