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Background: SLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear. Methods: We collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR, and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione, and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS, and CD14 changes. Results: Elevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response. Conclusion: Our study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation, and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE. [ABSTRACT FROM AUTHOR]

Transcobalamin II (TC) promotes the cellular uptake of cobalamin (Cbl) through receptor-mediated endocytosis of the TC-cbl complex in peripheral tissues. TC deficiency is a rare disorder that causes intracellular Cbl depletion. It presents in early infancy with a failure to thrive, diarrhea, anemia, agammaglobulinemia, and pancytopenia. Data from five TC-deficient patients including clinical, biochemical, and molecular findings, as well as long-term outcomes, were collected. Mutation analysis revealed one unreported pathogenic variant in the TCN2 gene. One patient had exocrine pancreatic insufficiency. We conducted a retrospective analysis of C3 and C3/C2 from dried blood samples, as this is implemented for newborn screening (NBS). We detected a marked increase in the C3/C2 ratio in two samples. Treatment was based on parenteral Cbl. Three patients treated before six months of age had an initial favorable outcome, whereas the two treated later or inadequately had neurological impairment. This is the first report of Argentinean patients with TC deficiency that detected a new variant in TCN2. NBS may be a tool for the early detection of TC deficiency. This data emphasizes that TC deficiency is a severe disorder that requires early detection and long-term, aggressive therapy. Accurate diagnosis is imperative, because early detection and treatment can be life-saving. [ABSTRACT FROM AUTHOR]

Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid‐phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B‐FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all‐cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B‐mediated frontotemporal dementia (FTD).31 members of the Danish CHMP2B‐FTD family were included.We used solid‐phase extraction and parallel reaction monitoring mass spectrometry.Six protein levels were significantly altered in CHMP2B‐FTD compared with controls.Lower CSF ubiquitin levels in patients suggest association with disease mechanisms. [ABSTRACT FROM AUTHOR]

Background: SLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear., Methods: We collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR, and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione, and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS, and CD14 changes., Results: Elevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response., Conclusion: Our study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation, and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Li, Liu, Zhou, Xu, Zuo, Xue and Cui.)

Purpose: It is hypothesized that vitamin B12 may prevent tumor initiation during the early stage of carcinogenesis such as esophageal precancerous lesions (EPL), whereas an excessive level may promote tumor progression during the later stages of carcinogenesis. This study aimed to determine the role of vitamin B12 in EPL by detecting vitamin B12-related markers in both blood and diet. Methods: This case–control study based on 3-day duplicated diet samples was conducted in a high-risk area of Huai'an, China. A 100 EPL cases and 100 healthy controls matched by gender, age (± 2 years) and villages were included. Dietary intake of vitamin B12 and cobalt, plasma cobalt level, the serum levels of vitamin B12 and transcobalamin II (TC II) were quantitatively analyzed. Results: Dietary vitamin B12 intake (p for trend = 0.384) and plasma cobalt level (p for trend = 0.253) were not associated with EPL risk, but high dietary cobalt intake (p for trend = 0.034), increased serum levels of vitamin B12 (p for trend = 0.036) and TC II (p for trend < 0.001) were significantly associated with the reduced EPL risk. However, the significant negative association between dietary cobalt intake, plasma cobalt level or serum vitamin B12 level and EPL was only found in female or male subjects. Conclusion: Excellent transport capability of bio-active vitamin B12 in vivo and adequate levels of vitamin B12 and cobalt may play preventive roles in EPL. Additionally, the association between vitamin B12, cobalt and the risk of EPL may vary in different genders. [ABSTRACT FROM AUTHOR]

