Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C677T and A1298C Mutations

Abstract

Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability.

Comment on ‘increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos’

“…12 A recent study by Volcik et al 11 has even demonstrated the existence of a MTHFR 677TT/1298CC genotype in a living Hispanic woman who had a child with spina bifida, providing further evidence that recombinant events between MTHFR mutation loci do occur despite their short physical distance of 2.1 kb. 8 In an adult Canadian population of predominantly European (Celtic) descent and other ethnic backgrounds, we have demonstrated a relatively high frequency of 677TT/1298AC genotypes, ranging from 9.2 to 12.5% in study and control groups, respectively, indicating a strong incidence of cis MTHFR mutations in this population. 9,13 This is in contrast to Weisberg et al 5 who studied Canadian groups of 133 children with spina bifida and 141 mothers of children with spina bifida and discovered only a single child with a MTHFR 677TT/1298AC genotype.…”

“…8 The absence of 677CT/1298CC and 677TT/1298CC genotype combinations in our neonatal control group 8 provides strong evidence that compound triple and quadruple MTHFR mutations may be associated with compromised foetal viability. There has been some criticism with the MboII restriction fragment length polymorphism detection of A1298C mutations, due to possible interference from silent T1317C mutations 5 however, these criticisms are unfounded, especially since the identification of mutated alleles would not be compromised.…”

“…3 Even within a country, such as Canada, there are regional differences in MTHFR allele distributions, as the Canadian population is ethnically heterogeneous. Canadian MTHFR 677T allele frequencies have been reported in Canadian Inuit (6.1%), 14 Manitoba neonates (24.97%), 15 French Canadians (38%) 16 and our neonatal (27.3%) 8 and adult (40%) control and study groups. 9 Considering the regional variations in MTHFR allele distributions, it is not completely surprising that some studies have recognised the common MTHFR mutations only in trans positions.…”

“…Although Zetterberg et al 1 investigated early spontaneous abortions, with all foetal deaths occurring before 6 and 20 weeks of gestation, the inherent limitation of their study, as well as other studies investigating foetal viability, 8 is that very early spontaneous abortions are not examined in study populations. The true contribution of MTHFR mutations to reduced foetal viability may be difficult to determine, as the majority of pregnancies that spontaneously terminate before 6 weeks of gestation is not identified clinically.…”

Reply to ‘MTHFR C677T and A1298C polymorphisms and mutated sequences occurring in cis’

“…These data, together with the studies mentioned above, demonstrate that 677T and 1298C alleles in cis are possible, but indeed very rare, and support the hypothesis that triple mutation combinations probably reflect recombinant events having occurred either de novo or in the relatively late ancestral history of specific sub-populations. Obviously, it is not excluded that specific subpopulations, such as the ones studied by Isotalo et al 10,11 may display higher frequencies of triple (and possibly quadruple) mutation combinations. In these sub-populations it is also possible that triple and quadruple mutation combinations may have a negative influence on embryonic survival.…”