title: Genetic modulation of homocysteinemia.
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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal Children's Hospital, Canada. mdrr@musica.mcgill.ca
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D019943:Amino Acid Substitution; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology / Q000235:genetics; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000502:physiology; D003545:Cysteine / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006712:Homocystinuria / Q000097:blood / Q000150:complications / Q000235:genetics; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics*; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases / Q000378:metabolism; D020125:Mutation, Missense; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D017354:Point Mutation; D011110:Polymorphism, Genetic; D013455:Sulfur / Q000378:metabolism; D013763:Tetrahydrofolates / Q000097:blood
chemical_list: D013763:Tetrahydrofolates; D006710:Homocysteine; D013455:Sulfur; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases; D003541:Cystathionine beta-Synthase; D003545:Cysteine; C005984:5-methyltetrahydrofolate