Hostname: page-component-8448b6f56d-m8qmq Total loading time: 0 Render date: 2024-04-18T12:16:37.730Z Has data issue: false hasContentIssue false
  • English
  • Français

Genetic variation in genes of folate metabolism and neural-tube defect risk*

Published online by Cambridge University Press:  07 March 2007

Ivon J. M. van der Linden ,
Lydia A. Afman ,
Sandra G. Heil  and
Henk J. Blom
Ivon J. M. van der Linden
Affiliation:
Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Lydia A. Afman
Affiliation:
Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Sandra G. Heil
Affiliation:
Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Henk J. Blom*
Affiliation:
Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
*
†Corresponding author: Dr Henk J. Blom, fax + 31 24 3668754, email h.blom@cukz.umcn.nl
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Neural-tube defects (NTD) are common congenital malformations that can lead to severe disability or even death. Periconceptional supplementation with the B-vitamin folic acid has been demonstrated to prevent 50–70% of NTD cases. Since the identification of the first genetic risk factor of NTD, the C677T single-nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene, and the observation that elevated plasma homocysteine levels are associated with NTD, research has focused on genetic variation in genes encoding for enzymes of folate metabolism and the closely-related homocysteine metabolism. In the present review relevant SNP in genes that code for enzymes involved in folate transport and uptake, the folate cycles and homocysteine metabolism are summarised and the importance of these SNP discussed in relation to NTD risk.

Keywords

Neural-tube defectsFolateGenetic variation
Type
Symposium on ‘Micronutrients through the life cycle’
Information
Proceedings of the Nutrition Society , Volume 65 , Issue 2 , May 2006 , pp. 204 - 215
Copyright
Copyright © The Nutrition Society 2006

References

Afman, LA Lievers, KJ Kluijtmans, LA, Trijbels, FJ Blom, HJ (2003a) Gene-gene interaction between the cystathionine beta-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C→T polymorphism on homocysteine levels and risk for neural tube defects Molecular Genetics and Metabolism 78 211–215.CrossRefGoogle Scholar
Afman, LA Lievers, KJ van der Put, NM Trijbels, FJ, Blom, HJ (2002) Single nucleotide polymorphisms in the transcobalamin gene: relationship with transcobalamin concentrations and risk for neural tube defects European Journal of Human Genetics 10 433–438.CrossRefGoogle ScholarPubMed
Afman, LA Trijbels, FJ Blom, HJ (2003b) The H475Y polymorphism in the glutamate carboxypeptidase II gene increases plasma folate without affecting the risk for neural tube defects in humans. Journal of Nutrition 133 75–77.CrossRefGoogle ScholarPubMed
Afman, LA van der Put, NM Thomas, CM, Trijbels, JM Blom, HJ (2001) Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects Quarterly Journal of Medicine 94 159–166.CrossRefGoogle ScholarPubMed
Akar, N Akar, E Deda, G Arsan, S (2000) Spina bifida and common mutations at the homocysteine metabolism pathway Clinical Genetics 57 230–231.CrossRefGoogle ScholarPubMed
Barber, RC Shaw, GM Lammer, EJ, Greer, KA Biela, TA, Lacey, SW Wasserman, CR, Finnell, RH (1998) Lack of association between mutations in the folate receptor-alpha gene and spina bifida American Journal of Medical Genetics 76 310–317.3.0.CO;2-T>CrossRefGoogle ScholarPubMed
Becerra, JE Khoury, MJ Cordero, JF Erickson, JD (1990) Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study Pediatrics 85 1–9.CrossRefGoogle ScholarPubMed
Blatter, BM Roelevelo, N Zielhuis, GA Mullaart, RA Gabreels, FJ (1996) Spina bifida and parental occupation Epidemiology 7 188–193.CrossRefGoogle ScholarPubMed
