Folate-mediated 1-carbon metabolism is a network of interconnected metabolic pathways necessary for the synthesis of purine nucleotides, thymidylate and the remethylation of homocysteine to methionine. Disruptions in this pathway influence both DNA synthesis and stability and chromatin methylation, and result from nutritional deficiencies and common gene variants. The mechanisms underlying folate-associated pathologies and developmental anomalies have yet to be established. This review focuses on the relationships among folate-mediated 1-carbon metabolism, chromatin methylation and human disease, and the role of gene-nutrient interactions in modifying epigenetic processes.

1.
Bird A: Perceptions of epigenetics. Nature 2007;447:396–398.
2.
Ptashne M: On the use of the word ‘epigenetic’. Curr Biol 2007;17:R233–R236.
3.
Reik W, Walter J: Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001;2:21–32.
4.
Koerner MV, Barlow DP: Genomic imprinting – an epigenetic gene-regulatory model. Curr Opin Genet Dev 2010;20:164–170.
5.
Kim KC, Friso S, Choi SW: DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging. J Nutr Biochem 2009;20:917–926.
6.
Waterland RA, Garza C: Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 1999;69:179–197.
7.
Feil R: Epigenetics: ready for the marks. Nature 2009;461:359–360.
8.
Mosammaparast N, Shi Y: Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem 2010;79:155–179.
9.
Ciccone DN, Su H, Hevi S, Gay F, Lei H, et al: KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 2009;461:415–418.
10.
Skinner MK: Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics 2011;6:838–842.
11.
Loenen WA: S-adenosylmethionine: jack of all trades and master of everything? Biochem Soc Trans 2006;34:330–333.
12.
Luka Z, Mudd SH, Wagner C: Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J Biol Chem 2009;284:22507–22511.
13.
Fox JT, Stover PJ: Folate-mediated one-carbon metabolism. Vitam Horm 2008;79:1–44.
14.
Stover PJ, Caudill MA: Genetic and epigenetic contributions to human nutrition and health: managing genome-diet interactions. J Am Diet Assoc 2008;108:1480–1487.
15.
Yang Q, Cogswell ME, Hamner HC, Carriquiry A, Bailey LB, et al: Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003–2006. Am J Clin Nutr 2009;91:64–72.
16.
Appling DR: Compartmentation of folate-mediated one-carbon metabolism in eukaryotes. FASEB J 1991;5:2645–2651.
17.
Herbig K, Chiang EP, Lee LR, Hills J, Shane B, et al: Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J Biol Chem 2002;277:38381–38389.
18.
Davis SR, Stacpoole PW, Williamson J, Kick LS, Quinlivan EP, et al: Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. Am J Physiol Endocrinol Metab 2004;286:E272–E279.
19.
Anderson DD, Stover PJ: SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS One 2009;4:e5839.
20.
Martinov MV, Vitvitsky VM, Banerjee R, Ataullakhanov FI: The logic of the hepatic methionine metabolic cycle. Biochim Biophys Acta 2010;1804:89–96.
21.
Miranda TB, Jones PA: DNA methylation: the nuts and bolts of repression. J Cell Physiol 2007;213:384–390.
22.
Winter-Vann AM, Kamen BA, Bergo MO, Young SG, Melnyk S, et al: Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci USA 2003;100:6529–6534.
23.
Stead LM, Jacobs RL, Brosnan ME, Brosnan JT: Methylation demand and homocysteine metabolism. Adv Enzyme Regul 2004;44:321–333.
24.
Stover PJ: Physiology of folate and vitamin B12 in health and disease. Nutr Rev 2004;62:S3–S12, discussion S13.
25.
Linhart HG, Troen A, Bell GW, Cantu E, Chao WH, et al: Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase DNA point mutations. Gastroenterology 2009;136:227.e3–235.e3.
26.
Baik HW, Russell RM: Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999;19:357–377.
27.
