One-carbon metabolism enzyme polymorphisms and uteroplacental insufficiency

Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population

“…Although this polymorphism had no effect on enzyme activity under normal assay conditions, it was shown to affect enzyme thermostability, diminishing its capacity on DNA synthesis (Christensen et al, 2009). This polymorphism has been described as a maternal risk factor for several conditions, including neural tube defects (Parle-McDermott et al, 2006), severe placental abruption and miscarriage (Parle-McDermott et al, 2005a;Parle-McDermott et al, 2005b), intrauterine growth restriction (Furness et al, 2008), and congenital heart defects in children (Christensen et al, 2009). Interesting, few studies describe the association of rs2236225 polymorphism and maternal risk for NSCL/P, and the results are unclear.…”

Genetic variation in the folate metabolic pathway and risk of childhood leukemia

“…40 This may provide a possible mechanism by which this polymorphism could mediate risk as hypermethylation is important in acute leukemia. 41 In addition, in a prospective cohort study investigating pregnancy complications, the presence of the fetal MTR 2756 G-allele was associated with uteroplacental insufficiency, 42 suggesting that it plays a part in normal fetal development, which combined with the knowledge that childhood ALL and AML originate in utero provides further support for its role in disease etiology. The only other study to investigate the association between MTR 2756 and childhood leukemia is that by Gast et al 43 ; and although no evidence was found to support a role for MTR, a protective effect with polymorphisms in methionine synthase reductase was observed.…”

Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development

“…This variant reduces formate incorporation into purines (18) and may increase risk for NTDs (19) and other adverse pregnancy outcomes (18,(20)(21)(22). Risk may be modulated by folate intake (6,23) because the R653Q protein is stabilized by folic acid in vitro (18).…”

“…The R653Q variant [w20% QQ in Caucasians (18)(19)(20)(21)(22); rs2236225] in methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) destabilizes the synthetase domain that converts formate and tetrahydrofolate to 10-formyltetrahydrofolate for purine synthesis. This variant reduces formate incorporation into purines (18) and may increase risk for NTDs (19) and other adverse pregnancy outcomes (18,(20)(21)(22).…”