A 2ND 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) mutati on in the methylenetetrahydrofolate reductase (MTHFR) gene, causing th ermolability 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 frequen cy of .33. This 1298(A-->C) mutation results in decreased MTHFR activi ty tone-way analysis of variance [ANOVA] P < .0001), which is more pro nounced in the homozygous than heterozygous state. Neither the homozyg ous nor the heterozygous state is associated with higher plasma homocy steine (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 (AN OVA P < .0001), higher Hey, and decreased plasma folate levels (ANOVA P < .03). Thus, combined heterozygosity for both MTHFR mutations resul ts in similar features as observed in homozygotes for the 677(C-->T) m utation. 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 mut ations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an a dditional genetic risk factor for NTDs.