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Keiko Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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six cases of citrin deficiency in korea
International Journal of Molecular Medicine, 2007Co-Authors: Guhwan Kim, Keiko Kobayashi, Miharu Ushikai, Jinho Choi, Ju Hyun Kim, Jaeyoung Kim, Hanwook YooAbstract:Citrin deficiency resulting from mutations of the SLC25A13 gene is associated with two major clinical phenotypes; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type 2 Citrullinemia (CTLN2). In Korea, 6 cases of citrin deficiency were diagnosed based on biochemical and molecular findings. Four NICCD patients (2 boys and 2 girls) presented high citrulline levels on a newborn screening test or neonatal cholestasis. They were associated with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminemia, mild hyperammonemia, elevated citrulline, methionine and threonine. All of the hepatic manifestations were resolved spontaneously at the age of 5-9 months. Mutation analysis identified them as compound heterozygotes carrying each of the c.851del4, IVS11+1G>A, IVS13+1G>A, G393S, and IVS16ins3kb mutant alleles. Two adult male CTLN2 patients were identified. They were aged 24 and 37 years, and presented sudden loss of consciousness, hyperammonemia and Citrullinemia. They were compound heterozygotes with IVS13+1G>A and IVS16ins3kb, and with c.851del4 and IVS11+1G>A mutant alleles. This report describes the clinical characteristics, biochemical findings and molecular analysis of the SLC25A13 gene of patients with citrin deficiency in Korea.
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novel diagnostic approach to citrin deficiency analysis of citrin protein in lymphocytes
Molecular Genetics and Metabolism, 2007Co-Authors: Daisuke Tokuhara, Keiko Kobayashi, Mikio Iijima, 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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effects of citrin deficiency in the perinatal period feasibility of newborn mass screening for citrin deficiency
Pediatric Research, 2004Co-Authors: Akiko Tamamori, Keiko Kobayashi, Yoshiyuki Okano, Akie Fujimoto, Yasuko Tagami, Yosuke Shigematsu, Hazime Takei, Ikue Hata, Hajime OzakiAbstract:Deficiency of citrin due to mutations of the SLC25A13 gene causes adult-onset type II Citrullinemia (CTLN2) and one type of neonatal intrahepatic cholestasis (NICCD). About half of the NICCD patients are detected based on high galactose, phenylalanine, and/or methionine concentrations on newborn mass screening (NMS). To clarify the perinatal and neonatal effects and the inconsistent results on NMS, we examined aminograms, the levels of bile acids and galactose in dried blood spots for NMS from 20 patients with NICCD. Birth weight was low for gestational age (-1.4 +/- 0.7 SD). Affected fetuses may have suffered intrauterine citrin deficiency. The first abnormality detected after birth was Citrullinemia, and 19 of 20 patients had citrulline levels higher than +2 SD of controls. Tyrosine, phenylalanine, methionine, galactose, and bile acids were less affected than citrulline on d 5 after birth. Galactose and bile acids levels were increased at 1 mo in comparison with d 5 after birth due to impairment of the cytosolic NADH reducing-equivalent supply into mitochondria of hepatocytes. Patients with negative findings on NMS had low levels of total 20 amino acids. Citrulline/serine, citrulline /leucine plus isoleucine, and citrulline/total amino acids ratios, controlled for the confounding effect of low amount of total amino acids, were higher in all patients than +2 SD, +2 SD, and +3 SD of controls, respectively. NMS for citrin deficiency (frequency of homozygote with SLC25A13 mutation: 1/10,000-1/38,000 in East Asia) will be useful for clarification of the clinical course, treatment, and prevention of this disease.
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feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult onset type ii Citrullinemia
Liver Transplantation, 2004Co-Authors: Masahide Yazaki, Keiko Kobayashi, Takeyori Saheki, Yoichi Takei, Yasuhiko Hashikura, Toshihiko Ikegami, Shinichi Miyagawa, Kanji Yamamoto, Takahiko Tokuda, Shu-ichi IkedaAbstract:More than 20 patients with adult-onset type II Citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II Citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II Citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II Citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.
Takeyori Saheki - One of the best experts on this subject based on the ideXlab platform.
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feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult onset type ii Citrullinemia
Liver Transplantation, 2004Co-Authors: Masahide Yazaki, Keiko Kobayashi, Takeyori Saheki, Yoichi Takei, Yasuhiko Hashikura, Toshihiko Ikegami, Shinichi Miyagawa, Kanji Yamamoto, Takahiko Tokuda, Shu-ichi IkedaAbstract:More than 20 patients with adult-onset type II Citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II Citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II Citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II Citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.
