Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, University of Texas at Austin, Austin, TX 78723.
Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, University of Texas at Austin , Austin, TX 78723.
Proc Natl Acad Sci U S A. 2018 May 1;115(18):4690-4695. doi: 10.1073/pnas.1800138115. Epub 2018 Apr 16.
Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of () in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function variants in a cranial NTD case. These data demonstrate that the loss of functional results in cranial NTDs in mice and has also been observed in a human NTD patient.
围孕期叶酸（FA）补充显著降低了神经管缺陷（NTD）的发生率。不幸的是，一些 NTD 对 FA 有抗性，因此，NTD 仍然是一个全球公共卫生关注的问题。先前的研究已经确定 SLC25A32 为一种线粒体叶酸转运体（MFT），它能够在体外将四氢叶酸（THF）从细胞质转移到线粒体。在这里，我们表明，在小鼠中基因陷阱失活 （）诱导 NTD，这些 NTD 对叶酸（5-甲基四氢叶酸，5-mTHF）具有抗性，但可以通过甲酸盐补充来预防。 胚胎在子宫内死亡，具有 100%颅 NTD 穿透率。5-mTHF 补充未能促进突变胚胎的正常神经管闭合（NTC），而甲酸盐补充使大多数（78%）敲除胚胎能够完成 NTC。在具有 NTD 的人类受试者中的平行遗传研究中，在颅 NTD 病例中鉴定出功能性丧失的 等位基因变异。这些数据表明，功能性丧失导致小鼠的颅 NTD，并且在人类 NTD 患者中也观察到了这种情况。