Botto, LD Yang, Q (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review American Journal of Epidemiology 151 862–877.CrossRefGoogle ScholarPubMed
Brody, LC Conley, M Cox, C, Kirke, PN McKeever, MP Mills, JL Molloy, AM, O'Leary, VB Parle-McDermott, A Scott, JM Swanson, DA (2002) A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group American Journal of Human Genetics 71 1207–1215.CrossRefGoogle ScholarPubMed
Brown, KS Kluijtmans, LA Young, IS, McNulty, H Mitchell, LE Yarnell, JW et al. (2004) The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects Human Genetics 114 182–185.CrossRefGoogle Scholar
Buccimazza, SS Molteno, CD Dunne, TT Viljoen, DL (1994) Prevalence of neural tube defects in Cape Town, South Africa Teratology 50 194–199.CrossRefGoogle ScholarPubMed
Chandler, CJ Harrison, DA Buffington, CA, Santiago, NA Halsted, CH (1991) Functional specificity of jejunal brush-border pteroylpolyglutamate hydrolase in pig American Journal of Physiology 260 G865–G872.Google ScholarPubMed
Chango, A Emery-Fillon, N de Courcy, GP Lambert, D Pfister, M, Rosenblatt, DS Nicolas, JP (2000) A polymorphism (80G→A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia Molecular Genetics and Metabolism 70 310–315.CrossRefGoogle Scholar
Chatkupt, S Skurnick, JH Jaggi, M Mitruka, K, Koenigsberger, MR Johnson, WG (1994) Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the United States in the 1990s Neurology 44 65–70.CrossRefGoogle ScholarPubMed
Chen, J Stampfer, MJ Ma, J Selhub, J, Malinow, MR Hennekens, CH Hunter, DJ (2001) Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction Atherosclerosis 154 667–672.CrossRefGoogle ScholarPubMed
Christensen, B Arbour, L Tran, P, Leclerc, D Sabbaghian, N, Platt, R Gilfix, BM Rosenblatt, DS, Gravel, RA Forbes, P Rozen, R (1999) Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects American Journal of Medical Genetics 84 151–157.3.0.CO;2-T>CrossRefGoogle ScholarPubMed
Cunha, AL Hirata, MH Kim, CA, Guerra-Shinohara, EM Nonoyama, K Hirata, RD (2002) Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects Clinica Chimica Acta 318 139–143.CrossRefGoogle ScholarPubMed
Czeizel, AE Dudas, I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation New England Journal of Medicine 327 1832–1835.CrossRefGoogle ScholarPubMed
De Marco, P Calevo, MG Moroni, A Arata, L, Merello, E Finnell, RH Zhu, H Andreussi, L, Cama, A Capra, V (2002) Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. Journal of Human Genetics 47 319–324.CrossRefGoogle ScholarPubMed
De Marco, P Calevo, MG Moroni, A Merello, E, Raso, A Finnell, RH Zhu, H Andreussi, L, Cama, A Capra, V (2003) Reduced folate carrier polymorphism (80A→G) and neural tube defects European Journal of Human Genetics 11 245–252.CrossRefGoogle Scholar
Devlin, AM Ling, EH Peerson, JM, Fernando, S Clarke, R, Smith, AD Halsted, CH (2000) Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia Human Molecular Genetics 9 2837–2844.CrossRefGoogle ScholarPubMed
Doolin, MT Barbaux, S McDonnell, M Hoess, K Whitehead, AS Mitchell, LE (2002) Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida American Journal of Human Genetics 71 1222–1226.CrossRefGoogle ScholarPubMed
Edwards, MJ Shiota, K Smith, MS Walsh, DA (1995) Hyperthermia and birth defects Reproductive Toxicology 9 411–425.CrossRefGoogle ScholarPubMed
Elin, RJ Winter, WE (2001) Methylmalonic acid: A test whose time has come? Archives of Pathology and Laboratory Medicine 125 824–827.CrossRefGoogle ScholarPubMed
Feix, A Winkelmayer, WC Eberle, C Sunder-Plassmann, G Fodinger, M (2004) Methionine synthase reductase MTRR 66A→G has no effect on total homocysteine, folate, and Vitamin B(12) concentrations in renal transplant patients Atherosclerosis 174 43–48.CrossRefGoogle Scholar
