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PubMed1976

Fractionation of serum transcobalamins on charged cellulose filters.

A simple and rapid fractionation procedure of the three transcobalamins, TCI, TCII, and TCII, of human serum was achieved by filtration through a stack of charged cellulose filters composed of one cellulose-nitrate and three DEAE-cellulose (DE-81) disks. A reaction mixture containing microliter amounts of serum was incubated with excess of 57Co B12 of high specific activity, diluted with 0.1 M sodium borate buffer (pH 8.5), and passed through the filter stack by applying vacuum. Under these conditions TCII is selectively and quantitatively adsorbed to the cellulose-nitrate filter while both TCI and TCIII adsorb to the DE-81 filters. In the second step TCIII is selectively desorbed from the latter filters by a 0.05 M monopotassium phosphate solution of pH 4.6. Using sera of different distribution of transcobalamins the data obtained were comparable to those determined by the more laborious methods employing DE-52 column chromatography combined with procedures to remove TCII.

Blood Proteins↗
PubMed2003

Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults.

BACKGROUND: Transcobalamin II is a serum transport protein for vitamin B12. Small variations in TC-II affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B12 deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes. OBJECTIVES: To study 23 members of a four-generation family with hereditary vitamin B12 deficiency and neurologic disorders. METHODS: Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members. RESULTS: Partial TC-II deficiency was found in 19 subjects. Apo TC-II (free TC-II unbound to vitamin B12) and total unsaturated B12 binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B12) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B12 levels but were not anemic. Low serum B12 levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B12 injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency. CONCLUSIONS: We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances--despite normal serum vitamin B12 levels. Low serum UBBC and apo TC-II should confirm the diagnosis. Early vitamin B12 therapy may prevent irreversible neurologic damage.

Adolescent↗
PubMed1978

Detection of genetic variation with radioactive ligands. III. genetic polymorphism of transcobalamin II in human plasma.

We detected genetically determined, electrophoretic variants of vitamin B12 binding proteins, most probably transcobalamin II, in human plasma. Polymorphic variants were observed in all populations tested; the two most common alleles (of at least four detected to date) attain frequencies of greater than 40% in Caucasians and Orientals. The variants are autosomally inherited and are seen as doublets in homozygotes, and four-banded patterns, the sum of two dissimilar homozygote patterns, in heterozygotes. The technique used in this survey, polyacrylamide gel electrophoresis (PAGE) autoradiography of plasma and serum labeled in vitro with 57Co-vitamin B12 is particularly applicable to the study of trace proteins such as the transcobalamins (10(-9)M). Possible functional variation in the TC II allele products is described, and the selective significance of this worldwide polymorphism is considered.

Autoradiography↗
PubMed1982

Structural homologies of cobalamin-binding proteins. Tryptic peptide mapping of intrinsic factor, transcobalamin and haptocorrin from man, hog and rabbit.

We have explored the structural features of cobalamin binding proteins by peptide mapping. The present report is a comparison of the radioiodinated tryptic peptides of intrinsic factor, transcobalamin and haptocorrin from man, hog and rabbit. The results show that the homology between analogous proteins from different species is close for intrinsic factor and transcobalamin and weaker for haptocorrin. The results also suggest the existence of one or more regions which, with minor changes, are conserved among all proteins investigated. This implies a common evolutionary origin for all the cobalamin binding proteins studied.

Animals↗
PubMed1974

Studies on derivation of transcobalamin 3 from granulocytes. Enhancement by lithium and elimination by fluoride of in vitro increments in vitamin B12-binding capacity.

