title: Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.
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.
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HV Amsterdam, the Netherlands. benjamin.nota@gmail.com
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nota
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Ana
authors.initials: A
authors.lastname: Pop
authors.forename: Erwin E
authors.initials: EE
authors.lastname: Jansen
authors.forename: Matilde R
authors.initials: MR
authors.lastname: Fernandez Ojeda
authors.forename: Warsha A
authors.initials: WA
authors.lastname: Kanhai
authors.forename: Martijn
authors.initials: M
authors.lastname: Kranendijk
authors.forename: Silvy J M
authors.initials: SJ
authors.lastname: van Dooren
authors.forename: Marianna R
authors.initials: MR
authors.lastname: Bevova
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.forename: Aggie W M
authors.initials: AW
authors.lastname: Nieuwint
authors.forename: Magalie
authors.initials: M
authors.lastname: Barth
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Marie T
authors.initials: MT
authors.lastname: McDonald
authors.forename: Alf
authors.initials: A
authors.lastname: Meberg
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nuoffer
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Read
authors.forename: Axel
authors.initials: A
authors.lastname: Renneberg
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.forename: Thomas
authors.initials: T
authors.lastname: Strahleck
authors.forename: Emile
authors.initials: E
authors.lastname: van Schaftingen
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
mesh_terms: D000595:Amino Acid Sequence; D027321:Anion Transport Proteins / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis; D020739:Brain Diseases, Metabolic, Inborn / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D019343:Citric Acid / Q000378:metabolism*; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005808:Genes, Recessive; D005977:Glutarates / Q000652:urine; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D027361:Organic Anion Transporters; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012189:Retrospective Studies; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: D027321:Anion Transport Proteins; D015415:Biomarkers; D005977:Glutarates; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; C532592:Slc25a1 protein, human; C019417:alpha-hydroxyglutarate; D019343:Citric Acid
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Neuropediatrics. 2000 Jun;31(3):137-40
references.pmid: 10963100
references.citation: J Bioenerg Biomembr. 1998 Jun;30(3):277-84
references.pmid: 9733094
references.citation: Am J Hum Genet. 2005 Feb;76(2):358-60
references.pmid: 15609246
references.citation: Hum Mol Genet. 2009 Nov 1;18(21):4180-8
references.pmid: 19654186
references.citation: Oncotarget. 2012 Oct;3(10):1220-35
references.pmid: 23100451
references.citation: Science. 2009 May 22;324(5930):1076-80
references.pmid: 19461003
references.citation: Genome Res. 2001 May;11(5):863-74
references.pmid: 11337480
references.citation: Science. 2010 Oct 15;330(6002):336
references.pmid: 20847235
references.citation: Arch Dis Child. 2004 Feb;89(2):148-51
references.pmid: 14736631
references.citation: Genomics. 1995 Sep 20;29(2):451-6
references.pmid: 8666394
references.citation: Bioessays. 2009 Jan;31(1):10-20
references.pmid: 19153992
references.citation: Biochim Biophys Acta. 2012 Jan;1825(1):111-6
references.pmid: 22101401
references.citation: Hum Mol Genet. 2004 Nov 15;13(22):2803-11
references.pmid: 15385440
references.citation: Nature. 2012 Feb 15;483(7390):484-8
references.pmid: 22343896
references.citation: J Neurooncol. 2009 Jan;91(2):233-6
references.pmid: 18931888
references.citation: Nature. 2009 Dec 10;462(7274):739-44
references.pmid: 19935646
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Nature. 2012 Feb 15;483(7390):479-83
references.pmid: 22343889
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16849-54
references.pmid: 15548604
references.citation: Tumour Biol. 2011 Apr;32(2):325-33
references.pmid: 21080253
references.citation: Bioinformatics. 2009 Sep 1;25(17):2283-5
references.pmid: 19542151
references.citation: Hum Genet. 1996 Jul;98(1):113-5
references.pmid: 8682495
references.citation: Pflugers Arch. 2004 Feb;447(5):689-709
references.pmid: 14598172
references.citation: J Inherit Metab Dis. 2012 Jul;35(4):571-87
references.pmid: 22391998
references.citation: Trends Mol Med. 2011 Nov;17(11):641-9
references.pmid: 21764377
references.citation: Clin Chem. 2003 Jul;49(7):1133-8
references.pmid: 12816910
references.citation: Trends Mol Med. 2010 Sep;16(9):387-97
references.pmid: 20692206
references.citation: Am J Physiol Cell Physiol. 2006 Dec;291(6):C1114-20
references.pmid: 16760265
references.citation: Nature. 2012 Feb 15;483(7390):474-8
references.pmid: 22343901