Fisher, MC Zeisel, SH Mar, MH Sadler, TW (2002) Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro FASEB Journal 16 619–621.CrossRefGoogle ScholarPubMed
Frosst, P Blom, HJ Milos, R Goyette, P, Sheppard, CA Matthews, RG, Boers, GJ den Heijer, M Kluijtmans, LA van den Heuvel, LP (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase Nature Genetics 10 111–113.CrossRefGoogle ScholarPubMed
Gaughan, DJ Kluijtmans, LA Barbaux, S McMaster, D Young, IS Yarnell, JW, Evans, A Whitehead, AS (2001) The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations Atherosclerosis 157 451–456.CrossRefGoogle ScholarPubMed
Gaughan, DJ Kluijtmans, LA Barbaux, S McMaster, D Young, IS Yarnell, JW, Evans, A Whitehead, AS (2002) Corrigendum to 'The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations' [ATH 157 (2001) 451–456] Atherosclerosis 167 373CrossRefGoogle Scholar
Geisel, J Hubner, U Bodis, M, Schorr, H Knapp, JP Obeid, R Herrmann, W (2003) The role of genetic factors in the development of hyperhomocysteinemia Clinical Chemistry and Laboratory Medicine 41 1427–1434.CrossRefGoogle ScholarPubMed
Gos, M Sliwerska, E Szpecht-Potocka, A (2004) Mutation incidence in folate metabolism genes and regulatory genes in Polish families with neural tube defects. Journal of Applied Genetics 45 363–368.Google ScholarPubMed
Graham, JM Jr Edwards, MJ Edwards, MJ (1998) Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans Teratology 58 209–221.3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
Gueant-Rodriguez, RM Juilliere, Y Candito, M, Adjalla, CE Gibelin, P Herbeth, B, Van, OE Gueant, JL (2005) Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population Thrombosis and Haemostasis 94 510–515.Google ScholarPubMed
Gueant-Rodriguez, RM Rendeli, C Namour, B, Venuti, L Romano, A, Anello, G et al. (2003) Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans Neuroscience Letters 344 189–192.CrossRefGoogle ScholarPubMed
Hall, JG Friedman, JM Kenna, BA, Popkin, J Jawanda, M Arnold, W (1988) Clinical, genetic, and epidemiological factors in neural tube defects American Journal of Human Genetics 43 827–837.Google ScholarPubMed
Harmon, DL Shields, DC Woodside, JV, McMaster, D Yarnell, JW Young, IS, Peng, K Shane, B, Evans, AE Whitehead, AS (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations Genetic Epidemiology 17 298–309.3.0.CO;2-V>CrossRefGoogle ScholarPubMed
Heil, SG Lievers, KJ Boers, GH, Verhoef, P den Heijer, M Trijbels, FJ Blom, HJ (2000) Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans Molecular Genetics and Metabolism 71 511–519.CrossRefGoogle ScholarPubMed
Heil, SG van der Put, NM Trijbels, FJ, Gabreels, FJ Blom, HJ (1999) Molecular genetic analysis of human folate receptors in neural tube defects European Journal of Human Genetics 7 393–396.CrossRefGoogle ScholarPubMed
Heil, SG van der Put, NM Waas, ET, den Heijer, M Trijbels, FJ Blom, HJ (2001) Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Molecular Genetics and Metabolism 73 164–172.CrossRefGoogle ScholarPubMed
Hol, FA van der Put, NM Geurds, MP, Heil, SG Trijbels, FJ, Hamel, BC Mariman, EC Blom, HJ (1998) Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects Clinical Genetics 53 119–125.CrossRefGoogle ScholarPubMed
Horie, N Aiba, H Oguro, K, Hojo, H Takeishi, K (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase Cell Structure and Function 20 191–197.CrossRefGoogle ScholarPubMed
Hum, DW Bell, AW Rozen, R MacKenzie, RE (1988) Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. Journal of Biological Chemistry 263 15946–15950.CrossRefGoogle ScholarPubMed
Jacques, PF Bostom, AG Selhub, J Rich, S, Curtis, ER Eckfeldt, JH, Gravel, RA Rozen, R (2003) Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study Atherosclerosis 166 49–55.CrossRefGoogle ScholarPubMed