Unsaturated vitamin B(12)-binding capacity (UBBC) of human serum is not reproducibly measurable because it increases variably in vitro in relation to time, temperature, and, in the case of plasma, anticoagulant present before removal of cells. This variable increase proved to be due to variable release in vitro of transcobalamin III (TC III) from granulocytes. UBBC increase was greatest (up to fourfold normal levels) in the presence of lithium, which is the heparin salt used in many laboratories doing UBBC studies. In vitro increase was least when blood was collected in EDTA at 0 degrees C and immediately centrifuges at 0 degrees C (T(0) sample); results equivalent to T(0) were obtained at room temperature even after several hours delay when 47 mM fluoride was present; either cold temperature or 47 mM fluoride appeared to prevent TC III release from granulocytes. The measured levels of the three transcobalamins with T(0) methods of collection, which presumably reflect most closely the in vivo circulating levels, suggest that TC I and TC III in normal plasms are of the same order of magnitude and together normally comprise less than 10% of the UBBC. Approximately 90% of the UBBC content of sonicates of peripheral blood granulocytes and of bone marrow aspirates of normal individuals appears to be TC III, with the rest being TC I. Thus, normal myelocytes, like normal granulocytes, appear to contain mainly TC III. No TC II was present in any of the sonicates. The general practice in most laboratories has been to determine serum UBBC. Because in vitro increments of up to 119% were found to occur in serum, this practice should be replaced by collection using methods that prevent such increments. Blood collected in EDTA-47 mM NaF had a stable, reproducible UBBC with no significant in vitro increment with time.EDTA-NaF UBBC was 640+/-168 (range 380-921 pg B(12) bound/ml plasma) for 12 normal adult men and 809+/-232 (range 505-1208) for normal adult women. It presumably approximates circulating UBBC and is substantially below the serum UBBC mean of 935+/-262 (range 611-1506 for the same 12 men) and 1273+/-355 (range 811-2306 for the same 10 women).

Adult↗
PubMed1977

Serum vitamin B12 and transcobalamin abnormalities in patients with cancer.

One hundred and thirty-nine patients with non-hematologic malignancy were studied to define the incidence of vitamin B12-related abnormalities and correlate them with clinical findings. Based on vitamin B12-binding patterns, the following relatively distinct groups were defined: (A) 50% had normal results; (B) 6% had very high transcobalamin (TC) I and vitamin B12 levels as reported in isolated instances previously: most had hepatic metastases and early death, and all had definite metastatic disease; (C) 11% had high vitamin B12 levels with little or no unsaturated TC I elevation: most also had hepatic and other metastases and early death; (D) 23% had high vitamin B12-binding capacity with normal TC I and vitamin B12 levels: there were no distinguishing features for this group other than an increased proportion of black patients; and (E) 10% had low vitamin B12 levels, in many cases not associated with vitamin B12 deficiency or other known causes of low serum levels. Thus, high serum vitamin B12 level, with or without unsaturated TC I elevation, usually implies a poor prognosis in a patient with cancer. However, while most such patients have hepatic and other metastases, hepatic involvement was not universal nor did most patients with hepatic disease have high vitamin B12 levels. High serum TC I thus is not always due to increased granulocytic proliferation or to hepatic tumor, and alternative mechanisms for TC I accumulation should be sought.

Black People↗
PubMed1983

Transcobalamin II as an indicator of activity in metastatic renal adenocarcinoma.

Transcobalamin (TC) II, the cellular membrane carrier of vitamin B 12 has recently attracted attention as an acute phase reactant in autoimmune disorders and reticuloendothelial malignancies. In a prospective clinical evaluation, 20 patients presenting with proven metastatic renal adenocarcinoma underwent nephrectomy and were followed till death, or at least 3 years. Two patients obtained a complete remission. TCII was significantly elevated (P less than 0.005) preoperatively and varied with activity of the carcinoma, supplementing the erythrocyte sedimentation rate and fibrinogen. The postoperative response and pattern of TCII activity correlated with disease progression. No relation was found to liver metastases. This study supports the recent findings of TCII as an indicator of activity in disorders affecting the immune mechanisms probably acting as an acute phase reactant, and is a useful supplement in renal adenocarcinoma.

