We demonstrate that impairments in MTHFD1 activity compromise both homocysteine remethylation and de novo thymidylate biosynthesis, and provide evidence that MTHFD1-associated disruptions in de novo thymidylate biosynthesis lead to genome instability that may underlie folate-associated immunodeficiency and birth defects.
The minor allelic frequencies of the MTHFD1 1958G>A and MTHFR 1298A>C in our populations were similar to those reported from Southeast Asian population, suggesting a possible explanation for the prevalence of this malformation in these regions.
A polymorphism in methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), R653Q (MTHFD1 c.1958 G > A), has also been associated with increased birth defect risk, likely through reduced purine synthesis.