Abnormal folate metabolism in foetuses affected by neural tube defects

Abstract

Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs.

Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice

“…In the cytoplasm, SHMT1 regulates the partitioning of one-carbon units between thymidylate biosynthesis and homocysteine remethylation (24), whereas in the nucleus SHMT1 is a source of folate-activated one-carbon units for thymidylate synthesis (16). Consequently, de novo thymidylate biosynthesis is impaired in the nuclei of Shmt1 null mice (15), and decreased Shmt1 expression increases Sp mutant (10), as well as in NTD-affected human fetuses (29), this is the first direct evidence that disruption of folate-and SHMT1-dependent thymidylate biosynthesis underlies NTD pathogenesis. Impairments in de novo thymidylate biosynthesis may disrupt neural tube closure by reducing proliferative capacity or by increasing genomic instability via misincorporation of uracil into DNA (30).…”

The emerging role of epigenetic mechanisms in the etiology of neural tube defects

“…2). 55 Defective thymidylate biosynthesis has been implicated in NTDs in humans and mouse models, [61][62][63] suggesting that adequate supply of nucleotides for cellular proliferation is essential for closure of the neural tube. dietary imposition of choline deficiency has been found to alter DNA and histone methylation patterns in fetal mouse hippocampus.…”

Understanding the causes and prevention of neural tube defects: Insights from the splotch mouse model

“…The incorporation of thymidine into DNA is suppressed by exogenous dUMP, owing to activation of de novo synthesis of dTMP, provided that 5,10-methylene tetrahydrofolate, a folate cycle intermediate, is available as cosubstrate. A recent study also used this test to analyze cell lines derived from human NTD fetuses and revealed that a subset of cases exhibit an abnormality in folate metabolism, which is presumably genetically determined (Dunlevy et al, 2007).…”