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effectiveness of carbohydrate restricted diet and arginine granules therapy for adult onset type ii Citrullinemia a case report of siblings showing homozygous slc25a13 mutation with and without the disease
Hepatology Research, 2003Co-Authors: Yasushi Imamura, Keiko Kobayashi, Toshihiko Shibatou, Sachiko Aburada, Kenji Tahara, Osamu Kubozono, Takeyori SahekiAbstract:Case 1 is a 37-year-old Japanese man who was admitted to this hospital with a disturbance of consciousness. A diagnosis of adult-onset type II Citrullinemia was made by DNA analysis of SLC25A13 (851del4/851del4) and measurement of hepatic ASS activity (2% of control value). After regaining consciousness, Case 1 was started on a dietary therapy, revealing that hypertriglyceridemia and ketogenesis impairment deteriorated on a low-protein diet and ameliorated on a carbohydrate-restricted (high-protein) diet. Case 1 could tolerate 70 g/day of protein while using arginine granules and developed hyperammonemia only after discontinuation of the administration. Case 2 (an elder brother of Case 1) is also homozygote for the same SLC25A13 mutation. The hepatic activity of argininosuccinate synthetase was about 20% of the control value. However, Case 2 exhibited neither hyperammonemia nor lipid metabolism abnormalities. These results suggest that, although adult-onset type II Citrullinemia is caused by a deficiency of citrin, which plays key roles in carbohydrates, amino acids and even lipid metabolism, some other environmental or genetic factors are required for the onset of the disease, and from the authors' clinical experience, a carbohydrate-restricted (relatively high-protein) diet is advocated as a benefit to the patients, and that arginine granules are indispensable to this new dietary therapy.
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recovery from marked altered consciousness in a patient with adult onset type ii Citrullinemia diagnosed by dna analysis and treated with a living related partial liver transplantation
Internal Medicine, 2002Co-Authors: Yasuhiro Takashima, Keiko Kobayashi, Makoto Koide, Hideyuki Fukunaga, Masahide Iwai, Masaki Miura, Ryoji Yoneda, Tsuneo Fukuda, Takeyori SahekiAbstract:A 21-year-old woman was admitted with altered consciousness and hyperammonemia. She was diagnosed as having adult-onset type II Citrullinemia (CTLN2) by DNA analysis. The patient had mutations of the SLC25A13 gene, which were compound heterozygotes of 851 del 4 and IVS11+1G>A. CTLN2 has a poor prognosis, in spite of various intensive medications, and we performed a living related partial liver transplantation (LRLT). Over a 2-year follow-up, the patient has been well. CTLN2 can be diagnosed by the DNA analysis and can be treated by LRLT.
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a patient with adult onset type ii Citrullinemia on long term hemodialysis reversal of clinical symptoms and brain mri findings
American Journal of Kidney Diseases, 2002Co-Authors: Saori Oshiro, Keiko Kobayashi, Takeyori Saheki, Tutomu Kochinda, Takeshi Tana, Masanobu Yamazato, Yukihiro Komine, Hiromi Muratani, Kunitoshi Iseki, Shuichi TakishitaAbstract:A 40-year-old woman was referred for several episodes of coma lasting from 2 hours to 2 days. She had been on maintenance hemodialysis for polycystic kidney disease for 9 months. Laboratory findings showed high serum levels of ammonia and citrulline, and a diagnosis of adult-onset type II Citrullinemia was made. Multiple areas of focal brain edema were shown by magnetic resonance imaging. The clinical manifestations of coma and abnormal behavior were resolved with intensified dialysis (ie, four 5-hour sessions per week with glycerol and continuous ambulatory peritoneal dialysis). No abnormal shadow was present on follow-up magnetic resonance imaging. Such intensified dialysis therapy may be effective for adult-onset type II Citrullinemia and may be applicable even in patients who do not have end-stage renal disease if liver transplant is not an option.
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type ii adult onset citrullinaemia clinical pictures and the therapeutic effect of liver transplantation
Journal of Neurology Neurosurgery and Psychiatry, 2001Co-Authors: Shu-ichi Ikeda, Keiko Kobayashi, Yoichi Takei, Seiji Kawasaki, Masahide Yazaki, Yasuhiko Hashikura, Masahide Iwai, Toshihiko Ikegami, Takeyori SahekiAbstract:Objective—Adult onset type II Citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to. Methods—Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member. Results—There were six men and four women;the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diVuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work. Conclusions—The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach. (J Neurol Neurosurg Psychiatry 2001;71:663‐670)
Shu-ichi Ikeda - One of the best experts on this subject based on the ideXlab platform.
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feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult onset type ii Citrullinemia
Liver Transplantation, 2004Co-Authors: Masahide Yazaki, Keiko Kobayashi, Takeyori Saheki, Yoichi Takei, Yasuhiko Hashikura, Toshihiko Ikegami, Shinichi Miyagawa, Kanji Yamamoto, Takahiko Tokuda, Shu-ichi IkedaAbstract:More than 20 patients with adult-onset type II Citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II Citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II Citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II Citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.
