The effect of 677C → T and 1298A → C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects

Abstract

We have studied the effect of common mutations (677C ! T and 1298A ! C) of the methylenetetrahydrofolate reductase (MTHFR) gene in sixty-six healthy French subjects, aged 27±47 years. Serum folate, vitamin B 12 , and plasma total homocysteine were measured as well as the speci®c activity of MTHFR in lymphocytes. The frequency of subjects homozygous for the 677TT genotype was 18 %, and that of those homozygous for the 1298CC genotype was 12×5 %. The frequency of individuals heterozygous for both mutations was 23×5 %. The 1298A ! C mutation was associated with decreased MTHFR speci®c activity in subjects with both 677CC and 677CT genotypes. This activity was 60 % for the 677CC/1298AC genotype and 52 % for the 677CC/ 1298CC genotype when compared with the MTHFR speci®c activity of the 677CC/1298AA genotype. Heterozygotes for both mutations (677CT/1298AC genotype) had 36 % of the reference speci®c activity. Although homocysteine levels in 677TT and 1298CC genotype subjects were higher than for other genotypes, no signi®cant differences were observed among different genotypes. This may be due to high serum folate level in our samples, and suggests that folate therapy may be useful to prevent hyperhomocysteinaemia in homozygous mutant subjects.

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

“…These data corroborate several earlier investigations in the field. 3,19,20,33 As the physical distance of 2.1 kb between the two polymorphisms is short, it is not surprising that recombination events very rarely have been observed. 19,34,35 However, these and our results are in apparent contradiction with those reported in two studies by Isotalo et al 21,36 who found a substantial number of combined MTHFR 677TT/1298AC genotypes in adults (approximately 10% of the study participants), 36 neonates (1.7%) 21 and aborted embryos (1.2%), 21 and 677CT/1298CC and 677TT/1298CC genotypes selectively in aborted embryos (3.7%).…”

“…3,19 The 1298C allele clearly leads to a decreased enzyme activity, although not to the same extent as the 677T allele. 3,19,20 Individuals who are homozygous for the 1298C allele have about a 40% reduced enzyme activity in vitro, but do not appear to have higher plasma homocysteine levels than controls. 3,19 However, individuals who are compound heterozygous for the 677T and 1298C alleles, which produces a 677CT/1298AC genotype, have a 40 ± 50% reduced MTHFR activity in vitro and a biochemical profile similar to that seen among 677T homozygotes with increased homocysteine levels and decreased folate levels.…”

Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses

“…While several mutations within it were described, the best-characterized MTHFR gene polymorphisms are the alanine-to-valine C677T (Frosst et al 1995), and the glutamate-to-alanine A1298C (Van der Put et al 1998) missense mutations. While both SNPs induce milder forms of MTHFR deficiency (Frosst et al 1995, Chango et al 2000, the A1298C SNP, located in the enzyme regulatory domain, unlike the C677T SNP which is found within the enzyme catalytic domain, does not result in either a thermolabile protein or increased tHcy (Hanson et al 2001, Friso et al 2002. Interestingly, 677CT/1298AC compound heterozygosity reportedly has similar clinical impact as C677T homozygosity (Chango et al 2000, Chen et al 2005.…”

The Importance of Homozygous Polymorphisms of Methylenetetrahydrofolate Reductase Gene in Romanian Patients with Idiopathic Venous Thromboembolism

“…The incidence of the MTHFR C677T polymorphism in the general population is about 45% and 15% for heterozygous and homozygous genotypes, respectively. The prevalence of homozygotes for the MTHFR 677TT polymorphism in Europe varies between 5 and 15%; the heterozygous MTHFR C677T genotype presents the highest prevalence in Italy (44%) and the lowest in Norway (28%) (3,4,8,9).The role of MTHFR polymorphisms in VTE is controversial: some authors have shown an association between the MTHFR C677T polymorphism and VTE (10-14), whereas others have proven the contrary (15)(16)(17) …”