Disease relevance of SLC25A13

• BACKGROUND/AIMS: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans [1].
• Deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier (AGC), encoded by the SLC25A13 gene on chromosome 7q21.3, causes autosomal recessive disorders: adult-onset type II citrullinemia (CTLN2) and neonatal hepatitis associated with intrahepatic cholestasis (NICCD) [2].
• Most recently, the SLC25A13 mutations have been detected in neonatal/infantile patients with a type of neonatal hepatitis associated with cholestasis (NICCD) [3].
• BACKGROUND: Type II citrullinemia (CTLN2) characterized by a liver-specific argininosuccinate synthetase deficiency is an adult onset genetical disorder caused by the mutation of SLC25A13 gene, which results in fulminant hyperammonemia often with poor prognosis [4].
• Three patients with infantile cholestatic jaundice were found to have mutations of the SLC25A13 gene [5].
• Patients presenting with non-alcoholic fatty liver unrelated to obesity and metabolic syndrome might have citrin deficiency, and serum PSTI may be a useful indicator for distinguishing this from conventional NAFLD [6].

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

• From the viewpoint of the metabolic functions of citrin as aspartate glutamate carrier in urea synthesis and NADH shuttle, symptoms of CTLN2 and neonatal intrahepatic cholestasis caused by citrin deficiency are analyzed [11].
• Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels: mutations in the SLC25A13 gene [12].
• These results demonstrate that citrin and aralar1 are isoforms of the hitherto unidentified aspartate/glutamate carrier and explain why mutations in citrin cause type II citrullinemia in humans [13].
• A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency [14].
• OBJECTIVE: We report a risk of worsening of encephalopathy by glycerol infusion when this osmotic agent is used for the treatment of brain edema in patients with adult-onset type II citrullinemia (CTLN2) caused by citrin deficiency [15].

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

• The localization of Aralar2/citrin expressed in human cell lines is mitochondrial, the C-terminal half containing sufficient information for import and assembly into mitochondria [20].
• The activity of citrin and aralar1 as aspartate/glutamate exchangers was stimulated by Ca(2+) on the external side of the inner mitochondrial membrane, where the Ca(2+)-binding domains of these proteins are localized [13].
• Loss of citrin first cause deficiency of aspartate in the cytosol, which results in an increase in cytosolic NADH/NAD(+) ratio and then activation of fatty acid synthesis pathway to compensate the aberrant ratio [19].
• Affected fetuses may have suffered intrauterine citrin deficiency [21].
• Thus, we aimed to examine citrin protein in lymphocytes isolated from peripheral blood as an alternative diagnostic method [22].

Associations of SLC25A13 with chemical compounds

• Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle [16].
• Moreover citrin and its isoform aralar were found to be aspartate glutamate carrier [11].
• Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria [13].
• Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice [1].
• We have previously reported that although citrin-knockout (Ctrn(-/-)) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio [1].

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

• Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) [16].

Analytical, diagnostic and therapeutic context of SLC25A13

• We have identified a new class of substrates, citrin and aralar1, which are Ca2+-binding aspartate/glutamate carriers (AGCs) of the mitochondrial inner membrane, using cross-linking and immunoprecipitation assays in isolated mitochondria [24].
• We have detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the seven mutations by Western blot analysis with anti-human citrin antibody [25].
• Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency [21].
• Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation [26].
• CONCLUSION: the differential diagnosis of cholestatic jaundice of unknown origin in infants should therefore include citrin deficiency [14].

References