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

  • ️Tue Jan 01 2013

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

Benjamin Nota et al. Am J Hum Genet. 2013.

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.

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1

Schematic Overview of Genomic Organization and Protein Domain Structure of SLC25A1 (A) SLC25A1 contains nine exons that encode a 311 amino acid long product. The first 13 amino acids are a transit peptide (red) for mitochondrial targeting, and the mature protein contains six membrane-spanning helices (orange). Locations of the 12 different identified mutations are shown. An alignment of the involved amino acids with different species is shown in Figure S1. (B) Immunoblot analysis of SLC25A1 accumulation in fibroblasts derived from control “C” and affected subjects 1–5, 7, and 9. SLC25A1 is immunodetected in control, subjects 1–3 (homozygous missense mutations), and subject 5 with mutation c.18_24dup (p.Ala9Profs∗82) and c.499G>A (p.Gly167Arg). Low detection in subject 4 (homozygous mutation c.821C>T [p.Ala274Ilefs∗24]) and no detection in subject 7 with mutation c.18_24dup (p.Ala9Profs∗82) and c.768C>G (p.Tyr256∗) and subject 9 (homozygous mutation c.18_24dup [p.Ala9Profs∗82]) is consistent with the presence of truncating mutations. The whole-blot image and a blot with a lower exposure time are shown in Figure S3.

Figure 2
Figure 2

Decreased Citrate and Isocitrate Levels in Combined D,L-2-HGA (A and B) Urinary levels of (A) citrate and (B) isocitrate were measured with LC-MS/MS in samples of controls (n = 40) and of individuals with combined D,L-2-HGA (n = 11) with SLC25A1 mutations. Horizontal lines indicate the group sample means. The differences observed between controls and combined D,L-2-HGA-affected individuals were statistically significant by Mann-Whitney’s test for both citrate (p = 0.0011) and isocitrate (p = 0.0015) levels (p < 0.05 was considered significant). Urinary levels of an unrelated metabolite (α-aminoadipic acid) was not significantly different between individuals with combined D,L-2-HGA and controls (Figure S4). (C) Fibroblast cultures derived from affected subjects (n = 7) were given [U-13C6]glucose, which is metabolized by glycolysis predominantly to [13C2]acetyl-CoA. [13C2]acetyl-CoA is converted to [13C2]citrate within mitochondria via the Krebs cycle. Levels of [13C2]citrate were measured after 72 hr incubation in culture medium and are expressed as percentage compared to control fibroblasts (n = 2). Error bars indicate standard error of mean of replicate measurements (n = 3).

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