Hoey L, Strain JJ, McNulty H: Studies of biomarker responses to intervention with vitamin B-12: a systematic review of randomized controlled trials. Am J Clin Nutr 2009;89:1981S–1996S.
28.
Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G: The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Food Nutr Bull 2008;29:S67–S73.
29.
van der Put NM, Blom HJ: Neural tube defects and a disturbed folate dependent homocysteine metabolism. Eur J Obstet Gynecol Reprod Biol 2000;92:57–61.
30.
Scott JM: Evidence of folic acid and folate in the prevention of neural tube defects. Bibl Nutr Dieta 2001;192–195.
31.
Ueland PM, Refsum H, Beresford SA, Vollset SE: The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000;72:324–332.
32.
Gerhard GT, Duell PB: Homocysteine and atherosclerosis. Curr Opin Lipidol 1999;10:417–428.
33.
Lindenbaum J, Allen RH: Clinical spectrum and diagnosis of folate deficiency; in: Bailey LB (ed): Folate in Health and Disease. New York,l Dekker, 1995.
34.
Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, et al: Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 1997;94:3290–3295.
35.
Ames BN: DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res 2001;475:7–20.
36.
Choi SW, Mason JB: Folate and carcinogenesis: an integrated scheme. J Nutr 2000;130:129–132.
37.
Pogribny IP, Basnakian AG, Miller BJ, Lopatina NG, Poirier LA, et al: Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 1995;55:1894–1901.
38.
Kim YI: Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev 1999;57:314–321.
39.
Kerr MA, Livingstone B, Bates CJ, Bradbury I, Scott JM, et al: Folate, related B vitamins, and homocysteine in childhood and adolescence: potential implications for disease risk in later life. Pediatrics 2009;123:627–635.
40.
Refsum H, Ueland PM, Nygard O, Vollset SE: Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62.
41.
Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, et al: Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995;345:149–151.
42.
Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, et al: Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449–1455.
43.
Bailey LB: Folate requirements and dietary recommendations; in Bailey LB (ed): Folate in Health and Disease. New York, Dekker, 1995.
44.
McNulty H: Folate requirements for health in different population groups. Br J Biomed Sci 1995;52:110–119.
45.
Scott JM: How does folic acid prevent neural tube defects? Nat Med 1998;4:895–896.
46.
Finkelstein JD: Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine. Clin Chem Lab Med 2007;45:1694–1699.
47.
Jhaveri MS, Wagner C, Trepel JB: Impact of extracellular folate levels on global gene expression. Mol Pharmacol 2001;60:1288–1295.
48.
Waterland RA, Jirtle RL: Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 2004;20:63–68.
49.
Satta R, Maloku E, Zhubi A, Pibiri F, Hajos M, et al: Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. Proc Natl Acad Sci USA 2008;105:16356–16361.
50.
Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, et al: Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 2000;275:29318–29323.
51.
Caudill MA, Wang JC, Melnyk S, Pogribny IP, Jernigan S, et al: Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine beta-synthase heterozygous mice. J Nutr 2001;131:2811–2818.
52.
Jamaluddin MD, Chen I, Yang F, Jiang X, Jan M, et al: Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene. Blood 2007;110:3648–3655.
53.
Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, et al: Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 2003;361:1693–1699.
54.
Dobosy JR, Fu VX, Desotelle JA, Srinivasan R, Kenowski ML, et al: A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate. Prostate 2008;68:1187–1195.
55.
Jin M, Kawakami K, Fukui Y, Tsukioka S, Oda M, et al: Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels. Cancer Sci 2009;100:2325–2330.
56.
Brunaud L, Alberto JM, Ayav A, Gerard P, Namour F, et al: Vitamin B12 is a strong determinant of low methionine synthase activity and DNA hypomethylation in gastrectomized rats. Digestion 2003;68:133–140.
57.
Figueiredo JC, Grau MV, Wallace K, Levine AJ, Shen L, et al: Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors. Cancer Epidemiol Biomarkers Prev 2009;18:1041–1049.
