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. 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport, Active / genetics
  • Formates / pharmacology*
  • Humans
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Neural Tube Defects* / embryology
  • Neural Tube Defects* / genetics
  • Neural Tube Defects* / pathology
  • Neural Tube Defects* / prevention & control
  • Neural Tube* / embryology
  • Neural Tube* / pathology


  • Formates
  • Membrane Transport Proteins
  • SLC25A32 protein, human
  • formic acid