title: 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.
authors.affiliation: Department of Pediatrics, University Hospital Nijmegen, Nijmegen, The Netherlands.
authors.forename: N M
authors.initials: NM
authors.lastname: van der Put
authors.forename: F
authors.initials: F
authors.lastname: Gabreëls
authors.forename: E M
authors.initials: EM
authors.lastname: Stevens
authors.forename: J A
authors.initials: JA
authors.lastname: Smeitink
authors.forename: F J
authors.initials: FJ
authors.lastname: Trijbels
authors.forename: T K
authors.initials: TK
authors.lastname: Eskes
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: H J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000225:Adenine; D000328:Adult; D003596:Cytosine; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009436:Neural Tube Defects / Q000201:enzymology* / Q000235:genetics*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D015995:Prevalence; D011736:Pyridoxine / Q000097:blood; D014805:Vitamin B 12 / Q000097:blood
chemical_list: D006710:Homocysteine; D003596:Cytosine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000225:Adenine; D011736:Pyridoxine; D014805:Vitamin B 12