An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy.
The effect of four polymorphic genes of folate-dependent methionine biosynthesis have been investigated in mothers affected by a neural tube defect pregnancy (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-formyl-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 polymorphisms 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 that C677T 5,10-methylenetetrahydrofolate reductase is the most important of these polymorphisms. Control mother folate profiles seem reasonably predictive 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 folate lesion is causal for NTD. In NTD-C677T 5,10-methylenetetrahydrofolate reductase in particular, indexes of folate depletion such as high-performance liquid chromatography (HPLC) folate level, oligo-gamma-glutamyl chain length, homocysteine, and radioassay folate values all seem to deteriorate with increased mutant allele carriage. This indicates that this folate polymorphism may provide a critical threshold effect that helps to promote NTD occurrence in the presence of another, as yet unidentified folate-related factor. In more general terms, on a by genotype basis, all 11 genotypes studied give NTD mothers a higher homocysteine compared to controls. Furthermore, 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 consistent, and possibly specific, differences between participant groups is a statistically significant elevation of 5,10-methenyl-H(4)folate in NTD mothers (affects three genotypes). Possible interpretations of this finding are discussed.
Lucock
M
M
Academic Unit of Paediatrics, D Floor, Clarendon Wing, Leeds General Infirmary, University of Leeds, Leeds, West Yorkshire LS2 9NS, UK. M.Lucock@leeds.ac.uk
Daskalakis
I
I
Hinkins
M
M
Yates
Z
Z
D000328:Adult; D000483:Alleles; D004739:England; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D005787:Gene Frequency; D006801:Humans; D008715:Methionine / Q000096:biosynthesis / Q000378:metabolism; D008745:Methylation; D009154:Mutation / Q000235:genetics*; D011099:Polyglutamic Acid / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D016135:Spinal Dysraphism / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D014805:Vitamin B 12 / Q000378:metabolism
D011624:Pteroylpolyglutamic Acids; D011099:Polyglutamic Acid; D005492:Folic Acid; D008715:Methionine; D014805:Vitamin B 12