Formate rescues neural tube defects caused by mutations in Slc25a32

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 18; pp. 4690 - 4695
• Main Authors: Kim, Jimi, Lei, Yunping, Guo, Jin, Kim, Sung-Eun, Wlodarczyk, Bogdan J., Cabrera, Robert M., Lin, Ying Linda, Nilsson, Torbjorn K., Zhang, Ting, Ren, Aiguo, Wang, Linlin, Yuan, Zhengwei, Zheng, Yu-Fang, Wang, Hong-Yan, Finnell, Richard H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.05.2018
• Subjects: Animals; Biological Sciences; Biological Transport, Active - genetics; Cytoplasm; Deactivation; Defects; Embryos; folate; Folic acid; formate; Formates - pharmacology; Genes; Humans; Inactivation; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Membranes; Mice; Mice, Transgenic; Mitochondria; Mitochondrial DNA; Mutation; Neural Tube - embryology; Neural Tube - pathology; Neural tube defects; Neural Tube Defects - embryology; Neural Tube Defects - genetics; Neural Tube Defects - pathology; Neural Tube Defects - prevention & control; Public health; Skull; Slc25a32; Supplements; Tetrahydrofolic acid; Vitamin B; formate; folate; neural tube defects; Slc25a32
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1800138115

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.