58.
Kim M, Trinh BN, Long TI, Oghamian S, Laird PW: Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells. Nucleic Acids Res 2004;32:5742–5749.
59.
Schwahn BC, Laryea MD, Chen Z, Melnyk S, Pogribny I, et al: Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 2004;382:831–840.
60.
Kovacheva VP, Mellott TJ, Davison JM, Wagner N, Lopez-Coviella I, et al: Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 2007;282:31777–31788.
61.
Paukert JL, Straus LD, Rabinowitz JC: Formyl-methyl-methylenetetrahydrofolate synthetase-(combined). An ovine protein with multiple catalytic activities. J Biol Chem 1976;251:5104–5111.
62.
Tan LU, Drury EJ, MacKenzie RE: Methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. A multifunctional protein from porcine liver. J Biol Chem 1977;252:1117–1122.
63.
Smith GK, Mueller WT, Benkovic PA, Benkovic SJ: On the cofactor specificity of glycinamide ribonucleotide and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase from chicken liver. Biochemistry 1981;20:1241–1245.
64.
MacFarlane AJ, Perry CA, Girnary HH, Gao D, Allen RH, et al: Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism. J Biol Chem 2009;284:1533–1539.
65.
Christensen KE, Rohlicek CV, Andelfinger GU, Michaud J, Bigras JL, et al: The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat 2009;30:212–220.
66.
Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, et al: 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. Am J Hum Genet 2002;71:1207–1215.
67.
De Marco P, Merello E, Calevo MG, Mascelli S, Raso A, et al: Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk. J Hum Genet 2006;51:98–103.
68.
Parle-McDermott A, Kirke PN, Mills JL, Molloy AM, Cox C, et al: Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet 2006;14:768–772.
69.
Furness DL, Fenech MF, Khong YT, Romero R, Dekker GA: One-carbon metabolism enzyme polymorphisms and uteroplacental insufficiency. Am J Obstet Gynecol 2008;199:276.e1–276.e8.
70.
Weiner AS, Beresina OV, Voronina EN, Voropaeva EN, Boyarskih UA, et al: Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin’s lymphoma. Leuk Res 2011;35:508–515.
71.
Parle-McDermott A, Mills JL, Kirke PN, Cox C, Signore CC, et al: MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae. Am J Med Genet A 2005;132:365–368.
72.
Parle-McDermott A, Pangilinan F, Mills JL, Signore CC, Molloy AM, et al: A polymorphism in the MTHFD1 gene increases a mother’s risk of having an unexplained second trimester pregnancy loss. Mol Hum Reprod 2005;11:477–480.
73.
Mills JL, Molloy AM, Parle-McDermott A, Troendle JF, Brody LC, et al: Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate. Birth Defects Res A Clin Mol Teratol 2008;82:636–643.
74.
Palmieri A, Masiero E, Martinelli M, Scapoli L, Pezzetti F, et al: The MTHFD1 gene is not involved in cleft lip with or without palate onset among the Italian population. Ann Hum Genet 2008;72:297–299.
75.
Stevens VL, McCullough ML, Pavluck AL, Talbot JT, Feigelson HS, et al: Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers Prev 2007;16:1140–1147.
76.
Donato H, Krupenko NI, Tsybovsky Y, Krupenko SA: 10-Formyltetrahydrofolate dehydrogenase requires a 4′-phosphopantetheine prosthetic group for catalysis. J Biol Chem 2007;282:34159–34166.
77.
Cook RJ, Lloyd RS, Wagner C: Isolation and characterization of cDNA clones for rat liver 10-formyltetrahydrofolate dehydrogenase. J Biol Chem 1991;266:4965–4973.
78.
Anguera MC, Field MS, Perry C, Ghandour H, Chiang EP, et al: Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase. J Biol Chem 2006;281:18335–18342.
79.
