The differential translation capabilities of the human DHFR2 gene indicates a developmental and tissue specific endogenous protein of low abundance.

A functional role has been ascribed to the human Dihydrofolate reductase 2 (DHFR2) gene based on the enzymatic activity of recombinant versions of the predicted translated protein. However, the in vivo function is still unclear. The high amino acid sequence identity (92%) between DHFR2 and its parental homologue, DHFR, makes analysis of the endogenous protein challenging. This paper describes a targeted mass spectrometry proteomics approach in several human cell lines and tissue types to identify DHFR2 specific peptides as evidence of its translation. We show definitive evidence that the dihydrofolate reductase activity in the mitochondria is in fact mediated by DHFR, and not DHFR2. Analysis of Ribo-seq data and an experimental assessment of ribosome association using a sucrose cushion, showed that the two main Ensembl annotated mRNA isoforms of DHFR2, 201 and 202, show differential association with the ribosome. This indicates a functional role at both the RNA and protein level. However, we were unable to detect DHFR2 protein at a detectable level in most cell types examined despite various RNA isoforms of DHFR2 being relatively abundant. We did detect a DHFR2 specific peptide in embryonic heart, indicating that the protein may have a specific role during embryogenesis. We propose that the main functionality of the DHFR2 gene in adult cells is likely to arise at the RNA level

Contribució de l'estat nutricional matern i de la funció placentària sobre el desenvolupament del retard de creixement intrauterí

OBJECTIVES: We investigated whether early pregnancy hyperhomocysteinemiais a biomarker of pathological fetoplacental Doppler or intrauterine growth retardation (IUGR). METHODS: A nested case-control study with a group of cases based onpopulation birthweightcurves (IUGR-Pop) and another group with customisedcurves(IUGR-Cus) was performed. RESULTS: 43 cases were matched with 161 controls in the IUGR-Pop group, and 145 cases with 63 controls in the group IUGR-Cus. Hyperhomocysteinemia was defined as plasma homocysteine above the 90th percentile and was associated with reduced birth weight, increased resistance of the uterine arteries, increased risk of pathological umbilical Doppler (OR = 3.1), IUGR-Poprisk (OR=8.2) andIUGR-Cus risk (OR=4.9). CONCLUSION : Early pregnancy hyperhomocysteinemiais associated with reduced birth weight, altered feto-placental Doppler function and increased IUGR risk in the two populations studied

Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy

The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine) single nucleotide polymorphism (SNP) on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW) throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI): 28.3, 33.5). In participants with normal-high plasma folate status (>13.4 nmol/L), least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L) was lower in the GA (2.35 [2.23, 2.47]) versus GG (2.58 [2.46, 2.70]) genotype at ≤12 GW (p < 0.05) and in the GA (2.08 [1.97, 2.19]) and AA (1.94 [1.75, 2.16]) versus GG (2.29 [2.18, 2.40]) genotypes at 15 GW (p < 0.05). No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L) (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038). PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01)). Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (β coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy) and the AA compared to GG genotype was associated with lower pDMG (β coefficients [SEM] ranging from −0.11 [0.06], p = 0.055 to −0.23 [0.06], p < 0.001). Conclusion: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele