Genomes and Genes
Summary: A group of carrier proteins which bind with VITAMIN B12 in the BLOOD and aid in its transport. Transcobalamin I migrates electrophoretically as a beta-globulin, while transcobalamins II and III migrate as alpha-globulins.
- Carmel R, Vasireddy H, Aurangzeb I, George K. High serum cobalamin levels in the clinical setting--clinical associations and holo-transcobalamin changes. Clin Lab Haematol. 2001;23:365-71 pubmed..The much better known association of high cobalamin levels with leucocytic disorders is rare, and no association was seen with liver disease. ..
- Carmel R. Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr. 2011;94:348S-358S pubmed publisher..Much work remains to be done. ..
- Morkbak A, Pedersen J, Nexo E. Glycosylation independent measurement of the cobalamin binding protein haptocorrin. Clin Chim Acta. 2005;356:184-90 pubmed..Using this assay, a very strong correlation between total plasma HC and cobalamins in healthy donors is obtained. ..
- Wuerges J, Garau G, Geremia S, Fedosov S, Petersen T, Randaccio L. Structural basis for mammalian vitamin B12 transport by transcobalamin. Proc Natl Acad Sci U S A. 2006;103:4386-91 pubmed..Structural information is used to predict the overall fold of haptocorrin and intrinsic factor and permits a rational approach to the design of new Cbl-based bioconjugates for diagnostic or therapeutic drug delivery. ..
- Kalra S, Li N, Yammani R, Seetharam S, Seetharam B. Cobalamin (vitamin B12) binding, phylogeny, and synteny of human transcobalamin. Arch Biochem Biophys. 2004;431:189-96 pubmed
- Garrod M, Green R, Allen L, Mungas D, Jagust W, Haan M, et al. Fraction of total plasma vitamin B12 bound to transcobalamin correlates with cognitive function in elderly Latinos with depressive symptoms. Clin Chem. 2008;54:1210-7 pubmed publisher..HoloTC/B12 ratio is associated with cognitive function in elderly Latinos with depressive symptoms and may better reflect the adequacy of B12 for nervous system function than either holoTC or total B12 alone. ..
- Lloyd Wright Z, Hvas A, Møller J, Sanders T, Nexø E. Holotranscobalamin as an indicator of dietary vitamin B12 deficiency. Clin Chem. 2003;49:2076-8 pubmed
- von Castel Roberts K, Morkbak A, Nexo E, Edgemon C, Maneval D, Shuster J, et al. Holo-transcobalamin is an indicator of vitamin B-12 absorption in healthy adults with adequate vitamin B-12 status. Am J Clin Nutr. 2007;85:1057-61 pubmed..Our results indicate that a vitamin B-12 absorption test based on measurement of holo-TC after administration of three 9-mug doses of vitamin B-12 should run for 24 h. ..
- Stanisławska Sachadyn A, Woodside J, Sayers C, Yarnell J, Young I, Evans A, et al. The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status. Eur J Clin Nutr. 2010;64:1338-43 pubmed publisher..Thus, the TCN2 776C>G polymorphism may contribute to the risk of pathologies associated with a low B(12), and high tHcy phenotype. ..
- Miller J, Ramos M, Garrod M, Flynn M, Green R. Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults. Blood. 2002;100:718-20 pubmed..02). The PP genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCII genotype may thus influence susceptibility to B12 deficiency. ..
- Aléssio A, Hoehr N, Siqueira L, Bydlowski S, Annichino Bizzacchi J. Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children. Thromb Res. 2007;119:571-7 pubmed..Our results, if confirmed in other populations, highlight the necessity for investigation of the transcobalamin II C776G polymorphism in the research for hyperhomocysteinemia risk factors. ..
- Lildballe D, Nguyen K, Poulsen S, Nielsen H, Nexo E. Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma. Eur J Surg Oncol. 2011;37:72-9 pubmed publisher..Plasma HC proved to be a useful tumour marker in a patient with FLHCC, and we suggest the use of this protein as a marker of disease progression in these patients. ..