Objective: Transcobalamin II deficiency is a rare autosomal recessive disease characterized by decreased cobalamin availability, which in turn causes accumulation of homocysteine and methylmalonic acid. The presenting clinical features are failure to thrive, diarrhea, megaloblastic anemia, pancytopenia, neurologic abnormalities, and also recurrent infections due to immune abnormalities in early infancy. Materials and Methods: Here, we report the clinical and laboratory features of six children with transcobalamin II deficiency who were all molecularly confirmed. Results: The patients were admitted between 1 and 7 months of age with anemia or pancytopenia. Unexpectedly, one patient had a serum vitamin B12 level lower than the normal range and another one had nonsignificantly elevated serum homocysteine levels. Four patients had lymphopenia, four had neutropenia and three also had hypogammaglobulinemia. Suggesting the consideration of transcobalamin II deficiency in the differential diagnosis of immune deficiency. Hemophagocytic lymphohistiocytosis was also detected in one patient. Furthermore, two patients had vacuolization in the myeloid lineage in bone marrow aspiration, which may be an additional finding of transcobalamin II deficiency. The hematological abnormalities in all patients resolved after parenteral cobalamin treatment. In follow-up, two patients showed neurological impairments such as impaired speech and walking. Among our six patients who were all molecularly confirmed, two had the mutation that was reported in transcobalamin II-deficient patients of Turkish ancestry. Also, a novel TCN2 gene mutation was detected in one of the remaining patients. Conclusion: Transcobalamin II deficiency should be considered in the differential diagnosis of infants with immunological abnormalities as well as cytopenia and neurological dysfunction. Early recognition of this rare condition and initiation of adequate treatment is critical for control of the disease and better prognosis.

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: Transcobalamin II deficiency is a rare autosomal recessive disease characterized by decreased cobalamin availability, which in turn causes accumulation of homocysteine and methylmalonic acid. The presenting clinical features are failure to thrive, diarrhea, megaloblastic anemia, pancytopenia, neurologic abnormalities, and also recurrent infections due to immune abnormalities in early infancy. Materials and Methods: Here, we report the clinical and laboratory features of six children with transcobalamin II deficiency who were all molecularly confirmed. Results: The patients were admitted between 1 and 7 months of age with anemia or pancytopenia. Unexpectedly, one patient had a serum vitamin B12 level lower than the normal range and another one had nonsignificantly elevated serum homocysteine levels. Four patients had lymphopenia, four had neutropenia and three also had hypogammaglobulinemia. Suggesting the consideration of transcobalamin II deficiency in the differential diagnosis of immune deficiency. Hemophagocytic lymphohistiocytosis was also detected in one patient. Furthermore, two patients had vacuolization in the myeloid lineage in bone marrow aspiration, which may be an additional finding of transcobalamin II deficiency. The hematological abnormalities in all patients resolved after parenteral cobalamin treatment. In followup, two patients showed neurological impairments such as impaired speech and walking. Among our six patients who were all molecularly confirmed, two had the mutation that was reported in transcobalamin II-deficient patients of Turkish ancestry. Also, a novel TCN2 gene mutation was detected in one of the remaining patients. Conclusion: Transcobalamin II deficiency should be considered in the differential diagnosis of infants with immunological abnormalities as well as cytopenia and neurological dysfunction. Early recognition of this rare condition and initiation of adequate treatment is critical for control of the disease and better prognosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Transcobalamin II deficiency is one of the rare causes of inherited vitamin B12 disorders in which the patients have characteristically normal or high vitamin B12 levels related to the transport defect of vitamin B12 into the cell, ending up with intracellular cobalamin depletion and high homocysteine and methylmalonic acid levels. METHODS: Herein, we describe the findings at presentation of four patients who were diagnosed to have transcobalamin II deficiency with novel mutations. RESULTS: These patients with transcobalamin II deficiency were found to have novel mutations, of whom 2 had the same large deletion (homozygous c.1106+1516-1222+1231del). DISCUSSION AND CONCLUSION: Transcobalamin II deficiency should be considered in differential diagnosis of any infant with pancytopenia, failure to thrive, diarrhea, and vomiting.

