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Cobalamin transport

About: Cobalamin transport is a research topic. Over the lifetime, 72 publications have been published within this topic receiving 3088 citations.


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Journal ArticleDOI
TL;DR: A child with TC deficiency who presented with classical clinical and lab stigmata of inborn error of vitamin B12 metabolism except normal serum B12 levels is described.
Abstract: Transcobalamin (TC) deficiency is a rare autosomal recessive inborn error of cobalamin transport which clinically manifests in early infancy. We describe a child with TC deficiency who presented with classical clinical and lab stigmata of inborn error of vitamin B12 metabolism except normal serum B12 levels. He was started on empirical parenteral cobalamin supplements at 2 months of age; however, the definitive diagnosis could only be established at 6 years of age when a genetic evaluation revealed homozygous nonsense variation in exon 8 of the TCN2 gene (chr22:g.31019043C>T).

5 citations

Journal ArticleDOI
TL;DR: Cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts, indicating a preserved disease phenotype in this cell type.
Abstract: Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.

5 citations

Journal ArticleDOI
TL;DR: A 39‐year‐old woman presented with mild anemia, glossitis, an increased MCV, a low serum cobalamin (Cbl) (vitamin B12), mild tissue deficiency of Cbl, but with neither malabsorption of C Bl, impaired intake, nor deficiency of or inactivity of transcobalamin II (TC II).
Abstract: A 39-year-old woman presented with mild anemia, glossitis, an increased MCV, a low serum cobalamin (Cbl) (vitamin B12), mild tissue deficiency of Cbl, but with neither malabsorption of Cbl, impaired intake, nor deficiency of or inactivity of transcobalamin II (TC II). Because of a persistently low holo-TC II (TC II carrying Cbl as the circulating complex of TC II-Cbl), much of the evaluation was focused on the patient's TC II. Her TC II promoted the uptake of Cbl, reacted with anti-TC II, and bound Cbl in vitro. A test dose of 200 micrograms of cyanocobalamin (CN-Cbl) i.m. increased her holo TC II to levels higher than those in healthy persons, but with a much more abrupt fall to a subnormal level. Two milligrams of CN-Cbl i.m. followed by 100 micrograms i.m. monthly failed to maintain normal amounts of circulating TC II-Cbl or to overcome the tissue deficiency of Cbl. One milligram i.m. weekly or daily p.o. corrected both. The low holo TC II was considered to be responsible for the clinical expression and may have been primary to the reduced amounts of total and holo R binder of Cbl in the circulation. This study of a newly recognized defect points out the need for circulating holo TC II, a rational use of pharmacologic amounts of Cbl, and a possible interrelationship between TC II and the R binder of Cbl.

5 citations

Journal ArticleDOI
TL;DR: The study showed that the polymorphisms of TCN2 and TCblR are associated with RIF and are potential genetic predisposing factors for RIF among Korean women, and their findings support a potential role for TCN 2 andTCblR in RIF.
Abstract: Vitamin B12 (cobalamin, Cbl) plays a role in the recycling of folate, which is important in pregnancy. Transcobalamin II (TCN2) and transcobalamin receptor (TCblR) proteins are involved in the cellular uptake of Cbl. TCN2 binds Cbl in the plasma, and TCblR binds TCN2-Cbl at the cell surface. Therefore, we investigated the potential association between polymorphisms in Cbl transport proteins, TCN2 and TCblR, and recurrent implantation failure (RIF) susceptibility. The genotypes of TCN2 67A>G, TCN2 776C>G, and TCblR 1104C>T were determined for RIF patients and healthy controls using a polymerase chain reaction restriction fragment length polymorphism assay. Additionally, statistical analysis was performed to compare the genotype frequencies between RIF patients and controls. The TCN2 67 polymorphism AG type was associated with RIF risk. Some allele combinations that contained the TCN2 67 polymorphism G allele were associated with increased RIF risk, whereas other allele combinations that contained the TCblR 1104 polymorphism T alleles were associated with decreased RIF risk. In genotype combination analysis, two combinations containing the TCN2 67 polymorphism AG type were associated with RIF risk. Our study showed that the polymorphisms of TCN2 and TCblR are associated with RIF and are potential genetic predisposing factors for RIF among Korean women. Additionally, our findings support a potential role for TCN2 and TCblR in RIF among Korean women. However, further studies are required to investigate the role of the polymorphisms in those proteins and RIF because the roles of the TCN2 and TCblR polymorphisms in RIF are not clear.

4 citations

Proceedings ArticleDOI
17 May 2000
TL;DR: Fluorescent analogs ofcobalamin (vitamin B12) have been developed as diagnostic markers ofcancer cells as discussed by the authors. But the results ofpreliininary studies suggest that fluorescent analogs may be a useful tool in therapeutic breast operations to define tumor margins and to distinguishneoplastic breast tissue from healthy breast tissue.
Abstract: Fluorescent analogs ofcobalamin (vitamin B12)have been developed as diagnostic markers ofcancer cells.These compounds are recognized by transcobalamin, a cobalamin transport protein, with high affinity, asshown by surface plasmon resonance. The cellular sequestration and gross distribution of fluorescentcobalamm bioconjugates in breast tissue is being examined by epifluorescence microscopy. Thedistribution ofeach compound is being evaluated in proliferative and non-proliferative tissue, ie. normaltissue and breast carcinoma. The results ofpreliininary studies suggest that fluorescent analogs ofcobalamin may be a useful tool in therapeutic breast operations to define tumor margins and to distinguishneoplastic breast tissue from healthy breast tissue.Keywords: cobalamin, vitamin B12, breast, neoplastic, fluorescent, transcobalamin, TCII 1. ENTRODUCFION Eukaryotic cells require cobalamin for metabolism and cell replication. Methionine synthase utilizesmethylcobalamin as a cofactor to methylate homocysteine in a coupled reaction with N5methyl-tetrahydrofolate. N5Methyl-tetrahydrofolate serves as a methyl group donor, thereby regeneratingtetrahydrofolate, which ultimately converts deoxyuridine monophosphate to deoxythymidinemonophosphate.' Rapidly proliferating cells have an increased demand for thymidine to support DNAreplication and thus have a need for high levels ofcobalamin. Tumor cells manifest this need forcobalamin by increasing their level ofcobalamin transport and storage.2'3In blood, cobalamin is bound to transcobalamin (TCII). Cobalamin enters cells via receptor-mediatedendocytososis ofthe TCII-cobalamin complex.4 This process allows a tumor to sequester high levels ofradiolabeled cobalamin, as seen in mice that have an implanted fibrosarcoma5 and in companion felineswith a primary mammary tumor.5 The unsaturated serum binding capacity ofvitamin B12 increases 3 to 26fold in patients with acute promyelocytic leukemia.6'7 In addition, elevated levels ofcirculating TCII havebeen observed in patients with breast carcinoma.8Breast cancer is the second most common type of cancer in women.9 Surgical therapy for breast cancerrequires the removal of a fraction of healthy breast tissue to ensure complete excision ofthe tumor. Areliable method for detecting neoplastic margins intraoperatively and differentiating it from healthy tissueis not available. Fluorescent derivatives ofcobalamin may be useful as tumor imaging agents to fill thisvoid in current medical technology. This would ensure complete excision ofneoplastic tissue whileminimizing the amount ofhealthy tissue removed. Cobalamin has been labeled with Oregon Green,naphthofluorescein, and fluorescein fluorophores. The internalization of these cobalamin bioconjugates bytumor (target) tissue is now being evaluated and compared with internalization levels in surroundingnormal (background) tissue in breast carcinoma.

4 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20213
20204
20192
20181
20174
20162