Oleinik NV, Krupenko NI, Krupenko SA: Epigenetic silencing of ALDH1L1, a metabolic regulator of cellular proliferation, in cancers. Genes Cancer 2011;2:130–139.
80.
Wagner C: Biochemical role of folate in cellular metabolism; in Bailey LB (ed): Folate in Health and Disease. New York, Dekker, 1995, pp 23–42.
81.
Jencks DA, Mathews RG: Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine. Effects of adenosylmethionine and NADPH on the equilibrium between active and inactive forms of the enzyme and on the kinetics of approach to equilibrium. J Biol Chem 1987;262:2485–2493.
82.
Gaughan DJ, Barbaux S, Kluijtmans LA, Whitehead AS: The human and mouse methylenetetrahydrofolate reductase (MTHFR) genes: genomic organization, mRNA structure and linkage to the CLCN6 gene. Gene 2000;257:279–289.
83.
Pejchal R, Campbell E, Guenther BD, Lennon BW, Matthews RG, et al: Structural perturbations in the Ala → Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation. Biochemistry 2006;45:4808–4818.
84.
Goyette P, Rozen R: The thermolabile variant 677C→T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase. Hum Mutat 2000;16:132–138.
85.
Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, et al: The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol 1999;6:359–365.
86.
Yamada K, Chen Z, Rozen R, Matthews RG: Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci USA 2001;98:14853–14858.
87.
Kang SS, Wong PW, Zhou JM, Sora J, Lessick M, et al: Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 1988;37:611–613.
88.
Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, et al: Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7–9.
89.
Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, et al: Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 1997;349:1591–1593.
90.
Parle-McDermott A, Mills JL, Molloy AM, Carroll N, Kirke PN, et al: The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels. Mol Genet Metab 2006;88:290–294.
91.
Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, et al: A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 2002;99:5606–5611.
92.
Oyama K, Kawakami K, Maeda K, Ishiguro K, Watanabe G: The association between methylenetetrahydrofolate reductase polymorphism and promoter methylation in proximal colon cancer. Anticancer Res 2004;24:649–654.
93.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, et al: MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023–2031.
94.
Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, et al: Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996;58:35–41.
95.
Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, et al: Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 1997;95:2032–2036.
96.
Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, et al: Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet 1999;84:151–157.
97.
Ou CY, Stevenson RE, Brown VK, Schwartz CE, Allen WP, et al: 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. Am J Med Genet 1996;63:610–614.
98.
van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, et al: Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346:1070–1071.
99.
Zhu J, Ren A, Hao L, Pei L, Liu J, et al: Variable contribution of the MTHFR C677T polymorphism to non-syndromic cleft lip and palate risk in China. Am J Med Genet A 2006;140:551–557.
100.
Keijzer MB, den Heijer M, Blom HJ, Bos GM, Willems HP, et al: Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002;88:723–728.
101.
Quere I, Perneger TV, Zittoun J, Bellet H, Gris JC, et al: Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet 2002;359:747–752.
102.
Zalavras ChG, Giotopoulou S, Dokou E, Mitsis M, Ioannou HV, et al: Lack of association between the C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene and venous thromboembolism in Northwestern Greece. Int Angiol 2002;21:268–271.
103.
Lewis SJ, Zammit S, Gunnell D, Smith GD: A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. Am J Med Genet B Neuropsychiatr Genet 2005;135:2–4.
104.
Muntjewerff JW, Hoogendoorn ML, Kahn RS, Sinke RJ, Den Heijer M, et al: Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study. Am J Med Genet B Neuropsychiatr Genet 2005;135:69–72.
105.
Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M: Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry 2006;11:143–149.
106.
Scher AI, Terwindt GM, Verschuren WM, Kruit MC, Blom HJ, et al: Migraine and MTHFR C677T genotype in a population-based sample. Ann Neurol 2006;59:372–375.
107.
Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, et al: Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 1999;96:12810–12815.
108.
Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, et al: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci USA 2001;98:4004–4009.
109.
Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, et al: A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 1996;56:4862–4864.