Adenyl cobamide (commonly known as pseudovitamin B12) is synthesized by intestinal bacteria or ingested from edible cyanobacteria. The effect of pseudovitamin B12 on the activities of cobalamin-dependent enzymes in mammalian cells has not been studied well. This study was conducted to investigate the effects of pseudovitamin B12 on the activities of the mammalian vitamin B12-dependent enzymes methionine synthase and methylmalonyl-CoA mutase in cultured mammalian COS-7 cells to determine whether pseudovitamin B12 functions as an inhibitor or a cofactor of these enzymes. Although the hydoroxo form of pseudovitamin B12 functions as a coenzyme for methionine synthase in cultured cells, pseudovitamin B12 does not activate the translation of methionine synthase, unlike the hydroxo form of vitamin B12 does. In the second enzymatic reaction, the adenosyl form of pseudovitamin B12 did not function as a coenzyme or an inhibitor of methylmalonyl-CoA mutase. Experiments on the cellular uptake were conducted with human transcobalamin II and suggested that treatment with a substantial amount of pseudovitamin B12 might inhibit transcobalamin II-mediated absorption of a physiological trace concentration of vitamin B12 present in the medium.

It has been proposed that transcobalamin 2 (TCN2) and the transcobalamin 2 receptor (TCN2R) are associated with idiopathic recurrent spontaneous abortion (RSA). The aim of the present study was to investigate the impact of TCN2 rs1801198 and TCN2R rs2336573 polymorphism on RSA in a sample of Iranian population. This case-control study was done on 92 RSA patients and 93 normal, fertile women. Genotyping of the TCN2 rs1801198 and TCN2R rs2336573 variants was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The findings showed no significant association between the TCN2 rs1801198 and TCN2R rs2336573 polymorphisms and the risk/protection of RSA. Our results did not support an association between the TCN2 polymorphism and the risk of RSA in a sample of southeast Iranian population. Larger studies with different ethnicities are needed to evaluate the possible impact of TCN2 and TCN2R polymorphisms on the pathogenesis of RSA. Impact statement What is already known on this subject? Recurrent spontaneous abortion (RSA), a multifactorial condition, is one of the most common complications of pregnancy. It has been proposed that genetic polymorphisms play a role in the pathogenesis of RSA. Few studies have examined the association between TNC2 and TCN2R polymorphisms and the RSA risk and the findings were inconsistent. The aim of the current study was to determine the possible association between the TCN2 rs1801198 and TCN2R rs2336573 polymorphisms and the RSA in a sample of the southeast Iranian population. What do the results of the study add? The findings of the present case-control study did not support an association between the TCN2 rs1801198 and TCN2R rs2336573 polymorphisms and the risk of RSA in a sample of the Iranian population. What are the implications of these findings for clinical practice and future research? The findings of this study may provide a basis for future studies with larger sample sizes and different ethnicities on the role of TCN2 and TCN2R polymorphisms in the pathogenesis of RSA. [ABSTRACT FROM AUTHOR]

Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions. Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease. Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition. Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): -0.445 (95% CI: -0.673, --0.217; P < 0.001); I² = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I² = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease. Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504. [ABSTRACT FROM AUTHOR]

It has been reported that abnormal elevation of homocysteine is quite prevalent in ulcerative colitis (UC) patients. We attempted to explore the relationship of UC with transcobalamin II (TCN2) gene polymorphisms and serum homocysteine, vitamin B, and folate levels in Chinese patients. TCN2 (rs1801198, rs9606756) genotypes were detected by the improved multiple ligase detection reaction (iMLDR) technique in 527 UC patients and 574 controls. Moreover, 128 UC patients and 138 controls were randomly selected for the measurement of homocysteine, vitamin B, and folate levels by enzymatic cycling assay or chemiluminescence immunoassay. For TCN2 (rs1801198), the frequency of allele G and combined frequencies of CG and GG genotypes were increased in patients with mild, moderate, and severe UC compared with those with remission UC (all P < 0.001). The average homocysteine level was elevated (10.78 ± 3.33 vs 9.91 ± 2.88 μmol/L, P = 0.024), whereas the average vitamin B and folate levels were reduced (408.66 ± 185.00 vs 457.42 ± 206.47 pg/mL, P = 0.044; 6.81 ± 3.06 vs 8.17 ± 2.58 ng/mL, P < 0.001, respectively) in UC patients than in controls. Compared with controls, the prevalence of hyperhomocysteinemia (HHcy >15.0 μmol/L), vitamin B deficiency (<203.0 pg/mL), and folate deficiency (<4.0 ng/mL) was higher in UC patients (all P < 0.05). Both HHcy and folate deficiency were shown to be independent risk factors for UC (95% CI = 1.206-12.293, P = 0.023; 95% CI = 1.910-11.129, P = 0.001, respectively). TCN2 (rs1801198, rs9606756) mutations might aggravate the severity of UC. HHcy and folate deficiency are independent risk factors for UC. [ABSTRACT FROM AUTHOR]

Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation., Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B -FTD family., Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein., Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD., Highlights: CSF markers of proteostasis were explored in CHMP2B -mediated frontotemporal dementia (FTD).31 members of the Danish CHMP2B -FTD family were included.We used solid-phase extraction and parallel reaction monitoring mass spectrometry.Six protein levels were significantly altered in CHMP2B -FTD compared with controls.Lower CSF ubiquitin levels in patients suggest association with disease mechanisms., Competing Interests: K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, and JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). The remaining authors (A.T., S.S., A.H.S., P.E., P.R., C.S.M., E.E.H., T.T.N., A.B., and J.E.N.) have no conflicts of interest to declare. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: Transcobalamin II deficiency is one of the rare causes of inherited vitamin B12 disorders in which the patients have characteristically normal or high vitamin B12 levels related to the transport defect of vitamin B12 into the cell, ending up with intracellular cobalamin depletion and high homocysteine and methylmalonic acid levels. Materials and Methods: Herein, we describe the findings at presentation of four patients who were diagnosed to have transcobalamin II deficiency with novel mutations. Results: These patients with transcobalamin II deficiency were found to have novel mutations, of whom 2 had the same large deletion (homozygous c.1106+1516-1222+1231del). Conclusion: Transcobalamin II deficiency should be considered in differential diagnosis of any infant with pancytopenia, failure to thrive, diarrhea, and vomiting. [ABSTRACT FROM AUTHOR]

Pernicious anaemia (PA) and some types of thyroid disease result from autoimmune processes. The autoimmune mechanisms in these conditions have not been fully elucidated. This review discusses the autoimmune mechanisms involved in PA and how these affect diagnosis and disease progression. In addition to gastric antibodies, antibodies to the vitamin B 12 binding protein transcobalamin which can result in high serum B 12 levels are also addressed with regard to how they affect clinical practice. The role of autoimmune susceptibility is investigated by comparing PA to one of its most common comorbidities, autoimmune thyroid disease (AITD). Thyroid disease (although not exclusively AITD) and B 12 deficiency are both also implicated in the pathology of hyperhomocysteinemia, an elevated homocysteine in plasma. Since hyperhomocysteinemia is a risk factor for cardiovascular occlusive disease, this review also addresses how thyroid disease in particular leads to changes in homocysteine levels. [ABSTRACT FROM AUTHOR]

Problem: The transcobalamin II (TCN2) 776C>G polymorphism has been reported to be a genetic risk factor for idiopathic recurrent spontaneous abortion (RSA). However, the sample size in previous studies was small, and other TCN2 polymorphisms have not been studied. Moreover, the TCN2 67A>G and 776C>G polymorphisms, and the transcobalamin II receptor (TCblR/CD320) 1104C>T polymorphism, have demonstrated associations with immune responses. Method of study: Three hundred and seventy-eight RSA patients who had at least two consecutive spontaneous abortions were enrolled. Two hundred and seven control subjects were collected from a convenience sample. Polymerase chain reaction and restriction fragment length polymorphism analysis were performed to identify the TCN2 67A>G and 776C>G polymorphisms, and the TCblR 1104C>T polymorphism. Results: RSA patients showed significantly different frequencies of the TCN2 67AG+GG genotypes compared with control subjects. Conclusion: The TCN2 67G allele is a possible risk factor for idiopathic RSA. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to measure the retention and absorption of vitamin B 12 from milk in pre-ruminant lambs as well as the effect of the activation of metabolic pathways in tissue concentration. According to the article, newborn lambs were divided into two groups, with the other given milk substitute alone while the other with added proportion by up to four weeks. In addition, it affirms that lambs that are being administered with the vitamins in the liver and plasma at a marginal range were able to maintain normal concentrations.