Johnson, WG Stenroos, ES Spychala, JR, Chatkupt, S Ming, SX Buyske, S (2004) New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy? American Journal of Medical Genetics 124A 339–345.CrossRefGoogle Scholar
Kamen, BA Smith, AK (2004) A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro Advance Drug Delivery Reviews 56 1085–1097.CrossRefGoogle ScholarPubMed
Kaneda, S Takeishi, K Ayusawa, D, Shimizu, K Seno, T, Altman, S (1987) Role in translation of a triple tandemly repeated sequence in the 5'-untranslated region of human thymidylate synthase mRNA Nucleic Acids Research 15 1259–1270.CrossRefGoogle ScholarPubMed
Kealey, C Brown, KS Woodside, JV, Young, I Murray, L, Boreham, CA McNulty, H Strain, JJ McPartlin, J Scott, JM Whitehead, AS (2005) A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations Human Genetics 116 347–353.CrossRefGoogle ScholarPubMed
Klerk, M Lievers, KJ Kluijtmans, LA, Blom, HJ Den, HM, Schouten, EG Kok, FJ Verhoef, P (2003) The 2756A→G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study Thrombosis Research 110 87–91.CrossRefGoogle Scholar
Kluijtmans, LA Young, IS Boreham, CA, Murray, L McMaster, D McNulty, H Strain, JJ McPartlin, J Scott, JM Whitehead, AS (2003) Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults Blood 101 2483–2488.CrossRefGoogle ScholarPubMed
Koch, MC Stegmann, K Ziegler, A, Schroter, B Ermert, A (1998) Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population European Journal of Pediatrics 157 487–492.CrossRefGoogle Scholar
Kraus, JP Oliveriusova, J Sokolova, J, Kraus, E Vlcek, C, de Franchis, R et al. (1998) The human cystathionine beta-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms Genomics 52 312–324.CrossRefGoogle ScholarPubMed
Lammer, EJ Sever, LE Oakley, GP Jr (1987) Teratogen update: valproic acid Teratology 35 465–473.CrossRefGoogle ScholarPubMed
Li, N Sood, GK Seetharam, S Seetharam, B (1994) Polymorphism of human transcobalamin II: substitution of proline and/or glutamine residues by arginine Biochimica et Biophysica Acta 1219 515–520.CrossRefGoogle ScholarPubMed
Lievers, KJ Kluijtmans, LA Boers, GH, Verhoef, P Den, HM Trijbels, FJ Blom, HJ (2002) Influence of a glutamate carboxypeptidase II (GCPII) polymorphism (1561C→T) on plasma homocysteine, folate and vitamin B(12) levels and its relationship to cardiovascular disease risk Atherosclerosis 164 269–273.CrossRefGoogle Scholar
Lievers, KJ Kluijtmans, LA Heil, SG, Boers, GH Verhoef, P van Oppenraay-Emmerzaal, D Den, HM Trijbels, FJ Blom, HJ (2001) A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels European Journal of Human Genetics 9 583–589.CrossRefGoogle ScholarPubMed
Lucock, M Daskalakis, I Briggs, D, Yates, Z Levene, M (2000) Altered folate metabolism and disposition in mothers affected by a spina bifida pregnancy: influence of 677c→t methylenetetrahydrofolate reductase and 2756a→g methionine synthase genotypes Molecular Genetics and Metabolism 70 27–44.CrossRefGoogle ScholarPubMed
Lucock, M Daskalakis, I Hinkins, M Yates, Z (2001) An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy Molecular Genetics and Metabolism 73 322–332.CrossRefGoogle ScholarPubMed
Miller, JW Ramos, MI Garrod, MG, Flynn, MA Green, R (2002) Transcobalamin II 775G→C polymorphism and indices of vitamin B12 status in healthy older adults Blood 100 718–720.CrossRefGoogle ScholarPubMed
Morin, I Devlin, AM Leclerc, D Sabbaghian, N, Halsted, CH Finnell, R Rozen, R (2003a) Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk Molecular Genetics and Metabolism 79 197–200.CrossRefGoogle ScholarPubMed
Morin, I Platt, R Weisberg, I, Sabbaghian, N Wu, Q, Garrow, TA Rozen, R (2003b) Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida American Journal of Medical Genetics 119A 172–176CrossRefGoogle ScholarPubMed
