Deng Liyuan, Elmore C Lee, Lawrance Andrea K, Matthews Rowena G, Rozen Rima
Department of Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Canada.
Mol Genet Metab. 2008 Jul;94(3):336-42. doi: 10.1016/j.ymgme.2008.03.004. Epub 2008 Apr 14.
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. Mtrr-deficient 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.
饮食中叶酸水平低以及叶酸代谢基因的多态性会影响妊娠并发症和出生缺陷的风险。甲硫氨酸合成酶还原酶（MTRR）是激活甲硫氨酸合成酶所必需的，甲硫氨酸合成酶是一种依赖叶酸和维生素B12的酶。MTRR中的一种多态性（p.I22M）在许多人群中25%的个体中呈纯合状态，可能会增加神经管缺陷的风险。为了研究MTRR缺乏对早期发育和先天性心脏缺陷的影响，我们使用了在Mtrr中携带基因捕获（gt）等位基因的小鼠。雌性小鼠（Mtrr(+/+)、Mtrr(+/gt)和Mtrr(gt/gt)）与雄性Mtrr(+/g)小鼠交配。在胚胎第14.5天评估生殖结局和心脏表型（缺陷的存在和心肌厚度）。Mtrr缺乏的母亲每窝的吸收和延迟胚胎更多（每窝吸收数：Mtrr(+/+)母亲为0.29±0.13；Mtrr(+/gt)母亲为1.21±0.41；Mtrr(gt/gt)母亲为1.87±0.38；每窝延迟胚胎数：Mtrr(+/+)母亲为0.07±0.07；Mtrr(+/gt)母亲为0.14±0.14；Mtrr(gt/gt)母亲为0.60±0.24）。Mtrr(gt/gt)母亲的胎盘较小，其胚胎也较小，伴有心肌发育不全，每窝室间隔缺损（VSD）的发生率较高（Mtrr(+/+)组为0；Mtrr(+/gt)组为0.57±0.30；Mtrr(gt/gt)组为1.57±0.67）。胚胎Mtrr(gt/gt)基因型与胚胎长度缩短、胚胎和胎盘重量减轻以及VSD发生率较高相关，但不影响心肌厚度或胚胎发育延迟。我们得出结论，Mtrr缺乏对小鼠生殖结局和心脏发育有不利影响。这些发现可能对心脏缺陷的营养预防有启示，特别是对于具有常见MTRR多态性的女性。
