Formate rescues neural tube defects caused by mutations in Slc25a32

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 (MF...

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Published inProceedings 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
LanguageEnglish
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
Online AccessGet full text
ISSN0027-8424
1091-6490
1091-6490
DOI10.1073/pnas.1800138115

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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.
AbstractList Periconceptional supplementation with folic acid (FA) has reduced the prevalence of neural tube defects (NTDs) in numerous global populations; however, more than 30% of NTDs remain FA resistant. Previous in vitro studies identified Slc25a32 -encoding mitochondrial folate transporter that delivers tetrahydrofolate across the mitochondrial membrane. Herein, we provide the original description of transgenic Slc25a32 gene trapped (Slc25a32 gt/gt ) knockout mice, who present with 100% penetrant NTDs. We demonstrate that formate supplementation rescues normal neural tube closure in the majority (78%) of Slc25a32 gt/gt embryos, whereas 5-methyltetrahydrofolate was not effective. Additionally, biallelic SLC25A32 loss-of-function mutations were identified in a human NTD case. Our findings add an NTD mouse model to several others that benefit developmentally from maternal formate supplementation. 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.
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.
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.
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.
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.
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.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.
Author Yuan, Zhengwei
Lin, Ying Linda
Zhang, Ting
Cabrera, Robert M.
Guo, Jin
Finnell, Richard H.
Wlodarczyk, Bogdan J.
Nilsson, Torbjorn K.
Zheng, Yu-Fang
Kim, Sung-Eun
Lei, Yunping
Ren, Aiguo
Wang, Linlin
Kim, Jimi
Wang, Hong-Yan
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  surname: Kim
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Keywords formate
folate
neural tube defects
Slc25a32
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Author contributions: J.K., Y.L., and R.H.F. designed research; J.K., Y.L., J.G., S.-E.K., B.J.W., R.M.C., Y.L.L., L.W., H.-Y.W., and R.H.F. performed research; J.K., Y.L., J.G., S.-E.K., B.J.W., R.M.C., T.K.N., T.Z., A.R., L.W., Z.Y., Y.-F.Z., H.-Y.W., and R.H.F. analyzed data; and J.K., Y.L., S.-E.K., B.J.W., R.M.C., T.Z., A.R., L.W., Z.Y., Y.-F.Z., H.-Y.W., and R.H.F. wrote the paper.
2Present address: Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030.
Edited by Patrick J. Stover, Cornell University, Ithaca, NY, and approved March 28, 2018 (received for review January 4, 2018)
1J.K. and Y.L. contributed equally to this work.
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Snippet Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant,...
Periconceptional supplementation with folic acid (FA) has reduced the prevalence of neural tube defects (NTDs) in numerous global populations; however, more...
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SubjectTerms 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
Title Formate rescues neural tube defects caused by mutations in Slc25a32
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