Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans

Guéant-Rodríguez, Rosa-María; Rendeli, Claudia; Namour, Bernard; Venuti, L.; Romano, Antonino; Anello, Guido; Bosco, Paolo; Debard, Renée; Gérard, P.; Viola, M.; Salvaggio, E; Guéant, Jean‐Louis

doi:10.1016/s0304-3940(03)00468-3

Cited by 78 publications

(36 citation statements)

References 20 publications

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“…von Castel-Dunwoody et al (2005) reported that the TC C776G polymorphism negatively affected the concentration of the TC-vitamin B12 complex and altered the cellular availability of vitamin B12, thus exacerbating the effects of low vitamin B12 status. There is evidence for an association between TC C776G polymorphism and the increased risk of bearing a child with NTD (Afman et al, 2002;Guéant-Rodriguez et al, 2003). However, no association was observed between the TC C776G polymorphism and the maternal risk of having a child with DS in the present study.…”

Section: Discussioncontrasting

confidence: 83%

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

Liao¹,

Zhang²,

Zhou³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. We examined whether polymorphisms in the methylenetetrahydrofolate dehydrogenase (MTHFD) and transcobalamin (TC) genes, which are involved in folate metabolism, affect maternal risk for Down syndrome. We investigated 76 Down syndrome mothers and 115 control mothers from Bengbu, China. Genomic DNA was isolated from the peripheral lymphocytes. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFD G1958A and TC C776G. The frequencies of the polymorphic alleles were 24.3 and 19.1% for MTHFD 1958A, 53.9 and 54.2% for TC 776G, in the case and control groups, respectively. No significant differences were found between two groups in relation to either the allele or the genotype frequency for both polymorphisms. However, when gene-gene interactions between these two polymorphisms together with previous studied C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) 1765©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (1): 1764-1773 (2014) Folate gene polymorphisms and the risk of Down syndrome gene were analyzed, the combined MTHFR 677CT/TT and MTHFD 1958AA/GA genotype was found to be significantly associated with the risk of having a Down syndrome child [odds ratio (OR) = 3.11; 95% confidence interval (95%CI) = 1.07-9.02]. In addition, the combined TC 776CG and MTHFR 677TT genotype increased the risk of having a child with Down syndrome 3.64-fold (OR = 3.64; 95%CI = 1.28-10.31).In conclusion, neither MTHFD G1958A nor TC C776G polymorphisms are an independent risk factor for Down syndrome. However, the combined MTHFD/MTHFR, TC/MTHFR genotypes play a role in the risk of bearing a Down syndrome child in the Chinese population.

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Section: Discussioncontrasting

confidence: 83%

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

Liao¹,

Zhang²,

Zhou³

et al. 2014

Genet. Mol. Res.

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“…Intracellular Cbl deficiency results in elevated plasma levels of substrates of Cbl-dependent enzymes, methylmalonic acid (MMA) and homocysteine. Increased total homocysteine (tHcy) is under intense investigation as a risk factor for vascular disease and stroke (32) as well as for neural tube defects (33). Numerous clinical studies investigated a possible association of TC polymorphisms, in particular the most common polymorphism P259R, with changes in plasma concentrations of holo-TC, total Cbl, MMA, or tHcy (12,(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Wuerges

Garau²,

Geremia³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

166

216

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Cobalamin (Cbl, vitamin B12) serves for two essential cofactors in mammals. The pathway for its intestinal absorption, plasma transport, and cellular uptake uses cell surface receptors and three Cbl-transporting proteins, haptocorrin, intrinsic factor, and transcobalamin (TC). We present the structure determination of a member of the mammalian Cbl-transporter family. The crystal structures of recombinant human and bovine holo-TCs reveal a two-domain architecture, with an N-terminal ␣6-␣6 barrel and a smaller C-terminal domain. One Cbl molecule in base-on conformation is buried inside the domain interface. Structural data combined with previous binding assays indicate a domain motion in the first step of Cbl binding. In a second step, the weakly coordinated ligand H 2O at the upper axial side of added H2O-Cbl is displaced by a histidine residue of the ␣6-␣6 barrel. Analysis of amino acid conservation on TC's surface in orthologous proteins suggests the location of the TC-receptor-recognition site in an extended region on the ␣6-␣6 barrel. The TC structure allows for the mapping of sites of amino acid variation due to polymorphisms of the human TC gene. 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.cobalamin ͉ crystal structure ͉ P259R polymorphism ͉ transport protein

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“…Polymorphisms in the human methionine synthase reductase gene have been found to correlate with an increased risk of neural tube defects [33][34][35][36][37]. If MTRR is functionally important for proper neural tube closure in mice, Mtrr expression would be expected in or around the neural tube between days E8.5 to E10.5 [38].…”

Section: Analyses Of Mtrr Expression In E95 Embryosmentioning

confidence: 99%

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

100

122

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Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of methionine synthase activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase. This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity. Mtrr gt/gt mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate. Unexpectedly, Mtrr gt/gt mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocysteinemia may be useful in understanding biological effects of elevated homocyst(e)ine.

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Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans

Cited by 78 publications

References 20 publications

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

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Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans

Cited by 78 publications

References 20 publications

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

Structural basis for mammalian vitamin B 12 transport by transcobalamin

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

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Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin