PMID:23561848

Citation	Nota, B, Struys, EA, Pop, A, Jansen, EE, Fernandez Ojeda, MR, Kanhai, WA, Kranendijk, M, van Dooren, SJ, Bevova, MR, Sistermans, EA, Nieuwint, AW, Barth, M, Ben-Omran, T, Hoffmann, GF, de Lonlay, P, McDonald, MT, Meberg, A, Muntau, AC, Nuoffer, JM, Parini, R, Read, MH, Renneberg, A, Santer, R, Strahleck, T, van Schaftingen, E, van der Knaap, MS, Jakobs, C and Salomons, GS (2013) Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 92:627-31
Abstract	The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.
Links	PubMed PMC3617390 Online version:10.1016/j.ajhg.2013.03.009
Keywords	Amino Acid Sequence; Anion Transport Proteins/genetics; Biological Markers/analysis; Brain Diseases, Metabolic, Inborn/etiology; Brain Diseases, Metabolic, Inborn/metabolism; Brain Diseases, Metabolic, Inborn/pathology; Case-Control Studies; Cells, Cultured; Chromatography, Liquid; Citric Acid/metabolism; Exome/genetics; Female; Fibroblasts/metabolism; Fibroblasts/pathology; Genes, Recessive; Glutarates/urine; Humans; Male; Mitochondria/metabolism; Mitochondrial Proteins/genetics; Molecular Sequence Data; Mutation/genetics; Phenotype; Protein Structure, Tertiary; Retrospective Studies; Sequence Homology, Amino Acid; Stereoisomerism; Tandem Mass Spectrometry
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TXTP		GO:0006843: mitochondrial citrate transport	ECO:0000315:		P		Figure 2 A and B shows a comparison of urine samples of individuals with a recessive mutation to those without the mutation. The graph shows that individuals with the mutation have a lower amount of citrate and isocitrate.	complete CACAO 9778

References

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