A Second Common Mutation in the Methylenetetrahydrofolate Reductase Gene: An Additional Risk Factor for Neural-Tube Defects?

SummaryRecently, 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