Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria

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• 作者：Benjamin Nota¹ ; ¹⁸ ; ^{benjamin.nota@gmail.com} ; Eduard A. Struys¹ ; ¹⁸ ; Ana Pop¹ ; Erwin E. Jansen¹ ; Matilde R. Fernandez Ojeda¹ ; Warsha A. Kanhai¹ ; Martijn Kranendijk¹ ; Silvy J.M. van Dooren¹ ; Marianna R. Bevova² ; Erik A. Sistermans² ; Aggie W.M. Nieuwint² ; Magalie Barth³ ; Tawfeg Ben-Omran⁴ ; Georg F. Hoffmann⁵ ; Pascale de Lonlay⁶ ; Marie T. McDonald⁷ ; Alf Meberg⁸ ; Ania C. Muntau⁹ ; Jean-Marc Nuoffer¹⁰ ; Rossella Parini¹¹ ; Marie-Hé ; lè ; ne Read¹² ; Axel Renneberg¹³ ; René ; Santer¹⁴ ; Thomas Strahleck¹⁵ ; Emile van Schaftingen¹⁶ ; Marjo S. van der Knaap¹⁷ ; Cornelis Jakobs¹ ; Gajja S. Salomons¹ ; ^{g.salomons@vumc.nl}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：4 April, 2013
• 年：2013
• 卷：92
• 期：4
• 页码：627-631
• 全文大小：292 K

文摘

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.