Mornet, E Muller, F Lenvoise-Furet, A Delezoide, AL Col, JY, Simon-Bouy, B Serre, JL (1997) Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects Human Genetics 100 512–514.CrossRefGoogle ScholarPubMed
Morrison, K Papapetrou, C Hol, FA Mariman, EC, Lynch, SA Burn, J Edwards, YH (1998) Susceptibility to spina bifida; an association study of five candidate genes Annals of Human Genetics 62 379–396.CrossRefGoogle ScholarPubMed
Nilsson, TK Borjel, AK (2004) Novel insertion and deletion mutations in the 5'-UTR of the folate receptor-alpha gene: an additional contributor to hyperhomocysteinemia? Clinical Biochemistry 37 224–229.CrossRefGoogle ScholarPubMed
O'Leary, VB Mills, JL Kirke, PN, Parle-McDermott, A Swanson, DA Weiler, A et al. (2003) Analysis of the human folate receptor beta gene for an association with neural tube defects Molecular Genetics and Metabolism 79 129–133.CrossRefGoogle ScholarPubMed
O'Leary, VB Mills, JL Pangilinan, F Kirke, PN Cox, C Conley, M et al. (2005) Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association Molecular Genetics and Metabolism 85 220–227.CrossRefGoogle ScholarPubMed
Olteanu, H Munson, T Banerjee, R (2002) Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase Biochemistry 41 13378–13385.CrossRefGoogle ScholarPubMed
Olteanu, H Wolthers, KR Munro, AW, Scrutton, NS Banerjee, R (2004) Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase Biochemistry 43 1988–1997.CrossRefGoogle ScholarPubMed
Park, EI Garrow, TA (1999) Interaction between dietary methionine and methyl donor intake on rat liver betaine-homocysteine methyltransferase gene expression and organization of the human gene. Journal of Biological Chemistry 274 7816–7824.CrossRefGoogle ScholarPubMed
Parle-McDermott, A Mills, JL Kirke, PN, O'Leary, VB Swanson, DA, Pangilinan, F Conley, M, Molloy, AM Cox, C Scott, JM Brody, LC (2003) Analysis of the MTHFR 1298A→C and 677C→T polymorphisms as risk factors for neural tube defects. Journal of Human Genetics 48 190–193.CrossRefGoogle Scholar
Pei, L Zhu, H Ren, A, Li, Z Hao, L, Finnell, RH Li, Z (2005) Reduced folate carrier gene is a risk factor for neural tube defects in a Chinese population Birth Defects Research 73A 430–433CrossRefGoogle Scholar
Piedrahita, JA Oetama, B Bennett, GD van Waes, J Kamen, BA Richardson, J Lacey, SW Anderson, RG Finnell, RH (1999) Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development Nature Genetics 23 228–232.CrossRefGoogle ScholarPubMed
Pietrzyk, JJ Bik-Multanowski, M (2003) 776C→G polymorphism of the transcobalamin II gene as a risk factor for spina bifida Molecular Genetics and Metabolism 80 364CrossRefGoogle Scholar
Pietrzyk, JJ Bik-Multanowski, M Sanak, M, Twardowska, M (2003) Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida. Journal of Applied Genetics 44 111–113.Google ScholarPubMed
Quere, I Paul, V Rouillac, C, Janbon, C London, J, Demaille, J Kamoun, P, Dufier, JL Abitbol, M Chasse, JF (1999) Spatial and temporal expression of the cystathionine beta-synthase gene during early human development Biochemical and Biophysical Research Communications 254 127–137.CrossRefGoogle ScholarPubMed
Ramsbottom, D Scott, JM Molloy, A Weir, DG Kirke, PN, Mills, JL Gallagher, PM, Whitehead, AS (1997) Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects Clinical Genetics 51 39–42.CrossRefGoogle ScholarPubMed
Relton, CL Wilding, CS Jonas, PA, Lynch, SA Tawn, EJ, Burn, J (2003) Genetic susceptibility to neural tube defect pregnancy varies with offspring phenotype Clinical Genetics 64 424–428.CrossRefGoogle ScholarPubMed
Relton, CL Wilding, CS Laffling, AJ, Jonas, PA Burgess, T Binks, K, Janet, TE Burn, J (2004a) Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy Molecular Genetics and Metabolism 81 273–281.CrossRefGoogle ScholarPubMed
