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Am J Hum Genet. May 1998; 62(5): 1044–1051.
PMCID: PMC1377082

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?


Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.

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Selected References

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  • Copp AJ, Brook FA, Estibeiro JP, Shum AS, Cockroft DL. The embryonic development of mammalian neural tube defects. Prog Neurobiol. 1990;35(5):363–403. [PubMed]
  • Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992 Dec 24;327(26):1832–1835. [PubMed]
  • den Heijer M, Blom HJ, Gerrits WB, Rosendaal FR, Haak HL, Wijermans PW, Bos GM. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet. 1995 Apr 8;345(8954):882–885. [PubMed]
  • Engbersen AM, Franken DG, Boers GH, Stevens EM, Trijbels FJ, Blom HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995 Jan;56(1):142–150. [PMC free article] [PubMed]
  • Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111–113. [PubMed]
  • Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet. 1988 Oct;43(4):414–421. [PMC free article] [PubMed]
  • Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993 Nov;86(11):703–708. [PubMed]
  • Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997 Jun;17(6):1157–1162. [PubMed]
  • Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, Scott JM. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet. 1995 Jan 21;345(8943):149–151. [PubMed]
  • Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JM. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet. 1997 May 31;349(9065):1591–1593. [PubMed]
  • Molloy AM, Mills JL, Kirke PN, Whitehead AS, Weir DG, Scott JM. Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radioassay and microbiological assays. Clin Chem. 1998 Jan;44(1):186–188. [PubMed]
  • Ramsbottom D, Scott JM, Molloy A, Weir DG, Kirke PN, Mills JL, Gallagher PM, Whitehead AS. Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects? Clin Genet. 1997 Jan;51(1):39–42. [PubMed]
  • Steegers-Theunissen RP, Boers GH, Trijbels FJ, Finkelstein JD, Blom HJ, Thomas CM, Borm GF, Wouters MG, Eskes TK. Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism. 1994 Dec;43(12):1475–1480. [PubMed]
  • te Poele-Pothoff MT, van den Berg M, Franken DG, Boers GH, Jakobs C, de Kroon IF, Eskes TK, Trijbels JM, Blom HJ. Three different methods for the determination of total homocysteine in plasma. Ann Clin Biochem. 1995 Mar;32(Pt 2):218–220. [PubMed]
  • van der Put NM, Eskes TK, Blom HJ. Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM. 1997 Feb;90(2):111–115. [PubMed]
  • van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995 Oct 21;346(8982):1070–1071. [PubMed]
  • van der Put NM, Thomas CM, Eskes TK, Trijbels FJ, Steegers-Theunissen RP, Mariman EC, De Graaf-Hess A, Smeitink JA, Blom HJ. Altered folate and vitamin B12 metabolism in families with spina bifida offspring. QJM. 1997 Aug;90(8):505–510. [PubMed]
  • van der Put NM, van den Heuvel LP, Steegers-Theunissen RP, Trijbels FJ, Eskes TK, Mariman EC, den Heyer M, Blom HJ. Decreased methylene tetrahydrofolate reductase activity due to the 677C-->T mutation in families with spina bifida offspring. J Mol Med (Berl) 1996 Nov;74(11):691–694. [PubMed]
  • van der Put NM, van der Molen EF, Kluijtmans LA, Heil SG, Trijbels JM, Eskes TK, Van Oppenraaij-Emmerzaal D, Banerjee R, Blom HJ. Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease. QJM. 1997 Aug;90(8):511–517. [PubMed]
  • Viel A, Dall'Agnese L, Simone F, Canzonieri V, Capozzi E, Visentin MC, Valle R, Boiocchi M. Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Br J Cancer. 1997;75(8):1105–1110. [PMC free article] [PubMed]
  • Whitehead AS, Gallagher P, Mills JL, Kirke PN, Burke H, Molloy AM, Weir DG, Shields DC, Scott JM. A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects. QJM. 1995 Nov;88(11):763–766. [PubMed]

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