Genetic Modulation of Homocysteinemia

 

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ABSTRACT

With the identification of hyperhomocysteinemia as a risk factor for cardiovascular disease, an understanding of the genetic determinants of plasma homocysteine is important for prevention and treatment. It has been known for some time that homocystinuria, a rare inborn error of metabolism, can be due to genetic mutations that severely disrupt homocysteine metabolism. A more recent development is the finding that milder, but more common, genetic mutations in the same enzymes might also contribute to an elevation in plasma homocysteine. The best example of this concept is a missense mutation (alanine to valine) at base pair (bp) 677 of methylenetetrahydrofolate reductase (MTHFR), the enzyme that provides the folate derivative for conversion of homocysteine to methionine. This mutation results in mild hyperhomocysteinemia, primarily when folate levels are low, providing a rationale (folate supplementation) for overcoming the genetic deficiency.

Additional genetic variants in MTHFR and in other enzymes of homocysteine metabolism are being identified as the cDNAs/genes become isolated. These variants include a glutamate to alanine mutation (bp 1298) in MTHFR, an aspartate to glycine mutation (bp 2756) in methionine synthase, and an isoleucine to methionine mutation (bp 66) in methionine synthase reductase. These variants have been identified relatively recently; therefore additional investigations are required to determine their clinical significance with respect to mild hyperhomocysteinemia and vascular disease.