Adenocarcinoma↗
PubMed1984

Cyclic eosinophilic leukocytosis in eosinophilic leukemia with observations on transcobalamin I and eosinophils.

A patient with eosinophilic leukemia was noted to have spontaneous fluctuations in his eosinophil and total leukocyte counts over a 3-year period. The range of eosinophil counts observed was from 736/microliters to 401,400/microliters. Sharp fluctuations occurred whether chemotherapy was administered at the nadir or the peak of a cycle or was withheld. A shortening of the cycle length from 44 to 25 days, and a marked increase in amplitude of the cycle occurred in the terminal phase of his illness. Two additional observations merit mention. An abnormal alpha-2 globulin of 40,000 molecular weight was detected in his serum. In addition, cyclic fluctuations of serum transcobalamin I that accompanied his cyclic eosinophil counts were noted, and eosinophils were documented for the first time to be rich sources of this protein.

Adult↗
PubMed1979

A comparison of methods for the rapid quantitation of unsaturated transcobalamin II and the R-binding proteins.

Methods for the rapid quantitation on unsaturated transcobalamin II (TC II) and R-binders in serum following separation of these binders using a) adsorption by uncoated charcoal, b) adsorption by Quso G32, c) precipitation with ammonium sulphate, and d) acidification of serum, have been compared with the standard gel filtration technique. In serum from healthy subjects and patients with elevated R-binders, the serum acidification and Quso methods yielded results in closest agreement with those obtained by gel filtration. When TC II was markedly elevated, the recommended concentration of Quso failed to remove all TC II from serum. Both the serum acidification and Quso methods are suitable for routine use, providing that with the latter method the concentration of Quso is increased when elevated levels of TC II are anticipated, as, eg, in severe jaundice. All the rapid methods tested yielded clinically significant results in patients with myeloproliferative disorders.

Acids↗
PubMed1990

Transcobalamin II deficiency presenting with methylmalonic aciduria and homocystinuria and abnormal absorption of cobalamin.

An infant with deficiency of transcobalamin II (TCII) presented with virtually complete failure to thrive and life-threatening pancytopenia. Methylmalonic acid and homocystine were found in the urine. The concentration of B12 in the serum was 26 pg/ml. Fibroblasts derived from the patient failed to take up labeled cobalamin in the absence of a source of TCII. Uptake was normal in the presence of TCII. Treatment with parenteral cobalamin reversed the clinical and hematological manifestations of the disease but she developed glossitis when the interval between injections was lengthened. Intestinal absorption of 57Co-cobalamin was less than 1% and remained abnormal when highly purified human intrinsic factor was given along with the labeled B12. Absorption improved when the labeled B12 was given together with rabbit TCII. The data suggest that TCII as well as intrinsic factor is required for transport of cobalamin from the intestine to the blood.

Failure to Thrive↗
PubMed2005

Evaluation of transcobalamin II polymorphisms as neural tube defect risk factors in an Irish population.

BACKGROUND: Decreased maternal folate levels are associated with having a child with a neural tube defect (NTD), and periconceptual folic acid supplementation reduces this risk by >50%. Vitamin B(12) (as methylcobalamin) is a cofactor for methionine synthase, an enzyme that plays a key role in folate metabolism. Alterations in vitamin B(12) metabolism may influence the development of NTDs. Low levels of maternal plasma vitamin B(12) and reduced binding of vitamin B(12) by transcobalamin II (TCII) are independent risk factors for NTDs. TCII levels are altered in the amniotic fluid of pregnancies affected by NTDs. Given this evidence, inherited variants in genes involved in vitamin B(12) trafficking such as TCII are candidate NTD risk factors. METHODS: We used case/control and family-based association methods to investigate whether six common polymorphisms in the TCII gene influence NTD risk. TCII genotypes were determined for more than 300 Irish NTD families and a comparable number of Irish controls. RESULTS: Allele and genotype frequencies for each polymorphism did not differ between family members and controls. CONCLUSIONS: These six TCII polymorphisms do not strongly influence NTD risk in the Irish population. The Supplementary Material for this article can be found on the Birth Defects Research (Part A) website: http://www.mrw.interscience.wiley.com/suppmat/1542-0752/suppmat/2005/73/v73.4.swanson.html

Alleles↗
PubMed1985

The metabolism of cobalamin bound to transcobalamin II and to glycoproteins that bind Cbl in HepG2 cells (human hepatoma).

