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

Abstract

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.

Maternal dietary intake of folate, vitamin B12 and MTHFR 677C>T genotype: their impact on newborn’s anthropometric parameters

“…Methionine is also essential for DNA methylation as it plays an important role during critical periods of growth and development (Rush et al 2014). Two common polymorphisms in the gene coding for the MTHFR (677 C[T and 1298 A[C) are associated with decreased activity of the enzyme (van der Put et al 1998). In combination with these polymorphisms, a depleted status of folate and vitamin B 12 inhibits the regeneration of methionine which results in higher concentrations of Hcy and its metabolites (Cortese and Motti 2001).…”

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

“…The enzyme activity levels are approximately 70% lower than the common form, and individuals who are homozygous and heterozygous for this polymorphism have an increased amount of homocysteine [2,3]. Another common variant of the MTHFR gene is an A-to-C transversion at position 1298 (A1298C) in exon seven, which causes a glutamine to alanine exchange at position 429; this polymorphism influences specific activity of the enzyme to a lesser extent than the MTHFR C677T polymorphism [4].…”

No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort

“…The A1298C allele is characterized by a point mutation at position 1298 of the MTHFR gene (located 1p36.3) causing the replacement of glutamine by alanine in the corresponding enzyme [8]. The A66G polymorphism in the gene MTRR (located 5p15.3) alters an isoleucine into a methionine residue.…”