REFERENCES

• 1 Rozen R. Methylenetetrahydrofolate reductase in vascular disease, neural tube defects and colon cancer. in: Mato JM, Caballero A, eds. Proceedings of the 4th Workshop on Methionine Metabolism Madrid, Spain: Consejo Superior de Investigaciones Cientificas Publishers, 1998: 51-61
  Google Scholar
• 2 Leclerc D, Wilson A, Dumas R. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.  Proc Natl Acad Sci U S A . 1998;  95 3059-3064
  CrossrefPubMedGoogle Scholar
• 3 Garrow T A, Millian N S, Park E I. The influence of nutrition on rat liver betaine-homocysteine methyltransferase expression and preliminary characterization of recombinant human BHMT as a zinc metalloenzyme. in: Mato JM, Caballero A, eds. Proceedings of the 4th Workshop on Methionine Metabolism Madrid, Spain: Consejo Superior de Investigaciones Cientificas Publishers, 1998 : 63-76
  Google Scholar
• 4 Kraus J P, Miroslav J, Viktor K. Cystathionine β-synthase mutations in homocystinuria.  Hum Mutat . 1999;  13 362-375
  CrossrefPubMedGoogle Scholar
• 5 Leclerc D, Campeau E, Goyette P. Human methionine synthase:cDNA cloning, chromosomal localization, and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.  Hum Mol Genet . 1996;  5 1867-1874
  CrossrefPubMedGoogle Scholar
• 6 Li Y N, Gulati S, Baker P J. Cloning, mapping and RNA analysis of the human methionine synthase gene.  Hum Mol Genet . 1996;  5 1851-1858
  CrossrefPubMedGoogle Scholar
• 7 Chen L H, Liu M-L, Hwang H-Y. Human methionine synthase. cDNA cloning, gene localization and expression.  J Biol Chem . 1997;  272 3628-3634
  CrossrefPubMedGoogle Scholar
• 8 Gulati S, Baker P, Yunan L N. Defects in human methionine synthase in cblG patients.  Hum Mol Genet . 1996;  5 1859-1865
  CrossrefPubMedGoogle Scholar
• 9 Wilson A, Leclerc D, Saberi F. Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency.  Am J Hum Genet . 1998;  63 409-414
  CrossrefPubMedGoogle Scholar
• 10 Wilson A, Leclerc D, Rosenblatt D S, Gravel R A. Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism.  Hum Mol Genet . 1999;  8 2009-2016
  CrossrefPubMedGoogle Scholar
• 11 Sibani S, Christensen B, O'Ferrell E. Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria.  Human Mutation . 2000;  15 280-287
  CrossrefPubMedGoogle Scholar
• 12 Goyette P, Frosst P, Rosenblatt D S, Rozen, R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe MTHFR deficiency.  Am J Hum Genet . 1995;  56 1052-1059
  PubMedGoogle Scholar
• 13 Goyette P, Christensen B, Rosenblatt D S, Rozen R. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of 5 novel mutations in MTHFR.  Am J Hum Genet . 1996;  59 1268-1275
  PubMedGoogle Scholar
• 14 Kluijtmans L A, den Heijer J, Reitsma P H. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis.  Thromb Haemost . 1998;  79 254-258
  PubMedGoogle Scholar
• 15 Garrow T A. Purification, kinetic properties, and cDNA cloning of mammalian betaine-homocysteine methyltransferase.  J Biol Chem . 1996;  271 22831-22838
  PubMedGoogle Scholar
• 16 Rosenblatt D S. Inherited disorders of folate transport and metabolism. in: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed New York: McGraw-Hill, 1995: 3111-3128
  Google Scholar
• 17 Frosst P, Blom H J, Milos R. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase.  Nat Genet . 1995;  10 111-113
  CrossrefPubMedGoogle Scholar
• 18 Kang S-S, Wong P WK, Susmano A. Thermolabile methylenetetrahydrofolate reductase: An inherited risk factor for coronary disease.  Am J Hum Genet . 1991;  48 536-545
  PubMedGoogle Scholar
• 19 Engbersen A MT, Franken D G, Boers G HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia.  Am J Hum Genet . 1995;  56 142-150
  PubMedGoogle Scholar
• 20 Jacques P F, Bostom A G, Williams R R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation . 1996;  93 7-9
  CrossrefPubMedGoogle Scholar
• 21 Ma J, Stampfer M J, Giovannucci E. Methylenetetrahydrofolate reductase polymorphism, reduced risk of colorectal cancer and dietary interactions.  Cancer Res . 1997;  57 1098-1102
  PubMedGoogle Scholar
• 22 Chen J, Giovannucci E, Kelsey K. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer.  Cancer Res . 1996;  56 4862-4864
  PubMedGoogle Scholar
• 23 Morita H, Taguchi J-I, Kurihara H. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease.  Circulation . 1997;  95 2032-2036
  PubMedGoogle Scholar
• 24 Park K S, Podskarbi T, Yoo E A, Shin Y S. The C677T mutation in the methylenetetrahydrofolate reductase gene in Koreans.  Korean J Genet . 1998;  20 23-28
  PubMedGoogle Scholar
• 25 Cattaneo M, Tsai M Y, Bucciarelli P. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V :Q506).  Arterioscler Thromb Vasc Biol . 1997;  17 1662-1666
  PubMedGoogle Scholar
• 26 Margaglione M, D'Andrea G, d'Addedda M. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation.  Thromb Haemost . 1998;  79 907-911
  Article in Thieme ConnectPubMedGoogle Scholar
• 27 Shaw G M, Rozen R, Finnell R H, Wasserman C R, Lammer E J. Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase and risk for spina bifida.  Am J Epidemiol . 1998;  148 30-37
  PubMedGoogle Scholar
• 28 Vanegas O C, Giusti B, Fernandez C MR, Abbate R, Pepe G. Frequency of Factor V (FV) Leiden and C677T methylenetetrahydrofolate reductase (MTHFR) mutations in Colombians.  Thromb Haemost . 1998;  79 883-884
  PubMedGoogle Scholar
