Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 18, Pages 4690-4695Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1800138115
Keywords
neural tube defects; Slc25a32; folate; formate
Categories
Funding
- NIH [HD081216, HD083809, HD067244]
- Chinese Academy of Medical Sciences Initiative for Innovative Medicine [2016-12M-1-008]
- 973 Program of China [2013CB945400]
- National Key Research and Development Program, Ministry of Science and Technology, P.R. China [2016YFC1000501]
- National Natural Science Foundation of China [81472987]
Ask authors/readers for more resources
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. Slc25a32(gt/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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available