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Gene Review

SLC25A13  -  solute carrier family 25...

Homo sapiens

Synonyms: ARALAR2, CITRIN, CTLN2, Calcium-binding mitochondrial carrier protein Aralar2, Citrin, ...
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Disease relevance of SLC25A13


High impact information on SLC25A13

  • The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle [7].
  • The protein encoded by SLC25A13, named citrin, is bipartite in structure, containing a mitochondrial carrier motif and four EF-hand domains, suggesting it is a calcium-dependent mitochondrial solute transporter with a role in urea cycle function [8].
  • Using positional cloning we identified a novel gene, SLC25A13, and found five different DNA sequence alterations that account for mutations in all consanguineous patients examined [8].
  • We expressed in Chinese hamster ovary cells aralar1 and citrin, aspartate/glutamate exchangers that have Ca(2+)-binding sites in their sequence, and measured mitochondrial Ca2+ and ATP levels as well as cytosolic Ca2+ concentration with targeted recombinant probes [9].
  • A cDNA clone was isolated representing a citrin gene expressed in seeds when the majority of embryos were at the early globular stage of embryo development [10].

Chemical compound and disease context of SLC25A13


Biological context of SLC25A13

  • By using homozygosity mapping and positional cloning, we have shown that adult-onset type II citrullinemia (CTLN2) is caused by mutations of the SLC25A13 gene, which is localized on chromosome 7q21.3 and encodes a mitochondrial solute carrier protein named citrin [16].
  • The frequency of homozygotes carrying SLC25A13 mutations in both alleles is estimated to be minimally 1 in 21,000 from carrier detection (18 in 1,315 individuals tested) in the Japanese population [3].
  • The 851del4 mutation on the SLC25A13 gene accounts for the major genotype expression of patients with NICCD in Taiwan [17].
  • DNA analyses of SLC25A13 disclosed that the first patient was a compound heterozygote for the Ex16+74_IVS17-32del516 (del516-Ex16/IVS17) and IVS11+1G-->A mutations and the second one a homozygote for the del516-Ex16/IVS17 mutation [18].
  • Citrin as a liver-type AGC plays a role in supplying aspartate to the cytosol for urea, protein and nucleotide synthesis by exchanging mitochondrial aspartate for cytosolic glutamate and proton, and transporting cytosolic NADH reducing equivalent to mitochondria as a member of malate aspartate shuttle essential for aerobic glycolysis [19].

Anatomical context of SLC25A13


Associations of SLC25A13 with chemical compounds


Regulatory relationships of SLC25A13

  • Delivery may be a trigger for the development of CTLN2, while certain pathologic conditions associated with citrin gene abnormality are likely to induce hepatocellular carcinoma in patients with this disorder [23].