Relton, CL Wilding, CS Pearce, MS, Laffling, AJ Jonas, PA, Lynch, SA Tawn, EJ, Burn, J (2004b) Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. Journal of Medical Genetics 41 256–260.CrossRefGoogle Scholar
Richter, B Stegmann, K Roper, B, Boddeker, I Ngo, ET Koch, MC (2001) Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population. Journal of Human Genetics 46 105–109.CrossRefGoogle Scholar
Rothenberg, SP da Costa, MP Sequeira, JM, Cracco, J Roberts, JL Weedon, J Quadros, EV (2004) Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect New England Journal of Medicine 350 134–142.CrossRefGoogle ScholarPubMed
Shaw, GM Lammer, EJ Zhu, H Baker, MW Neri, E Finnell, RH (2002) Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida American Journal of Medical Genetics 108 1–6.CrossRefGoogle ScholarPubMed
Shaw, GM Velie, EM Schaffer, D (1996) Risk of neural tube defect-affected pregnancies among obese women. Journal of the American Medical Association 275 1093–1096.CrossRefGoogle ScholarPubMed
Smithells, RW Sheppard, S Schorah, CJ Seller, MJ, Nevin, NC Harris, R Read, AP Fielding, DW (1980) Possible prevention of neural-tube defects by periconceptional vitamin supplementation Lancet i 339–340.CrossRefGoogle Scholar
Speer, MC Nye, J McLone, D Worley, G Melvin, EC Viles, KD, Franklin, A Drake, C, Mackey, J George, TM (1999) Possible interaction of genotypes at cystathionine beta-synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects. NTD Collaborative Group Clinical Genetics 56 142–144.CrossRefGoogle ScholarPubMed
Speer, MC Worley, G Mackey, JF Melvin, E Oakes, WJ George, TM (1997) The thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) is not a major risk factor for neural tube defect in American Caucasians. The NTD Collaborative Group Neurogenetics 1 149–150.CrossRefGoogle ScholarPubMed
Stegmann, K Ziegler, A Ngo, ET Kohlschmidt, N Schroter, B, Ermert, A Koch, MC (1999) Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects (NTD) American Journal of Medical Genetics 87 23–29.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Stover, PJ Chen, LH Suh, JR, Stover, DM Keyomarsi, K Shane, B (1997) Molecular cloning, characterization, and regulation of the human mitochondrial serine hydroxymethyltransferase gene. Journal of Biological Chemistry 272 1842–1848.CrossRefGoogle ScholarPubMed
Swanson, DA Pangilinan, F Mills, JL Kirke, PN, Conley, M Weiler, A et al. (2005) Evaluation of transcobalamin II polymorphisms as neural tube defect risk factors in an Irish population Birth Defects Research 73A 239–244CrossRefGoogle Scholar
Tamura, T Stokstad, EL (1973) The availability of food folate in man British Journal of Haematology 25 513–532.CrossRefGoogle ScholarPubMed
Trinh, BN Ong, CN Coetzee, GA, Yu, MC Laird, PW (2002) Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels Human Genetics 111 299–302.CrossRefGoogle ScholarPubMed
Tsai, MY Bignell, M Yang, F, Welge, BG Graham, KJ, Hanson, NQ (2000) Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels Atherosclerosis 149 131–137.CrossRefGoogle Scholar
Ulrich, CM Bigler, J Velicer, CM Greene, EA, Farin, FM Potter, JD (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene Cancer Epidemiology Biomarkers & Prevention 9 1381–1385.Google ScholarPubMed
van der Put, NM Eskes, TK, Blom, HJ (1997a) Is the common 677C→T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis Quarterly Journal of Medicine 90 111–115.CrossRefGoogle Scholar
van der Put, NM Gabreels, F Stevens, EM Smeitink, JA, Trijbels, FJ Eskes, TK, van den Heuvel, LP Blom, HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? American Journal of Human Genetics 62 1044–1051.CrossRefGoogle ScholarPubMed
