2. Academic Validation
  3. Formate rescues neural tube defects caused by mutations in Slc25a32

Formate rescues neural tube defects caused by mutations in Slc25a32

  • Proc Natl Acad Sci U S A. 2018 May 1;115(18):4690-4695. doi: 10.1073/pnas.1800138115.
Jimi Kim 1,  Yunping Lei 2,  Jin Guo 3,  Sung-Eun Kim 2,  Bogdan J Wlodarczyk 2,  Robert M Cabrera 2,  Ying Linda Lin 2,  Torbjorn K Nilsson 4,  Ting Zhang 3,  Aiguo Ren 5,  Linlin Wang 5,  Zhengwei Yuan 6,  Yu-Fang Zheng 7 8,  Hong-Yan Wang 9 8,  Richard H Finnell 10 11
Affiliations

Affiliations

  • 1 Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, University of Texas at Austin, Austin, TX 78723.
  • 2 Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, University of Texas at Austin , Austin, TX 78723.
  • 3 Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100700 Beijing, China.
  • 4 Department of Medical Biosciences, Clinical Chemistry, Umea University, SE-90185 Umea, Sweden.
  • 5 Institute of Reproductive and Child Health, Peking University, 100191 Beijing, China.
  • 6 Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, 117004 Shenyang, China.
  • 7 Obstetrics & Gynecology Hospital, State Key Laboratory of Genetic Engineering and School of Life Sciences of Fudan University, 20043 Shanghai, China.
  • 8 Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, Institute of Reproduction & Development and Children's Hospital of Fudan University, 200011 Shanghai, China.
  • 9 Obstetrics & Gynecology Hospital, State Key Laboratory of Genetic Engineering and School of Life Sciences of Fudan University, 20043 Shanghai, China; [email protected] [email protected].
  • 10 Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, University of Texas at Austin , Austin, TX 78723; [email protected] [email protected].
  • 11 Collaborative Innovation Center for Genetics & Development, School of Life Sciences, Fudan University, 200438 Shanghai, China.
PMID: 29666258 DOI: 10.1073/pnas.1800138115
Abstract

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 Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt 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 SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

Keywords

Slc25a32; folate; formate; neural tube defects.

Figures