DTYMK is an essential gene in mice and heterozygosity does not cause neural tube defects.

Regulation of nucleotide biosynthesis is necessary for maintaining cellular processes including DNA replication and repair. A key enzyme in this process is deoxythymidylate kinase (dTYMK), which catalyzes the initial step in the production of dTTP from dTMP. This gene constitutes the first merged step of dTTP synthesis from the de novo and salvage pathways which regulate dTMP biosynthesis. Decreased de novo dTMP biosynthesis causes dysregulated dTTP:dUTP pools, and leads to increased uracil in DNA and neural tube closure defect (NTD) development in mice. The goal of this research was to investigate if dTYMK, the downstream enzyme in dTTP production, is an essential gene in mice and if impairments in dTYMK play a causal role in development including NTD pathology in mice. Dtymk+/- C57BL/6J females were weaned onto either a control, excess folic acid, or folic acid deficient diet and timed breeding was performed after 8 weeks on diet. The offspring were analyzed for NTDs and other reproductive outcomes at embryonic day 12.5 (E12.5). Dtymk-/- mice were confirmed to be embryonic lethal before E12.5, and Dtymk+/- mice on all three experimental diets did not show the presence of open neural tube defects, spina bifida or exencephaly. However, the expression of dTYMK in Dtymk+/- mouse embryos was confirmed to be decreased by approximately 3-fold compared to Dtymk+/+ embryos. Although dTYMK was demonstrated to be an essential gene in mice and is required for the regulation of nucleotide pools in vitro, there was no evidence of increased risk of NTDs because of a reduction in expression of this enzyme during embryonic development. It is possible that a further reduction in expression may be required to see developmental anomalies in C57BL/6J mice.