Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria

Nota, Benjamin; Struys, Eduard A; Pop, Ana; Jansen, Erwin E; Fernandez Ojeda, Matilde R; Kanhai, Warsha A; Kranendijk, Martijn; van Dooren, Silvy J M; Bevova, Marianna R; Sistermans, Erik A; Nieuwint, Aggie W M; Barth, Magalie; Ben-Omran, Tawfeg; Hoffmann, Georg F; de Lonlay, Pascale; McDonald, Marie T; Meberg, Alf; Muntau, Ania C; Nuoffer, Jean-Marc; Parini, Rossella; ... (2013). Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. American journal of human genetics, 92(4), pp. 627-31. New York, N.Y.: Cell Press 10.1016/j.ajhg.2013.03.009

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Endokrinologie / Diabetologie / Metabolik (Pädiatrie) 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry 04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
UniBE Contributor:	Nuoffer, Jean-Marc
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0002-9297
Publisher:	Cell Press
Language:	English
Submitter:	Anette van Dorland
Date Deposited:	04 Oct 2013 14:41
Last Modified:	05 Dec 2022 14:12
Publisher DOI:	10.1016/j.ajhg.2013.03.009
PubMed ID:	23561848
Web of Science ID:	000317449700016
URI:	https://boris.unibe.ch/id/eprint/16555 (FactScience: 224212)