Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A13
SNOMEDCT: 716863007, 717155003;
Cytogenetic location: 7q21.3 Genomic coordinates (GRCh38): 7:96,120,220-96,322,098 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.3 | Citrullinemia, adult-onset type II | 603471 | Autosomal recessive | 3 |
| Citrullinemia, type II, neonatal-onset | 605814 | Autosomal recessive | 3 |
From information gathered from 18 individuals with citrullinemia type II (CTLN2; 603471, 605814) Kobayashi et al. (1999) used positional cloning and cDNA library screening to identify a novel gene, SLC25A13, which was found to encode a 675-amino acid protein with a molecular mass of 74 kD. The protein, termed citrin, is bipartite in structure, containing a mitochondrial carrier motif and 4 EF-hand domains. Northern blot analysis detected ubiquitous expression of a 3.4-kb transcript, with highest expression in liver.
Based on the structure of the citrin protein, Kobayashi et al. (1999) suggested that it is a calcium-dependent mitochondrial solute transporter with a role in urea cycle function.
Roesch et al. (2004) determined that citrin and aralar (SLC25A12; 603667), which are Ca(2+)-binding aspartate/glutamate carriers (AGC) of the mitochondrial inner membrane, are substrates for the TIMM8A (300356)/TIMM13 (607383) complex. The AGCs function in the aspartate-malate NADH shuttle that moves reducing equivalents from the cytosol to the mitochondrial matrix. Roesch et al. (2004) hypothesized that insufficient NADH shuttling, linked with changes in Ca(2+) concentration, in sensitive cells of the CNS might contribute to the pathologic process associated with Mohr-Tranebjaerg syndrome (MTS; 304700).
Kobayashi et al. (1999) determined that SLC25A13 contains 18 exons and encompasses approximately 200 kb of DNA.
Kobayashi et al. (1999) studied 118 CTLN2 families and localized the CTLN2 locus to chromosome 7q21.3 by homozygosity mapping analysis of individuals from 18 consanguineous unions.
Adult-Onset Type II Citrullinemia
In 18 adult patients with CTLN2 from consanguineous parents, Kobayashi et al. (1999) identified 5 distinct mutations (603859.0001-603859.0005) in the SLC25A13 gene and confirmed their causative role in the disease. The 5 recessive mutations all predicted truncation of the protein or loss of the loop between transmembrane-spanning regions, making it unlikely that the mutant protein would be translocated into the mitochondrial membrane.
The studies of adult-onset type II citrullinemia in Japanese were extended by Yasuda et al. (2000), who identified 2 novel mutations in the SLC25A13 gene. Diagnostic analysis for the 7 known mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies revealed that 102 patients had 1 or 2 of the 7 mutations and 93 patients were homozygotes or compound heterozygotes. Five of 22 patients from consanguineous unions were compound heterozygotes, suggesting a high frequency of the mutated genes. By Western blot analysis with antihuman citrin antibody, Yasuda et al. (2000) detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the 7 mutations and thus hypothesized that CTLN2 is caused by a complete deletion of citrin.
In a Pakistani man living in Europe who had episodic confusion and developed fatal hyperammonemic encephalopathy, Fiermonte et al. (2008) identified homozygosity for a missense mutation in the SLC25A13 gene (R588Q; 603859.0007). The authors noted that type II citrullinemia has rarely been reported outside of East Asia but must be considered in adults presenting with hyperammonemic encephalopathy.
Neonatal-Onset Type II Citrullinemia
Ohura et al. (2001) described children with neonatal onset of type II citrullinemia (605814) due to mutations in the SLC25A13 gene. One patient was a compound heterozygote for the 851del4 (603859.0001) and IVS11+1G-A (603859.0002) mutations; 2 sibs were homozygotes for the latter mutation.
Tazawa et al. (2001) described 3 children with neonatal onset of type II citrullinemia who presented between 1 and 5 months of age with cholestatic jaundice and were found to have mutations in the SLC25A13 gene.
Tamamori et al. (2002) reported 5 patients with neonatal intrahepatic cholestasis caused by citrin deficiency and confirmed by mutation analysis.
Sinasac et al. (2004) developed Slc25a13-null mice. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion demonstrated deficits in ureagenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Slc25a13-null mice up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic argininosuccinate synthetase (ASS; 603470) activity. Serologic measures of glucose, amino acid, and ammonia metabolism also showed no significant changes. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. Sinasac et al. (2004) hypothesized that Slc25a13 deficiency alone may be insufficient to produce a CTLN2-like phenotype in mice. Their observations were compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers may be involved.