• 29 Harmon D L, Woodside J V, Yarnell J WG. The common ``thermolabile'' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia.  QJM . 1996;  89 571-577
  CrossrefPubMedGoogle Scholar
• 30 Guttormsen A B, Ueland P M, Nesthus I. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (>40 μmol/liter).  J Clin Invest . 1996;  98 2174-2183
  CrossrefPubMedGoogle Scholar
• 31 Malinow M R, Nieto F J, Kruger W D. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes.  Arterioscler Thromb Vasc Biol . 1997;  17 1157-1162
  CrossrefPubMedGoogle Scholar
• 32 Guenther B D, Sheppard C A, Tran P. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli: A model for the role of folate in ameliorating hyperhomocysteinemia in humans.  Nat Struct Biol . 1999;  6 359-365
  CrossrefPubMedGoogle Scholar
• 33 Balasa V V, Gruppo R A, Glueck, C J. The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults.  Thromb Haemost . 1999;  81 739-744
  PubMedGoogle Scholar
• 34 Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydofolate reductase (MTHFR) associated with decreased enzyme activity.  Mol Genet Metab . 1998;  64 169-172
  CrossrefPubMedGoogle Scholar
• 35 van der Put N MY, Gabreels F, Stevens E MB. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects?.  Am J Hum Genet . 1998;  62 1044-1051
  CrossrefPubMedGoogle Scholar
• 36 Morita H, Kurihara H, Sugiyama T. Polymorphism of the methionine synthase gene-association with homocysteine metabolism and late-onset vascular diseases in the Japanese population.  Arterioscler Thromb Vasc Biol . 1999;  19 298-302
  PubMedGoogle Scholar
• 37 Tsai M Y, Welge B G, Hanson N Q. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases.  Atherosclerosis . 1999;  143 163-170
  CrossrefPubMedGoogle Scholar
• 38 Wilson A, Platt R, Wu Q. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.  Mol Genet Metab . 1999;  67 317-323
  CrossrefPubMedGoogle Scholar
• 39 Kluijtmans L AJ, van den Heuvel L P, Boers G HJ. 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
  PubMedGoogle Scholar
• 40 Gallagher P, Meleady R, Shields D. Homocysteine and risk of coronary heart disease: Evidence for a common gene mutation.  Circulation . 1996;  94 2154-2158
  PubMedGoogle Scholar
• 41 Arruda V R, von Zuben P M, Chiaparini L C, Annichino-Bizzacchi J M, Costa F F. The mutation Ala677 → Val in the methylene - tetrahydrofolate reductase gene : A risk factor for arterial disease and venous thrombosis.  Thromb Haemost . 1997;  77 818-821
  Google Scholar
• 42 Morita H, Kurihara H, Tsubaki S. Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese.  Arterioscler Thromb Vasc Biol . 1998;  18 1465-1469
  PubMedGoogle Scholar
• 43 Ma J, Stampfer M J, Hennekens C H. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in U.S  physicians. Circulation . 1996;  94 2410-2416
  PubMedGoogle Scholar
• 44 Wilcken D EL, Wang X L, Sim A S, McCredie R M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C₆₇₇T mutation.  Arterioscler Thromb Vasc Biol . 1996;  16 878-882
  PubMedGoogle Scholar
• 45 Markus H S, Ali N, Swaminathan R. A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease.  Stroke . 1997;  28 1739-1743
  CrossrefPubMedGoogle Scholar
• 46 Fletcher O, Kessling A M. MTHFR association with arteriosclerotic vascular disease?.  Hum Genet . 1998;  103 11-21
  PubMedGoogle Scholar
• 47 Stevenson R E, Schwartz C E, Du Y Z, Adams M J. Differences in methylenetetrahydrofolate reductase genotype frequencies, between whites and blacks.  Am J Hum Genet . 1997;  60 230-233
  PubMedGoogle Scholar
• 48 Inbal A, Freimark D, Modan B. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males.  Blood . 1999;  93 2186-2190
  PubMedGoogle Scholar
• 49 Arai K, Yamasaki Y, Kajimoto Y. Association of methylenetetrahydrofolate reductase gene polymorphism with carotid arterial wall thickening and myocardial infarction risk in NIDDM.  Diabetes . 1997;  46 2102-2104
  PubMedGoogle Scholar
• 50 Nelen W LDM, Steegers E AP, Eskes T KAB, Blom H J. Genetic risk factor for unexplained recurrent early pregnancy loss.  Lancet . 1997;  350 861
  PubMedGoogle Scholar
• 51 Kupferminc M J, Eldor A, Steinman N. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
  CrossrefPubMedGoogle Scholar
• 52 Loewenstein A, Winder A, Goldstein M, Lazar M, Eldor A. Bilateral retinal vein occlusion associated with 5,10-methylenetetrahydrofolate reductase mutation.  Am J Ophthalmol . 1997;  124 840-841
  PubMedGoogle Scholar
• 53 Neugebauer S, Baba T, Kurokawa K, Watanabe T. Defective homocysteine metabolism as a risk factor for diabetic retinopathy.  Lancet . 1997;  349 473-474
  PubMedGoogle Scholar
• 54 van der Put N MJ, Eskes T KAB, Blom H J. Is the common 677C → T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects?.  <~>A meta-analysis. QJM . 1997;  90 111-115
  PubMedGoogle Scholar
• 55 Regland B, Germgard T, Gottfries C G, Grenfeldt B, Koch-Schmidt A C. Homozygous thermolabile methylenetetrahydrofolate reductase in schizophrenia-like psychosis.  J Neural Transm . 1997;  104 931-941
  PubMedGoogle Scholar
• 56 Arinami T, Yamada N, Yamakawa-Kobayashi K, Hamaguchi H, Toru M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression.  Am J Med Genet . 1997;  74 526-528
  CrossrefPubMedGoogle Scholar
• 57 Ma J, Stampfer M J, Christensen B. A polymorphism of the methionine synthase gene: Association with plasma folate, vitamin B12, homocysteine, and colorectal cancer risk.  Cancer Epidemiol Biomarkers Prev . 1999;  8 825-829
  PubMedGoogle Scholar