van der Put, NM Steegers-Theunissen, RP Frosst, P Trijbels, FJ Eskes, TK, van den Heuvel, LP Mariman, EC, den Heyer, M Rozen, R, Blom, HJ (1995) Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida? Lancet 346 1070–1071.CrossRefGoogle ScholarPubMed
van der Put, NM van der Molen, EF Kluijtmans, LA, Heil, SG Trijbels, JM, Eskes, TK Van Oppenraaij-Emmerzaal, D Banerjee, R, Blom, HJ (1997b) Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease Quarterly Journal of Medicine 90 511–517.CrossRefGoogle ScholarPubMed
Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group Lancet 338 131–137.CrossRefGoogle Scholar
Volcik, KA Blanton, SH Tyerman, GH, Jong, ST Rott, EJ, Page, TZ Romaine, NK, Northrup, H (2000) Methylenetetrahydrofolate reductase and spina bifida: evaluation of level of defect and maternal genotypic risk in Hispanics American Journal of Medical Genetics 95 21–27.3.0.CO;2-M>CrossRefGoogle ScholarPubMed
Volcik, KA Shaw, GM Zhu, H Lammer, EJ Laurent, C Finnell, RH (2003) Associations between polymorphisms within the thymidylate synthase gene and spina bifida Birth Defects Research 67A 924–928CrossRefGoogle Scholar
von Castel-Dunwoody, KM Kauwell, GP, Shelnutt, KP Vaughn, JD, Griffin, ER Maneval, DR, Theriaque, DW Bailey, LB (2005) Transcobalamin 776C→G polymorphism negatively affects vitamin B-12 metabolism American Journal of Clinical Nutrition 81 1436–1441.CrossRefGoogle Scholar
Wang, X Shen, F Freisheim, JH Gentry, LE, Ratnam, M (1992) Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and antifolates Biochemical Pharmacology 44 1898–1901.Google ScholarPubMed
Watkins, ML Scanlon, KS Mulinare, J Khoury, MJ (1996) Is maternal obesity a risk factor for anencephaly and spina bifida Epidemiology 7 507–512.CrossRefGoogle ScholarPubMed
Weisberg, I Tran, P Christensen, B, Sibani, S Rozen, R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity Molecular Genetics and Metabolism 64 169–172.CrossRefGoogle ScholarPubMed
Weisberg, IS Park, E Ballman, KV Berger, P Nunn, M, Suh, DS Breksa, AP III Garrow, TA Rozen, R (2003) Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease Atherosclerosis 167 205–214.CrossRefGoogle ScholarPubMed
Werler, MM Louik, C Shapiro, S, Mitchell, AA (1996) Prepregnant weight in relation to risk of neural tube defects? Journal of the American Medical Association 275 1089–1092.CrossRefGoogle ScholarPubMed
Wilding, CS Relton, CL Sutton, MJ, Jonas, PA Lynch, SA, Tawn, EJ Burn, J (2004) Thymidylate synthase repeat polymorphisms and risk of neural tube defects in a population from the northern United Kingdom Birth Defects Research 70A 483–485CrossRefGoogle Scholar
Wilson, A Platt, R Wu, Q, Leclerc, D Christensen, B, Yang, H Gravel, RA Rozen, R (1999) A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida Molecular Genetics and Metabolism 67 317–323.CrossRefGoogle ScholarPubMed
Winkelmayer, WC Skoupy, S Eberle, C, Fodinger, M Sunder-Plassmann, G (2004) Effects of TCN2 776C→G on vitamin B, folate, and total homocysteine levels in kidney transplant patients Kidney International 65 1877–1881.CrossRefGoogle ScholarPubMed
Yang, F Hanson, NQ Schwichtenberg, K Tsai, MY (2000) Variable number tandem repeat in exon/intron border of the cystathionine beta-synthase gene: a single nucleotide substitution in the second repeat prevents multiple alternate splicing American Journal of Medical Genetics 95 385–390.3.0.CO;2-V>CrossRefGoogle ScholarPubMed
Zhu, H Curry, S Wen, S, Wicker, NJ Shaw, GM, Lammer, EJ Yang, W Jafarov, T, Finnell, RH (2005) Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? American Journal of Medical Genetics 35A 274–277CrossRefGoogle Scholar
Zhu, H Wicker, NJ Shaw, GM, Lammer, EJ Hendricks, K Suarez, L, Canfield, M Finnell, RH (2003) Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects Molecular Genetics and Metabolism 78 216–221.CrossRefGoogle ScholarPubMed