M. Lucock et al., An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy, MOL GEN MET, 73(4), 2001, pp. 322-332
The effect of four polymorphic genes of folate-dependent methionine biosynt
hesis have been investigated in mothers affected by a neural tube defect pr
egnancy (NTD) and matched controls. The influence of the various genotypes
on total red cell 5-methyl-H(4)folate, 5,10-methenyl-H(4)folate, and 5-form
yl-H(4)folate is reported, as is the effect on homocysteine and radioassay
folate in both serum and red cells. All of the single nucleotide polymorphi
sms studied would seem to contribute to the cellular folate profile in some
way. From the data presented, and from the work of others, it is likely th
at C677T 5,10-methylenetetrahydrofolate reductase is the most important of
these polymorphisms. Control mother folate profiles seem reasonably predict
ive of any given methionine cycle mutation, but profiles in NTD mothers do
not. On this basis, it seems likely that some other, as yet unidentified fo
late lesion is causal for NTD. In NTD-C677T 5,10-methylenetetrahydrofolate
reductase in particular, indexes of folate depletion such as high-performan
ce liquid chromatography (HPLC) folate level, oligo-gamma -glutamyl chain l
ength, homocysteine, and radioassay folate values all seem to deteriorate w
ith increased mutant allele carriage. This indicates that this folate polym
orphism may provide a critical threshold effect that helps to promote NTD o
ccurrence in the presence of another, as yet unidentified folate-related fa
ctor. In more general terms, on a by genotype basis, all I I genotypes stud
ied give NTD mothers a higher homocysteine compared to controls. Furthermor
e, a trend that is less universal indicates that NTD mothers have higher 5,
10-methenyl-H(4)folate and 5-methyl-H(4)folate levels and lower 5-formyl-H(
4)folate and H(4)PteGlu(1) levels than do controls. One of the most consist
ent, and possibly specific, differences between participant groups is a sta
tistically significant elevation of 5,10-methenyl-H(4)folate in NTD mothers
(affects three genotypes). Possible interpretations of this finding are di
scussed. (C) 2001 Academic Press.