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Keiko Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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citrin deficiency and current treatment concepts
Molecular Genetics and Metabolism, 2010Co-Authors: Kanako Inoue, Kozo Mutoh, Anmi Tushima, Keiko KobayashiAbstract:In this paper, we describe the historical aspects of citrin and citrin deficiency, characteristic food preference and food aversion of citrin-deficient subjects, and carbohydrate toxicity in relation to ureogenesis and issues of the conventional treatment procedures for hyperammonemia in citrin deficiency, leading to current treatment concepts for citrin deficiency. We also emphasize the importance of a citrin deficiency mouse model in elucidating the pathophysiology and developing novel therapeutics based on the pathophysiology, such as sodium pyruvate.
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citrin mitochondrial glycerol 3 phosphate dehydrogenase double knock out mice recapitulate features of human citrin deficiency
Journal of Biological Chemistry, 2007Co-Authors: Mikio Iijima, Keiko Kobayashi, Masahisa Horiuchi, Miharu Ushikai, Fumihiko Okumura, Xiao Jian Meng, Ituro Inoue, Atsushi Tajima, Mitsuaki MoriyamaAbstract:Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol. Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD(+) ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.
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novel diagnostic approach to citrin deficiency analysis of citrin protein in lymphocytes
Molecular Genetics and Metabolism, 2007Co-Authors: Daisuke Tokuhara, Mikio Iijima, Keiko Kobayashi, Akiko Tamamori, Toshihiro Ohura, Junji Takaya, Shunichi Maisawa, Tsunekazu Yamano, Yoshiyuki OkanoAbstract:Citrin deficiency induces two clinical features; namely neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type II citrullinemia. Hypercitrullinemia is the most characteristic feature, whereas there are non-citrullinemic individuals. Diagnosis of citrin deficiency is performed by genetic analysis, although the 12 known mutations in the alleles are not detected in about 15% of cases. Thus, we aimed to examine citrin protein in lymphocytes isolated from peripheral blood as an alternative diagnostic method. We examined 38 children having an episode of cholestatic liver dysfunction, 8 heterozygotes, and 11 healthy individuals. All subjects were evaluated for citrin protein by Western blotting and for the 12 known mutations by gene analysis. Citrin protein was detected in 15 of 38 children with cholestatic liver dysfunction. Fourteen of them were negative for 12 known mutations in both alleles, whereas one patient was found to have a known mutation in one allele. Citrin protein was absent in 23 of the 38 patients. Among these 23, gene analysis diagnosed citrin deficiency in 19, whereas 2 patients were later revealed to be NICCD with novel mutations. In the remaining 2 patients, who exhibit the clinical features of NICCD, a known mutation was detected in one allele but no mutation was identified in another allele. Citrin protein was also detected in the 8 heterozygotes and 11 healthy individuals. We disclosed that citrin was deficient in lymphocytes among patients with citrin deficiency. Analysis of citrin is useful to diagnose citrin deficiency even in patients without known mutations or hypercitrullinemia.
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physiological role of citrin a liver type mitochondrial aspartate glutamate carrier and pathophysiology of citrin deficiency
Recent research developments in life sciences, 2005Co-Authors: Keiko KobayashiAbstract:Citrin is a mitochondrial aspartate-glutamate carrier predominantly expressed in the liver, heart, and kidney. It plays a role in various metabolic pathways, including aerobic glycolysis, gluconeogenesis, the urea cycle, and protein and nucleotide syntheses. We found that human citrin deficiency causes adult-onset type II citrullinemia (CTLN2) and neonatal cholestatic hepatitis (NICCD). Based on the current functions of citrin in the metabolism, we describe the pathophysiology and treatments of citrin deficiency.
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adult onset type ii citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle
Molecular Genetics and Metabolism, 2004Co-Authors: Keiko Kobayashi, Mikio Iijima, Md. Abdul Jalil, Laila Begum, Masahisa Horiuchi, Miharu Ushikai, Meng Xian Li, Yao Bang Lu, Ayako TabataAbstract:Abstract Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate–aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.
Mikio Iijima - One of the best experts on this subject based on the ideXlab platform.
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citrin mitochondrial glycerol 3 phosphate dehydrogenase double knock out mice recapitulate features of human citrin deficiency
Journal of Biological Chemistry, 2007Co-Authors: Mikio Iijima, Keiko Kobayashi, Masahisa Horiuchi, Miharu Ushikai, Fumihiko Okumura, Xiao Jian Meng, Ituro Inoue, Atsushi Tajima, Mitsuaki MoriyamaAbstract:Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol. Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD(+) ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.
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novel diagnostic approach to citrin deficiency analysis of citrin protein in lymphocytes
Molecular Genetics and Metabolism, 2007Co-Authors: Daisuke Tokuhara, Mikio Iijima, Keiko Kobayashi, Akiko Tamamori, Toshihiro Ohura, Junji Takaya, Shunichi Maisawa, Tsunekazu Yamano, Yoshiyuki OkanoAbstract:Citrin deficiency induces two clinical features; namely neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type II citrullinemia. Hypercitrullinemia is the most characteristic feature, whereas there are non-citrullinemic individuals. Diagnosis of citrin deficiency is performed by genetic analysis, although the 12 known mutations in the alleles are not detected in about 15% of cases. Thus, we aimed to examine citrin protein in lymphocytes isolated from peripheral blood as an alternative diagnostic method. We examined 38 children having an episode of cholestatic liver dysfunction, 8 heterozygotes, and 11 healthy individuals. All subjects were evaluated for citrin protein by Western blotting and for the 12 known mutations by gene analysis. Citrin protein was detected in 15 of 38 children with cholestatic liver dysfunction. Fourteen of them were negative for 12 known mutations in both alleles, whereas one patient was found to have a known mutation in one allele. Citrin protein was absent in 23 of the 38 patients. Among these 23, gene analysis diagnosed citrin deficiency in 19, whereas 2 patients were later revealed to be NICCD with novel mutations. In the remaining 2 patients, who exhibit the clinical features of NICCD, a known mutation was detected in one allele but no mutation was identified in another allele. Citrin protein was also detected in the 8 heterozygotes and 11 healthy individuals. We disclosed that citrin was deficient in lymphocytes among patients with citrin deficiency. Analysis of citrin is useful to diagnose citrin deficiency even in patients without known mutations or hypercitrullinemia.
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adult onset type ii citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle
Molecular Genetics and Metabolism, 2004Co-Authors: Keiko Kobayashi, Mikio Iijima, Md. Abdul Jalil, Laila Begum, Masahisa Horiuchi, Miharu Ushikai, Meng Xian Li, Yao Bang Lu, Ayako TabataAbstract:Abstract Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate–aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.
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Pathogenesis and Pathophysiology of Citrin (a Mitochondrial Aspartate Glutamate Carrier) Deficiency
Metabolic Brain Disease, 2002Co-Authors: Keiko Kobayashi, Mikio Iijima, Ikumi Nishi, Tomotsugu Yasuda, Naoki Yamaguchi, Hong Zhi Gao, Md. Abdul Jalil, Laila BegumAbstract:Adult-onset type II citrullinemia (CTLN2), characterized by a liver-specific deficiency of urea cycle enzyme, argininosuccinate synthetase, is caused by mutations in SLC25A13 that encodes a calcium binding mitochondrial solute carrier protein, citrin. Citrin deficiency causes not only CTLN2 but also neonatal intrahepatic cholestasis caused by citrin deficiency at neonatal period. Moreover citrin and its isoform aralar were found to be aspartate glutamate carrier. 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.
Mitsuaki Moriyama - One of the best experts on this subject based on the ideXlab platform.
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agc2 citrin deficiency from recognition of the disease till construction of therapeutic procedures
Biomolecules, 2020Co-Authors: Mitsuaki Moriyama, Aki Funahashi, Eishi KurodaAbstract:Can you imagine a disease in which intake of an excess amount of sugars or carbohydrates causes hyperammonemia? It is hard to imagine the intake causing hyperammonemia. AGC2 or citrin deficiency shows their symptoms following sugar/carbohydrates intake excess and this disease is now known as a pan-ethnic disease. AGC2 (aspartate glutamate carrier 2) or citrin is a mitochondrial transporter which transports aspartate (Asp) from mitochondria to cytosol in exchange with glutamate (Glu) and H+. Asp is originally supplied from mitochondria to cytosol where it is necessary for synthesis of proteins, nucleotides, and urea. In cytosol, Asp can be synthesized from oxaloacetate and Glu by cytosolic Asp aminotransferase, but oxaloacetate formation is limited by the amount of NAD+. This means an increase in NADH causes suppression of Asp formation in the cytosol. Metabolism of carbohydrates and other substances which produce cytosolic NADH such as alcohol and glycerol suppress oxaloacetate formation. It is forced under citrin deficiency since citrin is a member of malate/Asp shuttle. In this review, we will describe history of identification of the SLC25A13 gene as the causative gene for adult-onset type II citrullinemia (CTLN2), a type of citrin deficiency, pathophysiology of citrin deficiency together with animal models and possible treatments for citrin deficiency newly developing.
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citrin mitochondrial glycerol 3 phosphate dehydrogenase double knock out mice recapitulate features of human citrin deficiency
Journal of Biological Chemistry, 2007Co-Authors: Mikio Iijima, Keiko Kobayashi, Masahisa Horiuchi, Miharu Ushikai, Fumihiko Okumura, Xiao Jian Meng, Ituro Inoue, Atsushi Tajima, Mitsuaki MoriyamaAbstract:Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol. Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD(+) ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.
Masahisa Horiuchi - One of the best experts on this subject based on the ideXlab platform.
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citrin mitochondrial glycerol 3 phosphate dehydrogenase double knock out mice recapitulate features of human citrin deficiency
Journal of Biological Chemistry, 2007Co-Authors: Mikio Iijima, Keiko Kobayashi, Masahisa Horiuchi, Miharu Ushikai, Fumihiko Okumura, Xiao Jian Meng, Ituro Inoue, Atsushi Tajima, Mitsuaki MoriyamaAbstract:Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol. Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD(+) ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.
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adult onset type ii citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle
Molecular Genetics and Metabolism, 2004Co-Authors: Keiko Kobayashi, Mikio Iijima, Md. Abdul Jalil, Laila Begum, Masahisa Horiuchi, Miharu Ushikai, Meng Xian Li, Yao Bang Lu, Ayako TabataAbstract:Abstract Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate–aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.
Miharu Ushikai - One of the best experts on this subject based on the ideXlab platform.
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citrin mitochondrial glycerol 3 phosphate dehydrogenase double knock out mice recapitulate features of human citrin deficiency
Journal of Biological Chemistry, 2007Co-Authors: Mikio Iijima, Keiko Kobayashi, Masahisa Horiuchi, Miharu Ushikai, Fumihiko Okumura, Xiao Jian Meng, Ituro Inoue, Atsushi Tajima, Mitsuaki MoriyamaAbstract:Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol. Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD(+) ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.
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adult onset type ii citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle
Molecular Genetics and Metabolism, 2004Co-Authors: Keiko Kobayashi, Mikio Iijima, Md. Abdul Jalil, Laila Begum, Masahisa Horiuchi, Miharu Ushikai, Meng Xian Li, Yao Bang Lu, Ayako TabataAbstract:Abstract Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate–aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.