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http://purl.uniprot.org/citations/35727412http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35727412http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35727412http://www.w3.org/2000/01/rdf-schema#comment"The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a paucity of animal models. Here, we generated homozygous (Slc25a32Y174C/Y174C and Slc25a32K235R/K235R) and compound heterozygous (Slc25a32Y174C/K235R) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out (Slc25a32-/-) mouse was also generated. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32-/- mice die in utero with NTDs. None of the Slc25a32 mutations hindered the mitochondrial uptake of folate. Instead, the mitochondrial uptake of flavin adenine dinucleotide (FAD) was specifically blocked by Slc25a32Y174C/K235R, Slc25a32K235R/K235R, and Slc25a32-/- mutations. A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid β-oxidation and amino acid metabolism being impaired, Slc25a32-/- embryos also had a subunit of glycine cleavage system-dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulation. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32-/- embryos. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice had no glycine accumulation, but had another formate donor-dimethylglycine accumulated and formate deficiency. Meanwhile, they suffered from the absence of all folate intermediates in mitochondria. Formate supplementation increased the folate amounts, but this effect was not restricted to the Slc25a32 mutant mice only. In summary, we established novel animal models, which enabled us to understand the function of SLC25A32 better and to elucidate the role of SLC25A32 dysfunction in human disease development and progression."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.org/dc/terms/identifier"doi:10.1007/s00018-022-04404-0"xsd:string
http://purl.uniprot.org/citations/35727412http://purl.org/dc/terms/identifier"doi:10.1007/s00018-022-04404-0"xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Liu L."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Liu L."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Zhang W."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Zhang W."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Lin Y.T."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Lin Y.T."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Li X.Z."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Li X.Z."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Liu Z.C."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Liu Z.C."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Jiang X.L."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Jiang X.L."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Cai Y.N."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Cai Y.N."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Shao Y.X."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Shao Y.X."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Jiang M.Y."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Jiang M.Y."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Peng M.Z."xsd:string
http://purl.uniprot.org/citations/35727412http://purl.uniprot.org/core/author"Peng M.Z."xsd:string
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