The binding, internalization, processing and release of labeled cyanocobalamin (CN[57Co]Cbl) bound to human transcobalamin II (TC II) were studied in HepG2 cells, a line of hepatocytes derived from a human hepatoma. The cells bound the TC II-Cbl by specific, high affinity receptors. Within the cell, the CN-Cbl was promptly freed from TC II and the CN-Cbl converted to more active forms including adenosyl Cbl (AdoCbl) and methyl Cbl (MeCbl). Whereas free labeled Cbl was still present at 72 hours after entry, the cells also bound Cbl to an intracellular binder (ICB) presumed to represent the holo enzymes dependent on Cbl. At levels of TC II that saturated the receptors for TC II-Cbl, much of the Cbl entering the cells remained free and was converted to AdoCbl. Under these circumstances the cells released free Cbl, mostly AdoCbl. Human R type binders of Cbl, which are glycoproteins and some having a terminal galactose, were bound by the HepG2 cells. The binding was characteristic of the receptor system responsive to a terminal galactose, or asialoglycoproteins, but was inconsistent and of low affinity. Cbl bound to R binder was internalized and converted to coenzyme forms of Cbl, but the process was much less effective than when the Cbl entered via the TC II receptor system. It was concluded that the receptors for R-Cbl were unlikely to contribute to the physiologic transport of Cbl in man, but may function in some yet unknown way.

Asialoglycoprotein Receptor↗
PubMed1986

The modulation of transcobalamin II (TC-II) production by cyclic adenosine 3',5'-monophosphate in the murine macrophage cell line J774: relationship to growth behavior.

We undertook a study to define the role of cyclic AMP [cAMP] in modulating the secretion of transcobalamin II (TC-II) in the mouse macrophage like cell line J774. J774 was observed to secrete large amounts of TC-II, particularly in the presence of 8-bromo cAMP or cholera toxin or when grown in medium supplemented with low concentrations of horse serum (1% or 5%) or in serum-free medium. Variant cell lines derived from J774 and deficient either in adenylate cyclase (ac -) or cAMP-dependent protein kinase (pk -) activity showed very low and intermediate levels of basal secretory activity of TC-II, respectively, compared to J774. Maximum secretory activity of TC-II was observed in J774 under conditions in which growth was poorest (in the presence of 8-bromo-cAMP or 1% or 5% horse serum-supplemented medium or in serum-free medium). Cells grown in serum-free medium were found to have elevated basal adenylate cyclase activity and cAMP levels compared to those grown in medium supplemented with 20% horse serum. The data from this study demonstrate a negative correlation between growth activity and TC-II secretion in the J774 cell line. The stimulatory effect of exogenous cAMP on TC-II secretion by J774, the reduced secretory activity of the variant lines ac- and pk- and the observed increase in cell cAMP levels under conditions of serum starvation in which TC-II secretion is considerably enhanced, suggest that cell cAMP is an important modulator of TC-II secretion and growth behavior in the J774 cell line.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1987

Cyclic activity of the receptors of cobalamin bound to transcobalamin II.