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hepatocellular carcinoma in a case of adult onset type ii Citrullinemia
Internal Medicine, 2003Co-Authors: Naoki Hagiwara, Shu-ichi Ikeda, Yoichi Takei, Yoshiki Sekijima, Seiji Kawasaki, Keiko KobayashiAbstract:A 40-year-old woman was admitted with altered consciousness and hyperammonemia after she had delivered her first baby. DNA analysis of the citrin gene and enzymatic assay of argininosuccinate synthetase in the liver led to a diagnosis of adult-onset type II Citrullinemia (CTLN2). She was also found to have hepatocellular carcinoma (HCC) and underwent palliative surgery consisting of partial liver section of the HCC. 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.
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type ii adult onset citrullinaemia clinical pictures and the therapeutic effect of liver transplantation
Journal of Neurology Neurosurgery and Psychiatry, 2001Co-Authors: Shu-ichi Ikeda, Keiko Kobayashi, Yoichi Takei, Seiji Kawasaki, Masahide Yazaki, Yasuhiko Hashikura, Masahide Iwai, Toshihiko Ikegami, Takeyori SahekiAbstract:Objective—Adult onset type II Citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to. Methods—Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member. Results—There were six men and four women;the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diVuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work. Conclusions—The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach. (J Neurol Neurosurg Psychiatry 2001;71:663‐670)
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complete neurological recovery of an adult patient with type ii Citrullinemia after living related partial liver transplantation
Transplantation, 1996Co-Authors: Masahide Yazaki, Keiko Kobayashi, Shu-ichi Ikeda, Yoichi Takei, Seiji Kawasaki, Nobuo Yanagisawa, Hidetoshi Matsunami, Yasuhiko Hashikura, Masatoshi Makuuchi, Takeyori SahekiAbstract:Type II Citrullinemia is an adult-onset hepatocerebral disease caused by a deficiency of argininosuccinate synthetase in liver. A 25-year-old Japanese man suddenly developed encephalopathy, showing disorientation and flapping tremor. Plasma concentrations of ammonia and citrulline were extremely high, and hepatic argininosuccinate synthetase activity was deficient. The patient's condition deteriorated rapidly in spite of intensive medications. Therefore, we performed a partial liver transplantation using a graft obtained from his healthy 61-year-old father. After surgery, his neurological symptoms soon disappeared and plasma levels of ammonia and citrulline were normalized within 3 months after operation. Type II Citrullinemia is one fulminant form of various liver-based metabolic diseases, and immediate liver transplantation is necessary to rescue patients with this disease. As liver transplantation from cadaveric donor is still not possible in Japan, it seems justifiable to use living related partial liver transplantation for our patient.
Laila Begum - One of the best experts on this subject based on the ideXlab platform.
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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, Laila Begum, Md. Abdul Jalil, 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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slc25a13 knockout mice harbor metabolic deficits but fail to display hallmarks of adult onset type ii Citrullinemia
Molecular and Cellular Biology, 2004Co-Authors: David S Sinasac, Brian H. Robinson, Keiko Kobayashi, Mikio Iijima, Laila Begum, Mitsuaki Moriyama, Masahisa Horiuchi, Abdul M Jalil, Lapchee TsuiAbstract:Adult-onset type II Citrullinemia (CTLN2) is an autosomal recessive disease caused by mutations in SLC25A13, the gene encoding the mitochondrial aspartate/glutamate carrier citrin. The absence of citrin leads to a liver-specific, quantitative decrease of argininosuccinate synthetase (ASS), causing hyperammonemia and Citrullinemia. To investigate the physiological role of citrin and the development of CTLN2, an Slc25a13-knockout (also known as Ctrn-deficient) mouse model was created. The resulting Ctrn-/- mice were devoid of Slc25a13 mRNA and citrin protein. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion also demonstrated deficits in ureogenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Surprisingly, Ctrn-/- mice up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic ASS activity. Serological measures of glucose, amino acid, and ammonia metabolism also showed no significant alterations. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. These results suggest that citrin deficiency alone may not be sufficient to produce a CTLN2-like phenotype in mice. These observations are compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers are now suspected.
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Pathogenesis and Pathophysiology of Citrin (a Mitochondrial Aspartate Glutamate Carrier) Deficiency
Metabolic Brain Disease, 2002Co-Authors: Keiko Kobayashi, Mikio Iijima, Tomotsugu Yasuda, Ikumi Nishi, 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.