110.
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, et al: Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997;57:1098–1102.
111.
Stegmann K, Ziegler A, Ngo ET, Kohlschmidt N, Schroter B, et al: Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects (NTD). Am J Med Genet 1999;87:23–29.
112.
Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, et al: Targeted disruption of the methionine synthase gene in mice. Mol Cell Biol 2001;21:1058–1065.
113.
Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, et al: Human methionine synthase. cDNA cloning, gene localization, and expression. J Biol Chem 1997;272:3628–3634.
114.
Gulati S, Brody LC, Banerjee R: Posttranscriptional regulation of mammalian methionine synthase by B12. Biochem Biophys Res Commun 1999;259:436–442.
115.
Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, et al: Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet 1996;5:1867–1874.
116.
Harmon DL, Shields DC, Woodside JV, McMaster D, Yarnell JW, et al: Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol 1999;17:298–309.
117.
Paz MF, Avila S, Fraga MF, Pollan M, Capella G, et al: Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 2002;62:4519–4524.
118.
Burzynski M, Duriagin S, Mostowska M, Wudarski M, Chwalinska-Sadowska H, et al: MTR 2756 A>G polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population. Lupus 2007;16:450–454.
119.
Kempisty B, Sikora J, Lianeri M, Szczepankiewicz A, Czerski P, et al: MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatr Genet 2007;17:177–181.
120.
Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, et al: Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet 2002;71:1222–1226.
121.
Mostowska A, Hozyasz KK, Jagodzinski PP: Maternal MTR genotype contributes to the risk of non-syndromic cleft lip and palate in the Polish population. Clin Genet 2006;69:512–517.
122.
Blanton SH, Henry RR, Yuan Q, Mulliken JB, Stal S, et al: Folate pathway and nonsyndromic cleft lip and palate. Birth Defects Res A Clin Mol Teratol 2011;91:50–60.
123.
Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, et al: Methionine synthase (MTR) 2756 (A→G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet A 2003;121:219–224.
124.
de Vogel S, Wouters KA, Gottschalk RW, van Schooten FJ, de Goeij AF, et al: Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer. Cancer Epidemiol Biomarkers Prev 2009;18:3086–3096.
125.
Luka Z, Capdevila A, Mato JM, Wagner C: A glycine N-methyltransferase knockout mouse model for humans with deficiency of this enzyme. Transgenic Res 2006;15:393–397.
126.
Nieman KM, Rowling MJ, Garrow TA, Schalinske KL: Modulation of methyl group metabolism by streptozotocin-induced diabetes and all-trans-retinoic acid. J Biol Chem 2004;279:45708–45712.
127.
Rowling MJ, Schalinske KL: Retinoic acid and glucocorticoid treatment induce hepatic glycine N-methyltransferase and lower plasma homocysteine concentrations in rats and rat hepatoma cells. J Nutr 2003;133:3392–3398.
128.
Beagle B, Yang TL, Hung J, Cogger EA, Moriarty DJ, et al: The glycine N-methyltransferase (GNMT) 1289 C→T variant influences plasma total homocysteine concentrations in young women after restricting folate intake. J Nutr 2005;135:2780–2785.
129.
Dinopoulos A, Matsubara Y, Kure S: Atypical variants of nonketotic hyperglycinemia. Mol Genet Metab 2005;86:61–69.
130.
Lamers Y, Williamson J, Gilbert LR, Stacpoole PW, Gregory JF 3rd: Glycine turnover and decarboxylation rate quantified in healthy men and women using primed, constant infusions of [1,2-13C2]glycine and [2H3]leucine. J Nutr 2007;137:2647–2652.
131.
Van Hove JL, Lazeyras F, Zeisel SH, Bottiglieri T, Hyland K, et al: One-methyl group metabolism in non-ketotic hyperglycinaemia: mildly elevated cerebrospinal fluid homocysteine levels. J Inherit Metab Dis 1998;21:799–811.
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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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