- Valente E, Scott J, Ueland P, Cunningham C, Casey M, Molloy A. Diagnostic accuracy of holotranscobalamin, methylmalonic acid, serum cobalamin, and other indicators of tissue vitamin B?? status in the elderly. Clin Chem. 2011;57:856-63 pubmed publisher..Renal dysfunction compromised the diagnostic accuracy of MMA but not holoTC or serum cobalamin. This study supports the use of holoTC as the first-line diagnostic procedure for vitamin B?? status. ..
- Zetterberg H, Nexo E, Regland B, Minthon L, Boson R, Palmer M, et al. The transcobalamin (TC) codon 259 genetic polymorphism influences holo-TC concentration in cerebrospinal fluid from patients with Alzheimer disease. Clin Chem. 2003;49:1195-8 pubmed
- James S, Melnyk S, Jernigan S, Cleves M, Halsted C, Wong D, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:947-56 pubmed..We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism. ..
- Refsum H, Johnston C, Guttormsen A, Nexo E. Holotranscobalamin and total transcobalamin in human plasma: determination, determinants, and reference values in healthy adults. Clin Chem. 2006;52:129-37 pubmed..Determinants of holoTC and TC differed between men and women and according to age. Separate reference intervals for holoTC should be considered in younger women. ..
- Obeid R, Morkbak A, Munz W, Nexo E, Herrmann W. The cobalamin-binding proteins transcobalamin and haptocorrin in maternal and cord blood sera at birth. Clin Chem. 2006;52:263-9 pubmed..The close correlation between the amounts of holoTC present in cord blood and in maternal serum supports the importance of maternal cobalamin status for ensuring a sufficient supply to the baby. ..
- Hvas A, Nexo E. Holotranscobalamin--a first choice assay for diagnosing early vitamin B deficiency?. J Intern Med. 2005;257:289-98 pubmed..001). Only tHcy was significantly associated with thyroid stimulating hormone (P=0.02). HoloTC shows promise as first-line tests for diagnosing early vitamin B12 deficiency. ..
- Hvas A, Morkbak A, Nexo E. Plasma holotranscobalamin compared with plasma cobalamins for assessment of vitamin B12 absorption; optimisation of a non-radioactive vitamin B12 absorption test (CobaSorb). Clin Chim Acta. 2007;376:150-4 pubmed..In healthy individuals with baseline holotranscobalamin <75 pmol/L, vitamin B(12) absorption is well reflected by an increase in holotranscobalamin after 2 days administration of oral vitamin B(12). ..
- Obeid R, Herrmann W. Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clin Chem Lab Med. 2007;45:1746-50 pubmed..The majority of subjects with combined low holoTC and elevated MMA had normal concentrations of total cobalamin. HoloTC can be used as a first line parameter in detecting cobalamin deficiency. ..
- Wans S, Schüttler K, Jakubiczka S, Muller A, Luley C, Dierkes J. Analysis of the transcobalamin II 776C>G (259P>R) single nucleotide polymorphism by denaturing HPLC in healthy elderly: associations with cobalamin, homocysteine and holo-transcobalamin II. Clin Chem Lab Med. 2003;41:1532-6 pubmed..g., restriction fragment length polymorphism analysis. The results suggest that the common TC II 776C>G polymorphism has no major influence on vitamin B12 metabolism. ..
- Zetterberg H, Regland B, Palmer M, Rymo L, Zafiropoulos A, Arvanitis D, et al. The transcobalamin codon 259 polymorphism influences the risk of human spontaneous abortion. Hum Reprod. 2002;17:3033-6 pubmed..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. ..
- Loikas S, Lopponen M, Suominen P, Møller J, Irjala K, Isoaho R, et al. RIA for serum holo-transcobalamin: method evaluation in the clinical laboratory and reference interval. Clin Chem. 2003;49:455-62 pubmed..Low holoTC is found in individuals with biochemical signs of Cbl deficiency, but the sensitivity and specificity of low holoTC in diagnosis of Cbl deficiency need to be further evaluated. ..
- Nexo E, Hoffmann Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr. 2011;94:359S-365S pubmed publisher..To date, holoTC has not been used for population-based assessments of vitamin B-12 status, but we suggest that holoTC is a better marker than total vitamin B-12 for such studies. ..