The activity of receptors specific for human transcobalamin II-Cobalamin (TC II-Cbl) were measured in virus-transformed lymphoblasts, hepatocytes (hepatoma) and diploid fibro lasts. In all three types of human cells the receptor activity increased as cells went from a resting phase to the most actively dividing phase. Receptor activity declined as cell division slowed. The changes in activity of lymphoblasts and hepatocytes were produced by changes in receptor number and not by changes in affinity between receptors and TC II-Cbl. The basis of the change in fibroblasts was not clear. The Cbl-dependent methionine synthetase activity of fibroblasts, in contrast, tended to be greatest when the cultures were confluent and replication had slowed. As the fibroblasts became senescent the receptor activity for TC II-Cbl declined and the fluctuations with the phase of the cell were blunted. However, the release of apo TC II from the cells was maintained. These observations must be taken into consideration when the respective cells are used as models. Even more important are the implications of the observations of the changes in receptor activity for TC II-Cbl for the regulation of the entry of Cbl into cells.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1986

Transcobalamin I as a "marker" for fibrolamellar hepatoma.

A 12 year old girl with a localised fibrolamellar hepatoma had a raised serum unsaturated vitamin B12 binding capacity (UBBC) and transcobalamin I (TCI) prior to complete resection and chemotherapy. Regular clinical and radiological follow-up detected no recurrence of her disease, but the UBBC and TCI slowly rose. Local recurrence and pulmonary metastases became detectable 2 1/2 years after diagnosis, 18 months after the UBBC and TCI level became elevated. Measurement of UBBC and TCI can help in the early detection of recurrence long before there is clinical or radiological evidence of recurrent fibrolamellar hepatoma.

Carcinoma, Hepatocellular↗
PubMed1987

Expression of transcobalamin II by amniocytes.

Children with a genetic absence of transcobalamin 2 (TC2) are clinically asymptomatic at birth but develop severe megaloblastic anemia early in life. We have examined the incorporation of [57Co]-CN-B12 in the absence of any exogenous source of TC2 in control amniotic fluid derived cells and cultured diploid fibroblasts, and in fibroblasts from a patient with TC2 deficiency. Both control fibroblasts and amniocytes incorporated labelled B12 into TC2-B12, and the proportion of labelled TC2-B12 could be increased by growing cells in the presence of chloroquine which prevents intralysosomal hydrolysis of the TC2-B12 complex. In contrast, fibroblasts from the patient with TC2 deficiency incorporated almost no label as TC2-B12. These studies suggest that TC2 deficiency either due to aberrant production of TC2 or because of the production of an abnormal TC2 which does not bind B12 can be diagnosed before birth.

Amniotic Fluid↗
PubMed1994

Characterization of the human placental membrane receptor for transcobalamin II-cobalamin.

A specific receptor on the plasma membrane of mammalian cells facilitates the uptake of vitamin B12 (cobalamin, Cbl) by receptor-mediated endocytosis of transcobalamin II-bound Cbl (TCII-Cbl). Purification of this receptor has proven to be difficult because of the lability of the protein during solubilization. Using human placental membranes as the source of the receptor, we have investigated alternative methods for solubilization of this protein and characterized a number of functional and structural properties. Homogenized and washed placental membranes show specific, saturable binding of TCII-Cbl with a Ka of 0.26 nM-1. Following solubilization of the membranes in 3-[(3-cholamidopropyl)-dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO), the most efficient nonionic detergent tested, 21% of the receptor activity remained with the residual insoluble membrane fraction, a property of membrane proteins that are bound tightly to the cell cytoskeleton. Whereas 10 mM Chapso removed 79% of the receptor activity from the membrane preparation, only 3.7% of the TCII-Cbl binding activity was recovered in the solubilized fraction. The unstable TCII-Cbl binding in the soluble fraction was protected by the addition of 15% glycerol to the preparation and storage at -20 degrees C. The apparent M(r) of the receptor estimated by SDS-PAGE of the crosslinked receptor 125I-TCII-Cbl is approximately 58,000. The decrease in M(r) following digestion with several glycosidases and neuraminidase indicates that approximately 29% of the protein is carbohydrate which accounts for a core polypeptide of 41 kDa. Selective binding to a battery of lectins has established that the carbohydrate moiety of the receptor contains a large proportion of N-acetylglucosamine and terminal X-linked mannose.

Cell Membrane↗