Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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


Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease1–4. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism1,5–7. 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetra-hydrofolate, 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 disease5,6. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others


  1. Boers, G.H.J. et al. Heterozygosity for homocystinuria in premature peripheral and cerebral ocelusive arterial disease. New Engl. J. Mod. 313, 709–715 (1985).

    Article  CAS  Google Scholar 

  2. Genest, J.J. Jr., et al. Plasma homocysteine levels in men with premature coronary artery disease. J. Am. coll. Cartiiol. 16, 1114–1119 (1990).

    Article  Google Scholar 

  3. Clarke, R. et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. New Engl. J. Med. 324, 1149–1155 (1991).

    Article  CAS  Google Scholar 

  4. Stampfer, M.J. et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. J. Am. med. Assoc. 268, 877–881 (1992).

    Article  CAS  Google Scholar 

  5. Kang, S.-S. et al. Thermolabile methylenetetrahydrofolate reductase: An inherited risk factor for coronary artery disease. Am. J. hum. Genet. 48, 536–645 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Engbersen, A.M.T. et al. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinaemia. Am. J. hum. Genet. 56, 142–150 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Selhub, J., Jacques, P.F., Wilson, P.W.F., Rush, D. & Rosenberg, I.H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J. Am. med. Assoc. 270, 2693–2698 (1993).

    Article  CAS  Google Scholar 

  8. Rosenblatt, D.S. in The Metabolic Basis of Inherited Disease (eds Scriver, C.R., Beaudet, A.L, Sly, W.S. & Valle, D.) 2049–2064 (McGraw-Hill, New York, 1989).

    Google Scholar 

  9. Kang, S.-S., Passen, E.L., Ruggie, N., Wong, P.W.K. & Sora, H. Thermolabile defect of methytenetetrahydrofolate reductase in coronary artery disease. Circulation 88, 1463–1469 (1993).

    Article  CAS  Google Scholar 

  10. Goyette, P. et al. Human methylenetetrahydrofolate reductase:isolation of cDNA, mapping and mutation identification. Nature Genet. 7, 195–200 (1994).

    Article  CAS  Google Scholar 

  11. Goyette, P., Frosst, P., Rosenblatt, D.S. & Rozen, R. Seven novel mutations in the methylenetetrahydrofolate reductase gene andgenotype/phenotypecorrelations in severe methylenetetrahydrofolate reductase deficiency. Am. J. hum. Genet. 56, 1052–1059 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Daubner, S.C. & Matthews, R.G. Purification and properties of methylenetetrahydrofolate reductase from pig liver. J. biol. Chem. 257, 140–145 (1982).

    CAS  PubMed  Google Scholar 

  13. Davies, J.F. . et al. Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate. J. Biochem. 29, 9467–3479 (1990).

    Article  CAS  Google Scholar 

  14. Franken, D.G., Boers, G.H.J., Blom, H.J., Trijbels, J.M.F. & Kbppenborg, P.W.C. Treatment of mild hyperhomocysteinemia in vasculardisease patients. Arterioscler. Thromb. 14, 465–470 (1994).

    Article  CAS  Google Scholar 

  15. Kang, S.S., Zhou, J., Wong, P.W.K., Kowalisyn, J. & Strokosch, G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am. J. hum. Genet. 43, 414–421 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Horton, R.M. et al. Gene splicing by overlap extension. Meth. Enzymol. 217, 270–279 (1993).

    Article  CAS  Google Scholar 

  17. Rosenblatt, D.S. & Erbe, R.W. Methylenetetrahydrofolate reductase in cultured human cells. I. Growth and metabolic studies. Pediatr. Res. 11, 1137–1141 (1977).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and permissions

About this article

Cite this article

Frosst, P., Blom, H., Milos, R. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10, 111–113 (1995).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing