Abstract
Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability.
Full text
PDF
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Boushey C. J., Beresford S. A., Omenn G. S., Motulsky A. G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995 Oct 4;274(13):1049–1057. doi: 10.1001/jama.1995.03530130055028. [DOI] [PubMed] [Google Scholar]
- Frosst P., Blom H. J., Milos R., Goyette P., Sheppard C. A., Matthews R. G., Boers G. J., den Heijer M., Kluijtmans L. A., van den Heuvel L. P. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111–113. doi: 10.1038/ng0595-111. [DOI] [PubMed] [Google Scholar]
- Goyette P., Frosst P., Rosenblatt D. S., Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995 May;56(5):1052–1059. [PMC free article] [PubMed] [Google Scholar]
- Goyette P., Sumner J. S., Milos R., Duncan A. M., Rosenblatt D. S., Matthews R. G., Rozen R. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994 Jun;7(2):195–200. doi: 10.1038/ng0694-195. [DOI] [PubMed] [Google Scholar]
- Jacques P. F., Bostom A. G., Williams R. R., Ellison R. C., Eckfeldt J. H., Rosenberg I. H., Selhub J., Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996 Jan 1;93(1):7–9. doi: 10.1161/01.cir.93.1.7. [DOI] [PubMed] [Google Scholar]
- Kang S. S., Wong P. W., Bock H. G., Horwitz A., Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991 Mar;48(3):546–551. [PMC free article] [PubMed] [Google Scholar]
- Kang S. S., Wong P. W., Susmano A., Sora J., Norusis M., Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991 Mar;48(3):536–545. [PMC free article] [PubMed] [Google Scholar]
- Kluijtmans L. A., van den Heuvel L. P., Boers G. H., Frosst P., Stevens E. M., van Oost B. A., den Heijer M., Trijbels F. J., Rozen R., Blom H. J. 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 Jan;58(1):35–41. [PMC free article] [PubMed] [Google Scholar]
- Matthews R. G., Vanoni M. A., Hainfeld J. F., Wall J. Methylenetetrahydrofolate reductase. Evidence for spatially distinct subunit domains obtained by scanning transmission electron microscopy and limited proteolysis. J Biol Chem. 1984 Oct 10;259(19):11647–11650. [PubMed] [Google Scholar]
- Motulsky A. G. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet. 1996 Jan;58(1):17–20. [PMC free article] [PubMed] [Google Scholar]
- Rosenblatt D. S., Erbe R. W. Methylenetetrahydrofolate reductase in cultured human cells. II. Genetic and biochemical studies of methylenetetrahydrofolate reductase deficiency. Pediatr Res. 1977 Nov;11(11):1141–1143. doi: 10.1203/00006450-197711000-00005. [DOI] [PubMed] [Google Scholar]
- Rosenblatt D. S., Lue-Shing H., Arzoumanian A., Low-Nang L., Matiaszuk N. Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts. Biochem Med Metab Biol. 1992 Jun;47(3):221–225. doi: 10.1016/0885-4505(92)90029-x. [DOI] [PubMed] [Google Scholar]
- Sumner J., Jencks D. A., Khani S., Matthews R. G. Photoaffinity labeling of methylenetetrahydrofolate reductase with 8-azido-S-adenosylmethionine. J Biol Chem. 1986 Jun 15;261(17):7697–7700. [PubMed] [Google Scholar]
- Whitehead A. S., Gallagher P., Mills J. L., Kirke P. N., Burke H., Molloy A. M., Weir D. G., Shields D. C., Scott J. M. A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects. QJM. 1995 Nov;88(11):763–766. [PubMed] [Google Scholar]
- van der Put N. M., Steegers-Theunissen R. P., Frosst P., Trijbels F. J., Eskes T. K., van den Heuvel L. P., Mariman E. C., den Heyer M., Rozen R., Blom H. J. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995 Oct 21;346(8982):1070–1071. doi: 10.1016/s0140-6736(95)91743-8. [DOI] [PubMed] [Google Scholar]