Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Abstract

Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for pregnancy complications and birth defects. Methionine synthase reductase (MTRR) is required for activation of methionine synthase, a folate-and vitamin B 12 -dependent enzyme. A polymorphism in MTRR (p.I22M), present in the homozygous state in 25% of many populations, may increase risk for neural tube defects. To examine the impact of MTRR deficiency on early development and congenital heart defects, we used mice harboring a gene-trapped (gt) allele in Mtrr. Female mice (Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt ) were mated with male Mtrr +/g mice. Reproductive outcomes and cardiac phenotype (presence of defects and myocardial thickness) were assessed at E14.5. Mtrrdeficient mothers had more resorptions and more delayed embryos per litter (resorptions per litter: 0.29 ± 0.13; 1.21 ± 0.41; 1.87 ± 0.38 and delayed embryos per litter: 0.07 ± 0.07; 0.14 ± 0.14; 0.60 ± 0.24 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers respectively). Placentae of Mtrr gt/gt mothers were smaller and their embryos were smaller, with myocardial hypoplasia and a higher incidence of ventricular septal defects (VSD) per litter (0; 0.57 ± 0.30; 1.57 ± 0.67 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt groups respectively). Embryonic Mtrr gt/gt genotype was associated with reduced embryonic length, reduced embryonic and placental weight, and higher incidence of VSD, but did not affect myocardial thickness or embryonic delay. We conclude that Mtrr deficiency adversely impacts reproductive outcomes and cardiac development in mice. These findings may have implications for nutritional prevention of heart defects, particularly in women with the common MTRR polymorphism.

Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

“…26,27 A quarter of the offspring embryos from the MTRR gt/gt mother developed ventricular septal defects, and one third were affected by ventricular septal defect. 22 Consistent with this MTRR dosage sensitivity experiment, in our study, the c.56ϩ781 AϾC variant, which regulates MTRR gene transcription, is strongly correlated with ) with a high degree of significance. Because both the patients with inherited syndromes accompanied by defective MTRR and the MTRR gt/gt mice are characterized by elevated plasma levels of total homocysteine, 22,26,28 -32 we also analyzed the correlation between the MTRR genotype and plasma homocysteine levels in 522 healthy individuals.…”

“…22 Ϫ11 ) compared with the wild type. However, we did not observe any association between the reported MTRR c.66 AϾG variant and CHD risk in any of the 3 Han Chinese groups or in the combined study (Table IV in the online-only Data Supplement).…”

“…These results are consistent with the observations in the MTRR gene-trap mouse model that embryos bearing MTRR gt/gt develop ventricular septal defects with high frequency (28%) and that the myocardial walls in embryos from MTRR gt/gt mothers were much thinner compared with those from the other groups. 22 Moreover, folate supplementation has been implicated in specifically reducing conotruncal anomalies and ventricular septal defects. 9 In addition, isolated CHD cases showed significant associations with the MTRR c.56ϩ781 AϾC variant (2025 cases; Pϭ3.38ϫ10 Ϫ11 ) compared with nonisolated CHD (315 cases; Pϭ0.0006).…”

Insights into prevention of human neural tube defects by folic acid arising from consideration of mouse mutants

“…Embryos with partial Mtrr function (hypomorphic allele) are alive on GD 14.5. 30% have heart defects, but none have NTDs (Deng et al, 2008;Elmore et al, 2007).…”

A66G and C524T polymorphisms of the methionine synthase reductase gene are associated with congenital heart defects in the Chinese Han population

“…By catalyzing the reductive methylation of cob(II)alamin, MTRR restores MTR activity (Figure 1) (Olteanu and Banerjee, 2001;Silaste et al, 2001;Gellekink et al, 2005). Since MTRR plays a crucial role in maintaining the activity state of MTR, nonsynonymous genetic variations within the MTRR gene may confer susceptible or protective effects against CHDs (Swanson et al, 2001;Elmore et al, 2007;Deng et al, 2008). The MTRR gene is located on chromosome 5 at 5p15.3-p15.2 (Leclerc et al, 1999).…”