Abstract: One of the etiologies of hyperhomocysteinemia is decreased vitamin B12. Genetic variation in the transcobalamin II gene, the transporter of vitamin B12 to the cells, may produce altered homocysteine levels. We determined transcobalamin II C776G polymorphism, homocysteine, folate and vitamin B12 levels and analyzed the interactive effect with the methylenetetrahydrofolate reductase C677T and A1298C and methionine synthase reductase A66G polymorphisms in 207 healthy Brazilian children. The prevalence of GG genotype of transcobalamin II C776G polymorphism in this Brazilian population, a highly miscigeneous population was 12.5% and the statistical analysis showed that this population is in Hardy–Weinberg equilibrium, it could be considered representative of the general population. We observed a significant increase in homocysteine in the 776GG vs. 776CC genotype, corroborating the influence of age as a determinant of homocysteine in relation to this polymorphism. When we analyzed vitamin B12 and its relationship with the C776G polymorphism, we found no significant differences. Only 776CG/66AA or 776GG/66AG genotypes presented a significant increase in homocysteine when compared with other groups. In the multivariate analysis, transcobalamin II C776G (CC/CG vs. GG), methylenetetrahydrofolate reductase C677T (CC/CT vs. TT), folate, gender and age presented statistical significance in relation to the homocysteine. These can be considered independent risk factors for hyperhomocysteinemia in this children group. 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. [Copyright &y& Elsevier]

Objective: A common polymorphism of the transcobalamin II (TC-II) gene, Pro250Arg, has been implicated as a possible genetic factor in population-based differences in vitamin B12 metabolism. Our objective was to determine whether the prevalence of TC-II Pro259Arg polymorphism differs significantly between Caucasian, Asian and African-American groups.Methods: Genomic DNA was available on 187 Caucasians and 43 Asians from the Toronto area, and 51 African-Americans from Northeastern United States. A mutagenically separated PCR method was employed to genotype these groups for the TC-II Pro259Arg polymorphism (776C→G).Results: The frequency of the Arg 259 allele varied significantly among the three groups studied (0.439 in Caucasian, 0.558 in Asian and 0.363 in African; P = 0.022). The Asian group had a significantly higher frequency of the Arg 259 allele compared to the Caucasian (P = 0.030) and the African-American group (P = 0.006). The frequency of the Arg 259 allele in the Caucasian and African-American groups was not significantly different (P = 0.103).Conclusion: Population-based differences in TC-II Pro259Arg frequency are significant and could be a contributor to ethnic variation in susceptibility to vitamin B12 deficiency, a common and persistent problem. [Copyright &y& Elsevier]

Genetic determinants of the homocysteine level. Elevated total homocysteine (tHcy) plasma concentrations indicate folate and/or vitamin B12 deficiency and are associated with cardiovascular disease and neural tube defects. Evidence has accumulated that folate-, vitamin B12 -, and Hcy-metabolism are under genetic control. Because Hcy metabolism is impaired in renal failure, MTHFR 677 C>T, GCP2 1561C>T, RFC1 80G>A, and TCN2 776G>C may further aggravate hyperhomocysteinemia in these patients. The most consistent effect on tHcy plasma concentrations is observed for 677C>T of MTHFR , whereas GCP2 , RFC1 , and TCN2 polymorphisms show no major effect on tHcy concentrations. Much is yet to be learned about the impact of genetic variants on tHcy levels, human diseases, the genetic-nutrient interactions, as well as the pharmacogenetic consequences in Hcy and vitamin metabolism. [ABSTRACT FROM AUTHOR]

Purified human placental transcobalamin II receptor (TC II-R) dimer of molecular mass 124 kDa bound to Sepharose-linked bacterial immunoglobulin (IgG) binding proteins protein A, protein G, and protein A/G. TC II-R dimer was detected directly, by blotting human placental and rabbit and rat kidney membrane proteins with 125I-protein A, or indirectly, using antiserum to TC II-R or IgG–Fc region and 125I-protein. TC II-R antiserum, but not protein A, protein G, protein A/G, or antiserum to the IgG–Fc region, when added to culture medium of human intestinal epithelial Caco-2 cells or umbilical vein endothelial cells, inhibited ligand binding. However, protein A, protein G, protein A/G, or antiserum to the Fc region inhibited the internalization of the ligand TC II-[57Co]cyanocobalamin. Taken together, these studies strongly suggest TC II-R is an IgG-like molecule that contains an Fc-like region which is important in ligand internalization but not binding. [Copyright &y& Elsevier]

Transcobalamin II (TCII) is a plasma protein that transports cobalamin to tissues for cellular uptake by receptor-mediated endocytosis. Human umbilical vein endothelial cells (HUVEC) in culture constitutively express TCII. However, in other cell lines, TCII expression is dependent on high cell density. ECV304, a cell line with some properties of HUVEC, expresses TCII only when seeded at high density. An electrophoretic mobility-shift assay using nuclear extract from such high-density-seeded ECV 304 cells shifted a 24-bp oligonucleotide probe to generate an unique slow moving band that was competed out by unlabeled probe. This unique band was not observed with nuclear extract from low-density-seeded ECV304 cells. A 3′ sequence, 5′-TGGTCC-3′, in the 24-bp oligonucleotide was identified as the binding site for the nuclear protein(s) because this band was not competed out when the hexameric sequence was scrambled to 5′-CTTCTT-3′. Binding of a transcription factor(s) to this hexamer, that is located 121 bp upstream of the transcription start site, appears to be essential for the regulated or constitutive expression of TCII. [Copyright &y& Elsevier]

When one stops eating vitamin B-12 (cobalamins), one passes through four stages of negative cobalamin balance: serum depletion [low holotranscobalamin II, ie, low vitamin B-12 on transcobalamin II (TCII)], cell depletion (decreasing holohaptocorrin and low red cell vitamin B-12 concentrations), biochemical deficiency (slowed DNA synthesis, elevated serum homocysteine and methylmalonate concentrations), and, finally, clinical deficiency (anemia). Serum vitamin B-12 is on two proteins: the circulating vitamin B-12 delivery protein, TCII, and the circulating vitamin B-12 storage protein, haptocorrin. Because TCII is depleted of vitamin B-12 within days after absorption stops, the best screening test for early negative vitamin B-12 balance is a measurement of vitamin B-12 on TCII (holoTCII). Ho1oTCII falls below the bottom of its normal range long before total serum vitamin B-12 (which is mainly vitamin B-12 on haptocorrin) falls below the bottom of its normal range. [ABSTRACT FROM AUTHOR]

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Adenyl cobamide (commonly known as pseudovitamin B12) is synthesized by intestinal bacteria or ingested from edible cyanobacteria. The effect of pseudovitamin B12 on the activities of cobalamin-dependent enzymes in mammalian cells has not been studied well. This study was conducted to investigate the effects of pseudovitamin B12 on the activities of the mammalian vitamin B12-dependent enzymes methionine synthase and methylmalonyl-CoA mutase in cultured mammalian COS-7 cells to determine whether pseudovitamin B12 functions as an inhibitor or a cofactor of these enzymes. Although the hydoroxo form of pseudovitamin B12 functions as a coenzyme for methionine synthase in cultured cells, pseudovitamin B12 does not activate the translation of methionine synthase, unlike the hydroxo form of vitamin B12 does. In the second enzymatic reaction, the adenosyl form of pseudovitamin B12 did not function as a coenzyme or an inhibitor of methylmalonyl-CoA mutase. Experiments on the cellular uptake were conducted with human transcobalamin II and suggested that treatment with a substantial amount of pseudovitamin B12 might inhibit transcobalamin II-mediated absorption of a physiological trace concentration of vitamin B12 present in the medium. [ABSTRACT FROM AUTHOR]

Serum vitamin B[sub 12] radioimmunoassays may give falsely low results in patients with folate deficiency, multiple myeloma, megadose of vitamin C and following radioisotope organ scan. We evaluated 10 consecutive healthy women on oral contraceptives (OC) who had falsely low vitamin B[sub 12] levels, as reflected by normal urine methylmalonic acid and plasma homocysteine. After 1-month cessation of OCs, vitamin B[sub 12] returned to the normal range in all women. Transcobalamin I (TCI) blood level was decreased in 60% of patients. OCs may cause temporary low vitamin B[sub 12] blood levels of no clinical significance that can be associated with low TCI levelsCopyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]