- Pietrzyk J, Bik Multanowski M. 776C>G polymorphism of the transcobalamin II gene as a risk factor for spina bifida. Mol Genet Metab. 2003;80:364 pubmed
- Hardlei T, Nexo E. A new principle for measurement of cobalamin and corrinoids, used for studies of cobalamin analogs on serum haptocorrin. Clin Chem. 2009;55:1002-10 pubmed publisher..Our methods for measurement of unmodified corrinoids in serum demonstrate that HC carries cobalamin analogs not recognized by TC, and that on HPLC a substantial part of these analogs elute similarly to cobinamide. ..
- Fedosov S, Petersen T, Nexø E. Transcobalamin from cow milk: isolation and physico-chemical properties. Biochim Biophys Acta. 1996;1292:113-9 pubmed..In conclusion we have shown that TC is the main Cbl-binding protein in cow milk. This is surprising, since previous studies on human and rat milk have shown another Cbl-binder, apo-haptocorrin, to be the dominating Cbl-binding protein. ..
- Garrod M, Allen L, Haan M, Green R, Miller J. Transcobalamin C776G genotype modifies the association between vitamin B12 and homocysteine in older Hispanics. Eur J Clin Nutr. 2010;64:503-9 pubmed publisher..It remains to be determined whether the TC C776G polymorphism has a significant effect on the hematological and neurological manifestations of B12 deficiency or on vascular and other morbidities associated with hyperhomocysteinemia. ..
- Morkbak A, Poulsen S, Nexo E. Haptocorrin in humans. Clin Chem Lab Med. 2007;45:1751-9 pubmed
- Fedosov S, Fedosova N, Krautler B, Nexø E, Petersen T. Mechanisms of discrimination between cobalamins and their natural analogues during their binding to the specific B12-transporting proteins. Biochemistry. 2007;46:6446-58 pubmed..Calculations show that most of them could potentially bind to the specific transporters IF and TC under physiological conditions. Implications of this finding and the protective role of HC are discussed. ..
- Namour F, Olivier J, Abdelmouttaleb I, Adjalla C, Debard R, Salvat C, et al. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood. 2001;97:1092-8 pubmed..02 and P =.01, respectively). In conclusion, TC codon-259 polymorphism affects TC plasma concentration and may interfere in vitamin B(12) cellular availability and homocysteine metabolism. ..
- Zetterberg H, Zafiropoulos A, Spandidos D, Rymo L, Blennow K. Gene-gene interaction between fetal MTHFR 677C>T and transcobalamin 776C>G polymorphisms in human spontaneous abortion. Hum Reprod. 2003;18:1948-50 pubmed
- Namour F, Helfer A, Quadros E, Alberto J, Bibi H, Orning L, et al. Transcobalamin deficiency due to activation of an intra exonic cryptic splice site. Br J Haematol. 2003;123:915-20 pubmed..Until now, genetic studies have been reported in only five patients with TC deficiency and the molecular defect was different in each of them, which gives evidence for a genetic heterogeneity of the disease. ..
- Mørkbak A, Hvas A, Lloyd Wright Z, Sanders T, Bleie O, Refsum H, et al. Effect of vitamin B12 treatment on haptocorrin. Clin Chem. 2006;52:1104-11 pubmed..The HC concentration is decreased in severely cobalamin-deficient individuals and increases on treatment. The concentration of cobalamin also relates significantly to the HC concentration in nondeficient individuals. ..
- Herrmann W, Obeid R, Schorr H, Geisel J. Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med. 2003;41:1478-88 pubmed..Renal patients have a higher requirement of circulating holoTC. In renal dysfunction, holoTC cannot be used as a marker of vitamin B12 status. ..
- Bamonti F, Moscato G, Novembrino C, Gregori D, Novi C, De Giuseppe R, et al. Determination of serum holotranscobalamin concentrations with the AxSYM active B(12) assay: cut-off point evaluation in the clinical laboratory. Clin Chem Lab Med. 2010;48:249-53 pubmed publisher..The method is adequate for routine use and a cut-off threshold of 40 pmol/L is appropriate for assessing cobalamin deficiency in populations with reduced tB(12) values. ..
- Hewitt J, Seetharam B, Leykam J, Alpers D. Isolation and characterization of a cDNA encoding porcine gastric haptocorrin. Eur J Biochem. 1990;189:125-30 pubmed..K. et al. (1988) Proc. Natl Acad. Sci. USA 85, 46-50] showed considerable similarity, suggesting that these cobalamin-binding proteins may have a common evolutionary origin. ..
