A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase

Nat Genet. 1995 May;10(1):111-3. doi: 10.1038/ng0595-111.


Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Base Sequence
  • DNA, Complementary
  • Enzyme Stability
  • Escherichia coli / metabolism
  • Female
  • Homocysteine / metabolism
  • Humans
  • Kidney / metabolism
  • Liver / metabolism
  • Lymphocytes / metabolism
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation*
  • Oxidoreductases Acting on CH-NH Group Donors / deficiency*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Quebec
  • Risk Factors
  • Temperature
  • Vascular Diseases / epidemiology
  • Vascular Diseases / genetics*


  • DNA, Complementary
  • Homocysteine
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)