Slc25a13-knockout mice show reduced mitochondrial Asp transport, but have no apparent phenotype, likely due to increased hepatic activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2; 138430), which can transport NADH reducing equivalents into mitochondria. Saheki et al. (2007) found that mice with a combined disruption of the Slc25a13 and Gpd2 genes had poor growth and developed citrullinemia, hyperammonemia, hypoglycemia, and fatty liver, all features of human citrin deficiency. An altered cytosolic NADH/NAD(+) ratio was closely associated with hyperammonemia. The data indicated that the more severe phenotype present in the Slc25a13/Gpd2 double-knockout mice represents a more accurate model of human citrin deficiency than Slc25a13-knockout mice.
Kobayashi et al. (1999) found that 9 patients with adult-onset type II citrullinemia (603471) were homozygous for a 4-bp (GTAT) deletion from nucleotide 851 in exon 9, predicting a frameshift and introduction of a stop codon at position 286, leading to premature termination of the protein. Three other patients were heterozygous for the mutation.
Ohura et al. (2001) identified a child with neonatal-onset citrullinemia (605814) who was compound heterozygous for this mutation and an IVS11+1G-A mutation (603859.0002) in the SLC25A13 gene. The patient pursued a favorable clinical course, and all biochemical abnormalities normalized by the age of 12 months.
Tamamori et al. (2002) reported a patient with neonatal-onset citrullinemia who was compound heterozygous for the 4-bp deletion and IVS11+1G-A. She had an unusual disease course with a worsening of liver function at age 6 months, ultimately requiring a living-related liver transplant at 10 months of age. She had normal growth and mental development at age 3 years. Tamamori et al. (2002) noted that the same genotype had been identified in a patient with the usual course of spontaneous remission (Ohura et al., 2001), suggesting that the severe phenotype was not due to the genotype.
Kobayashi et al. (1999) found 5 patients with adult-onset type II citrullinemia (603471) who were homozygous for a G-to-A substitution at the 5-prime end of intron 11, resulting in abnormal splicing and deletion of exon 11 in mRNA. This caused loss of 53 amino acids (codons 340-392) within the first hydrophilic loop between the first and second predicted transmembrane (TM1 and TM2) domains of citrin.
Ohura et al. (2001) found homozygosity for this mutation in sibs who presented in the neonatal period (605814). Laboratory data suggested intrahepatic cholestasis. The sibs and a patient who was a compound heterozygote for this and the 4-bp deletion mutation (603859.0001) pursued a favorable clinical course. All biochemical abnormalities normalized by the age of 12 months.
Tomomasa et al. (2001) described 2 patients with type II citrullinemia who developed transient hypoproteinemia and jaundice in early infancy. Liver histology showed markedly fatty changes and fibrosis. Both patients were homozygous for the IVS11+1G-A mutation.
In a patient with adult-onset type II citrullinemia (603471), Kobayashi et al. (1999) identified a 23-bp homozygous insertion in exon 16 of SLC25A13, 1638ins23, resulting in a frameshift at codon 554 and the addition of 16 new amino acids. A stop codon was introduced at position 570, leading to premature termination of the C terminus of citrin. The inserted sequence was apparently a tandem repeat of 23 bp from nucleotide 1638-1660 of SLC25A13 cDNA.
In 2 patients with adult-onset type II citrullinemia (603471), Kobayashi et al. (1999) found a nonsense mutation, ser225 to ter, resulting from a C-to-A substitution at position 674 in exon 7 that changed serine to a stop codon at position 225 and predicted premature termination of the protein. The patients were heterozygous for the mutation and had the 851del4 mutation (603859.0001) on the other chromosome.
In a patient with adult-onset type II citrullinemia (603471), Kobayashi et al. (1999) found a splice site mutation, a G-to-A substitution at the 5-prime end of intron 13, resulting in the deletion of 27 amino acids (codons 411-437) between TM2 and TM3. The patient was a compound heterozygote for this mutation and the 851del4 mutation (603859.0001).
Yasuda et al. (2000) identified 2 patients with adult-onset type II citrullinemia (603471) who were compound heterozygous for the IVS11+1G-A mutation (603859.0002) and a 1-bp insertion at nucleotide 1800, predicting premature termination (Y200X) of the C terminus of the SLC25A13 gene.
Tazawa et al. (2001) identified the 1800ins1 mutation in compound heterozygous state with the S225X mutation (603859.0004) in a child with neonatal-onset type II citrullinemia (605814). Liver histology showed fatty tissue without evidence of giant cell hepatitis, the usual finding in most forms of transient neonatal jaundice.