Other interactions of SLC25A13


Analytical, diagnostic and therapeutic context of SLC25A13


  1. Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice. Moriyama, M., Li, M.X., Kobayashi, K., Sinasac, D.S., Kannan, Y., Iijima, M., Horiuchi, M., Tsui, L.C., Tanaka, M., Nakamura, Y., Saheki, T. J. Hepatol. (2006) [Pubmed]
  2. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. Lu, Y.B., Kobayashi, K., Ushikai, M., Tabata, A., Iijima, M., Li, M.X., Lei, L., Kawabe, K., Taura, S., Yang, Y., Liu, T.T., Chiang, S.H., Hsiao, K.J., Lau, Y.L., Tsui, L.C., Lee, D.H., Saheki, T. J. Hum. Genet. (2005) [Pubmed]
  3. Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: Identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations. Yamaguchi, N., Kobayashi, K., Yasuda, T., Nishi, I., Iijima, M., Nakagawa, M., Osame, M., Kondo, I., Saheki, T. Hum. Mutat. (2002) [Pubmed]
  4. Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor. Kasahara, M., Ohwada, S., Takeichi, T., Kaneko, H., Tomomasa, T., Morikawa, A., Yonemura, K., Asonuma, K., Tanaka, K., Kobayashi, K., Saheki, T., Takeyoshi, I., Morishita, Y. Transplantation (2001) [Pubmed]
  5. Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. Tazawa, Y., Kobayashi, K., Ohura, T., Abukawa, D., Nishinomiya, F., Hosoda, Y., Yamashita, M., Nagata, I., Kono, Y., Yasuda, T., Yamaguchi, N., Saheki, T. J. Pediatr. (2001) [Pubmed]
  6. Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. Komatsu, M., Yazaki, M., Tanaka, N., Sano, K., Hashimoto, E., Takei, Y., Song, Y.Z., Tanaka, E., Kiyosawa, K., Saheki, T., Aoyama, T., Kobayashi, K. J. Hepatol. (2008) [Pubmed]
  7. Mitochondrial transporters as novel targets for intracellular calcium signaling. Satrústegui, J., Pardo, B., Del Arco, A. Physiol. Rev. (2007) [Pubmed]
  8. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Kobayashi, K., Sinasac, D.S., Iijima, M., Boright, A.P., Begum, L., Lee, J.R., Yasuda, T., Ikeda, S., Hirano, R., Terazono, H., Crackower, M.A., Kondo, I., Tsui, L.C., Scherer, S.W., Saheki, T. Nat. Genet. (1999) [Pubmed]
  9. Recombinant expression of the Ca(2+)-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary cells. Lasorsa, F.M., Pinton, P., Palmieri, L., Fiermonte, G., Rizzuto, R., Palmieri, F. J. Biol. Chem. (2003) [Pubmed]
  10. Polyembryony in Citrus. Accumulation of seed storage proteins in seeds and in embryos cultured in vitro. Koltunow, A.M., Hidaka, T., Robinson, S.P. Plant Physiol. (1996) [Pubmed]
  11. Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency. Saheki, T., Kobayashi, K., Iijima, M., Nishi, I., Yasuda, T., Yamaguchi, N., Gao, H.Z., Jalil, M.A., Begum, L., Li, M.X. Metabolic brain disease. (2002) [Pubmed]
  12. Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels: mutations in the SLC25A13 gene. Maruyama, H., Ogawa, M., Nishio, T., Kobayashi, K., Saheki, T., Sunohara, N. J. Neurol. Sci. (2001) [Pubmed]
  13. Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. Palmieri, L., Pardo, B., Lasorsa, F.M., del Arco, A., Kobayashi, K., Iijima, M., Runswick, M.J., Walker, J.E., Saheki, T., Satrústegui, J., Palmieri, F. EMBO J. (2001) [Pubmed]
  14. A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Ohura, T., Kobayashi, K., Abukawa, D., Tazawa, Y., Aikawa, J., Sakamoto, O., Saheki, T., Iinuma, K. Eur. J. Pediatr. (2003) [Pubmed]
  15. Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2). Yazaki, M., Takei, Y., Kobayashi, K., Saheki, T., Ikeda, S. Intern. Med. (2005) [Pubmed]
  16. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). Saheki, T., Kobayashi, K. J. Hum. Genet. (2002) [Pubmed]
  17. Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants. Yeh, J.N., Jeng, Y.M., Chen, H.L., Ni, Y.H., Hwu, W.L., Chang, M.H. J. Pediatr. (2006) [Pubmed]
  18. Variant clinical courses of 2 patients with neonatal intrahepatic cholestasis who have a novel mutation of SLC25A13. Takaya, J., Kobayashi, K., Ohashi, A., Ushikai, M., Tabata, A., Fujimoto, S., Yamato, F., Saheki, T., Kobayashi, Y. Metab. Clin. Exp. (2005) [Pubmed]
  19. Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Saheki, T., Kobayashi, K., Iijima, M., Moriyama, M., Yazaki, M., Takei, Y., Ikeda, S. Hepatol. Res. (2005) [Pubmed]
  20. Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues. Del Arco, A., Agudo, M., Satrústegui, J. Biochem. J. (2000) [Pubmed]
  21. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Tamamori, A., Fujimoto, A., Okano, Y., Kobayashi, K., Saheki, T., Tagami, Y., Takei, H., Shigematsu, Y., Hata, I., Ozaki, H., Tokuhara, D., Nishimura, Y., Yorifuji, T., Igarashi, N., Ohura, T., Shimizu, T., Inui, K., Sakai, N., Abukawa, D., Miyakawa, T., Matsumori, M., Ban, K., Kaneko, H., Yamano, T. Pediatr. Res. (2004) [Pubmed]
  22. Novel diagnostic approach to citrin deficiency: Analysis of citrin protein in lymphocytes. Tokuhara, D., Iijima, M., Tamamori, A., Ohura, T., Takaya, J., Maisawa, S., Kobayashi, K., Saheki, T., Yamano, T., Okano, Y. Mol. Genet. Metab. (2007) [Pubmed]
  23. Hepatocellular carcinoma in a case of adult-onset type II citrullinemia. Hagiwara, N., Sekijima, Y., Takei, Y., Ikeda, S., Kawasaki, S., Kobayashi, K., Saheki, T. Intern. Med. (2003) [Pubmed]
  24. The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex. Roesch, K., Hynds, P.J., Varga, R., Tranebjaerg, L., Koehler, C.M. Hum. Mol. Genet. (2004) [Pubmed]
  25. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Yasuda, T., Yamaguchi, N., Kobayashi, K., Nishi, I., Horinouchi, H., Jalil, M.A., Li, M.X., Ushikai, M., Iijima, M., Kondo, I., Saheki, T. Hum. Genet. (2000) [Pubmed]
  26. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Tamamori, A., Okano, Y., Ozaki, H., Fujimoto, A., Kajiwara, M., Fukuda, K., Kobayashi, K., Saheki, T., Tagami, Y., Yamano, T. Eur. J. Pediatr. (2002) [Pubmed]
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