- Bor M, Cetin M, Aytac S, Altay C, Nexo E. Nonradioactive vitamin B12 absorption test evaluated in controls and in patients with inherited malabsorption of vitamin B12. Clin Chem. 2005;51:2151-5 pubmed..Measurement of holo-TC after administration of vitamin B(12) is a promising approach for evaluating vitamin B(12) absorption. ..
- Morkbak A, Heimdal R, Emmens K, Molloy A, Hvas A, Schneede J, et al. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project. Clin Chem Lab Med. 2005;43:1058-64 pubmed..The results obtained using the holoTC RIA were similar to those obtained using the holoTC ELISA assay. ..
- Aarsetøy H, Valente E, Reine A, Mansoor M, Grundt H, Nilsen D. Holotranscobalamin and methylmalonic acid as prognostic markers following an acute myocardial infarction. Eur J Clin Nutr. 2008;62:411-8 pubmed..76-1.19, P=0.67) after 18 months and 1.01 (95% CI 0.83-1.23, P=0.90) after 45 months. This study showed no increased risk of future cardiovascular events associated with low levels of holoTC or high levels of MMA following an acute MI. ..
- Hygum K, Lildballe D, Greibe E, Morkbak A, Poulsen S, Sorensen B, et al. Mouse transcobalamin has features resembling both human transcobalamin and haptocorrin. PLoS ONE. 2011;6:e20638 pubmed publisher..Mouse TC has features in common with both human TC and HC. Our results suggest that the Cbl-binding proteins present in the circulation and exocrine glands may vary amongst species. ..
- Lievers K, Afman L, Kluijtmans L, Boers G, Verhoef P, den Heijer M, et al. Polymorphisms in the transcobalamin gene: association with plasma homocysteine in healthy individuals and vascular disease patients. Clin Chem. 2002;48:1383-9 pubmed..Therefore, 259PP individuals, who represent >25% of the general population, may be more susceptible to reduction of plasma tHcy concentrations by increasing the vitamin B(12) status. ..
- Chen X, Remacha A, Sarda M, Carmel R. Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II. Am J Clin Nutr. 2005;81:110-4 pubmed..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. ..
- Hardlei T, Mørkbak A, Bor M, Bailey L, Hvas A, Nexo E. Assessment of vitamin B(12) absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin. Clin Chem. 2010;56:432-6 pubmed publisher..Our data demonstrate that CNCbl is absorbed unchanged and accumulates on circulating TC. We suggest that measuring TC-CNCbl will improve the assessment of vitamin B(12) absorption. ..
- Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003;78:131-6 pubmed..Vitamin B-12 status should be monitored in vegetarians. Health aspects of vegetarianism should be considered in the light of possible damaging effects arising from vitamin B-12 deficiency and hyperhomocysteinemia. ..
- Birn H, Nexø E, Christensen E, Nielsen R. Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis. Nephrol Dial Transplant. 2003;18:1095-100 pubmed
- Tanaka T, Scheet P, Giusti B, Bandinelli S, Piras M, Usala G, et al. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet. 2009;84:477-82 pubmed publisher..The ALPL gene likely influences the catabolism of vitamin B6 while FUT2 interferes with absorption of vitamin B12. These findings highlight mechanisms that affect vitamin B6, vitamin B12 and homocysteine serum levels. ..
- Quadros E, Sai P, Rothenberg S. Functional human transcobalamin II isoproteins are secreted by insect cells using the baculovirus expression system. Blood. 1993;81:1239-45 pubmed..A plausible mechanism for generating isoproteins of nonglycosylated peptides, such as TCII, may be by splicing of the leader peptide at alternative sites. ..
- Lildballe D, Fedosov S, Sherliker P, Hin H, Clarke R, Nexo E. Association of cognitive impairment with combinations of vitamin B??-related parameters. Clin Chem. 2011;57:1436-43 pubmed publisher..Cognitive impairment was associated with the combined effects of the 4 biomarkers of vitamin B?? deficiency when included in a wellness score but was not associated with binding proteins or analogs on haptocorrin. ..