In a 38-year-old Pakistani man with episodic confusion and elevated plasma ammonia and arginine levels, citrullinemia (CTLN2; 603471), normal glutamine, and low serine levels, who developed fatal hyperammonemic encephalopathy, Fiermonte et al. (2008) identified homozygosity for a 1763G-A transition in the SLC25A13 gene, resulting in an arg588-to-gln (R588Q) substitution at a highly conserved residue. Functional analysis of the mutant protein showed only about 10% of normal transport of aspartate and glutamate. The unrelated parents, who came from the same village in Pakistan, were heterozygous for the mutation, as were 3 other unaffected members of the pedigree; 2 unaffected members of the extended family were also found to be homozygous for the mutation but had no detectable biochemical abnormalities. The mutation was not found in 104 unrelated control chromosomes.
Fiermonte, G., Soon, D., Chaudhuri, A., Paradies, E., Lee, P. J., Krywawych, S., Palmieri, F., Lachmann, R. H. An adult with type 2 citrullinemia presenting in Europe. (Letter) New Eng. J. Med. 358: 1408-1409, 2008. [PubMed: 18367750] [Full Text: https://doi.org/10.1056/NEJMc0707353]
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. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nature Genet. 22: 159-163, 1999. [PubMed: 10369257] [Full Text: https://doi.org/10.1038/9667]
Ohura, T., Kobayashi, K., Tazawa, Y., Nishi, I., Abukawa, D., Sakamoto, O., Iinuma, K., Saheki, T. Neonatal presentation of adult-onset type II citrullinemia. Hum. Genet. 108: 87-90, 2001. [PubMed: 11281457] [Full Text: https://doi.org/10.1007/s004390000448]
Roesch, K., Hynds, P. J., Varga, R., Tranebjaerg, L., Koehler, C. M. The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex. Hum. Molec. Genet. 13: 2101-2111, 2004. [PubMed: 15254020] [Full Text: https://doi.org/10.1093/hmg/ddh217]
Saheki, T., Iijima, M., Li, M. X., Kobayashi, K., Horiuchi, M., Ushikai, M., Okumura, F., Meng, X. J., Inoue, I., Tajima, A., Moriyama, M., Eto, K., Kadowaki, T., Sinasac, D. S., Tsui, L.-C., Tsuji, M., Okano, A., Kobayashi, T. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency. J. Biol. Chem. 282: 25041-25052, 2007. [PubMed: 17591776] [Full Text: https://doi.org/10.1074/jbc.M702031200]
Sinasac, D. S., Moriyama, M., Jalil, M. A., Begum, L., Li, M. X., Iijima, M., Horiuchi, M., Robinson, B. H., Kobayashi, K., Saheki, T., Tsui, L.-C. Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Molec. Cell. Biol. 24: 527-536, 2004. [PubMed: 14701727] [Full Text: https://doi.org/10.1128/MCB.24.2.527-536.2004]
Tamamori, A., Okano, Y., Ozaki, H., Fujimoto, A., Kajiwara, M., Fukuda, K., Kobayashi, K., Saheki, T., Tagami, Y., Yamano, T. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Europ. J. Pediat. 161: 609-613, 2002. [PubMed: 12424587] [Full Text: https://doi.org/10.1007/s00431-002-1045-2]
Tazawa, Y., Kobayashi, K., Ohura, T., Abukawa, D., Nishinomiya, F., Hosoda, Y., Yamashita, M., Nagata, I., Kono, Y., Yasuda, T., Yamaguchi, N., Saheki, T. Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. J. Pediat. 138: 735-740, 2001. [PubMed: 11343052] [Full Text: https://doi.org/10.1067/mpd.2001.113264]
Tomomasa, T., Kobayashi, K., Kaneko, H., Shimura, H., Fukusato, T., Tabata, M., Inoue, Y., Ohwada, S., Kasahara, M., Morishita, Y., Kimura, M., Saheki, T., Morikawa, A. Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy. J. Pediat. 138: 741-743, 2001. [PubMed: 11343053] [Full Text: https://doi.org/10.1067/mpd.2001.113361]
Yasuda, T., Yamaguchi, N., Kobayashi, K., Nishi, I., Horinouchi, H., Jalil, M. A., Li, M. X., Ushikai, M., Iijima, M., Kondo, I., Saheki, T. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum. Genet. 107: 537-545, 2000. [PubMed: 11153906] [Full Text: https://doi.org/10.1007/s004390000430]