Nature Genetics
10, 111 - 113 (1995)
doi:10.1038/ng0595-111
A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductaseP. Frosst1, H.J. Blom2, R. Milos1, P. Goyette1, C.A. Sheppard3, R.G. Matthews3, G.J.H. Boers4, M. den Heijer2, 5, L.A.J. Kluijtmans2, L.P. van den Heuve2
& R. Rozen1
1Departments of Human Genetics, Pediatrics and Biology, McGill University, Montreal Children's Hospital, Montreal, Canada H3H 1P3
2Department of Pediatrics, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands.
3Biophysics Research Division and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA
4Department of Medicine, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands
5Department of Hematology, Municipal Hospital Leyenburg, 2545 CH The Hague, The Netherlands Correspondence should be addressed to R.R. 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.
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