- Bhat D, Thuse N, Lubree H, Joglekar C, Naik S, Ramdas L, et al. Increases in plasma holotranscobalamin can be used to assess vitamin B-12 absorption in individuals with low plasma vitamin B-12. J Nutr. 2009;139:2119-23 pubmed publisher..Because malabsorption is unlikely to be a major reason for the low plasma vitamin B-12 concentrations in this population, increasing dietary vitamin B-12 should improve their status. ..
- Lildballe D, Hardlei T, Allen L, Nexo E. High concentrations of haptocorrin interfere with routine measurement of cobalamins in human serum and milk. A problem and its solution. Clin Chem Lab Med. 2009;47:182-7 pubmed publisher..Haptocorrin in concentrations above 10 nM influences measurement of cobalamins giving rise to falsely elevated or decreased results. Removal of unsaturated haptocorrin by pretreatment with cobinamide-sepharose solves the problem. ..
- Smith A, Refsum H. Vitamin B-12 and cognition in the elderly. Am J Clin Nutr. 2009;89:707S-11S pubmed publisher..Pending the outcome of better trials, it is suggested that the elderly in particular should be encouraged to maintain a good, rather than just an adequate, vitamin B-12 status by dietary means. ..
- Brady J, Wilson L, McGregor L, Valente E, Orning L. Active B12: a rapid, automated assay for holotranscobalamin on the Abbott AxSYM analyzer. Clin Chem. 2008;54:567-73 pubmed publisher..The AxSYM Active B12 assay allows rapid, precise, sensitive, specific, and automated measurement of human holoTC in serum and plasma. ..
- Loikas S, Koskinen P, Irjala K, Lopponen M, Isoaho R, Kivela S, et al. Renal impairment compromises the use of total homocysteine and methylmalonic acid but not total vitamin B12 and holotranscobalamin in screening for vitamin B12 deficiency in the aged. Clin Chem Lab Med. 2007;45:197-201 pubmed..04, p=0.227) or holotranscobalamin (r(s)=-0.01, p=0.817). Either total vitamin B(12) or holotranscobalamin rather than homocysteine or methylmalonic acid should be used when screening an aged population prone to renal impairment. ..
- Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem. 2003;49:1367-74 pubmed..Severe TC I/HC deficiency also appears to be more common than suspected. Both diagnoses should be considered in all patients with unexplained low serum cobalamin. ..
- Zetterberg H, Palmer M, Boreström C, Rymo L, Blennow K. The transcobalamin codon 259 polymorphism should be designated 776C>G, not 775G>C. Blood. 2003;101:3749-50; author reply 3750-1 pubmed
- Fedosov S, Berglund L, Fedosova N, Nexo E, Petersen T. Comparative analysis of cobalamin binding kinetics and ligand protection for intrinsic factor, transcobalamin, and haptocorrin. J Biol Chem. 2002;277:9989-96 pubmed..The above data suggest presence of a histidine-containing cap shielding the Cbl-binding site in TC. The cap coordinates to certain corrinoids and, possibly, produces an incapsulated Ado-radical when Cbl small middle dotAdo is bound. ..
- Fedosov S, Berglund L, Nexo E, Petersen T. Sequence, S-S bridges, and spectra of bovine transcobalamin expressed in Pichia pastoris. J Biol Chem. 1999;274:26015-20 pubmed..This may be caused by significant deformation of the Cbl molecule and/or by its shielding when bound to TC. ..
- Carmel R, Parker J, Kelman Z. Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels. Br J Haematol. 2009;147:386-91 pubmed publisher..They also add new approaches to studying mild and severe TC I deficiency and to reducing confusion of its low cobalamin levels with those of cobalamin deficiency and its often dramatically different prognosis and management. ..
- Goringe A, Ellis R, McDowell I, Vidal Alaball J, Jenkins C, Butler C, et al. The limited value of methylmalonic acid, homocysteine and holotranscobalamin in the diagnosis of early B12 deficiency. Haematologica. 2006;91:231-4 pubmed..Supplementary tests of vitamin B12 status were not significantly better than total serum B12 concentration as predictors of a hematologic response to vitamin B12 therapy. ..
- Carmel R. Measuring and interpreting holo-transcobalamin (holo-transcobalamin II). Clin Chem. 2002;48:407-9 pubmed