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the gene mutated in adult onset type ii citrullinaemia encodes a putative mitochondrial carrier protein
Nature Genetics, 1999Co-Authors: Keiko Kobayashi, David S Sinasac, Mikio Iijima, Andrew P Boright, Laila Begum, Jeffrey R Lee, Tomotsugu Yasuda, Sayaka Ikeda, Ryuki Hirano, Hiroki TerazonoAbstract:Citrullinaemia (CTLN) is an autosomal recessive disease caused by deficiency of argininosuccinate synthetase (ASS). Adult-onset type II citrullinaemia (CTLN2) is characterized by a liver-specific ASS deficiency with no abnormalities in hepatic ASS mRNA or the gene ASS (refs 1–17). CTLN2 patients (1/100,000 in Japan13) suffer from a disturbance of consciousness and coma, and most die with cerebral edema within a few years of onset. CTLN2 differs from classical citrullinaemia (CTLN1, OMIM 215700) in that CTLN1 is neonatal or infantile in onset, with ASS enzyme defects (in all tissues) arising due to mutations in ASS on chromosome 9q34 (refs 18–21). We collected 118 CTLN2 families, and localized the CTLN2 locus to chromosome 7q21.3 by homozygosity mapping analysis of individuals from 18 consanguineous unions. 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. SLC25A13 encodes a 3.4-kb transcript expressed most abundantly in liver. 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.
Mikio Iijima - One of the best experts on this subject based on the ideXlab platform.
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novel diagnostic approach to citrin deficiency analysis of citrin protein in lymphocytes
Molecular Genetics and Metabolism, 2007Co-Authors: Daisuke Tokuhara, Keiko Kobayashi, Mikio Iijima, 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, Laila Begum, Md. Abdul Jalil, 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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slc25a13 knockout mice harbor metabolic deficits but fail to display hallmarks of adult onset type ii Citrullinemia
Molecular and Cellular Biology, 2004Co-Authors: David S Sinasac, Brian H. Robinson, Keiko Kobayashi, Mikio Iijima, Laila Begum, Mitsuaki Moriyama, Masahisa Horiuchi, Abdul M Jalil, Lapchee TsuiAbstract:Adult-onset type II Citrullinemia (CTLN2) is an autosomal recessive disease caused by mutations in SLC25A13, the gene encoding the mitochondrial aspartate/glutamate carrier citrin. The absence of citrin leads to a liver-specific, quantitative decrease of argininosuccinate synthetase (ASS), causing hyperammonemia and Citrullinemia. To investigate the physiological role of citrin and the development of CTLN2, an Slc25a13-knockout (also known as Ctrn-deficient) mouse model was created. The resulting Ctrn-/- mice were devoid of Slc25a13 mRNA and citrin protein. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion also demonstrated deficits in ureogenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Surprisingly, Ctrn-/- mice up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic ASS activity. Serological measures of glucose, amino acid, and ammonia metabolism also showed no significant alterations. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. These results suggest that citrin deficiency alone may not be sufficient to produce a CTLN2-like phenotype in mice. These observations are compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers are now suspected.
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Pathogenesis and Pathophysiology of Citrin (a Mitochondrial Aspartate Glutamate Carrier) Deficiency
Metabolic Brain Disease, 2002Co-Authors: Keiko Kobayashi, Mikio Iijima, Tomotsugu Yasuda, Ikumi Nishi, 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.
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type ii Citrullinemia citrin deficiency a mysterious disease caused by a defect of calcium binding mitochondrial carrier protein
Calcium : The Molecular Basis of Calcium Action in Biology and Medicine, 2000Co-Authors: Keiko Kobayashi, David S Sinasac, Mikio Iijima, Tomotsugu Yasuda, Naoki Yamaguchi, Lapchee Tsui, Stephen W Scherer, Takeyori SahekiAbstract:Citrullinemia (OMIM 215700) (McKusick, 1998) is an autosomal recessive disease that is caused by a deficiency of argininosuccinate synthetase (ASS; EC 6.3.4.5). The clinical, biochemical and molecular aspects of Citrullinemia have been reviewed elsewhere (Walser, 1983; Saheki et al., 1987a; McKusick, 1998). So far, we have analyzed almost 200 patients with Citrullinemia in our laboratory and have classified them into three types according to enzyme abnormality and into two forms according to pathogenesis (Figure 1) (Saheki et al., 1981, 1985a, 1987a, b; Kobayashi et al., 1993, 1999). The first form is the classical form (CTLN1) found in most patients with neonatal/infantile-onset Citrullinemia (type I and type III), first described by (1962); the second form is the adult-onset type II Citrullinemia (CTLN2) caused by a liver-specific ASS deficiency. In CTLN1, the enzyme defect is found in all tissues and cells in which ASS is expressed (Saheki et al., 1980, 1981, 1982, 1983a, 1985a, b, 1987a, b). To date, we have identified 36 mutations in the ASS gene located on chromosome 9q34 and have clarified the pathogenesis of most CTLN1 patients at the molecular level (Kobayashi et al., 1987, 1990, 1991, 1994, 1995a; Kakinoki et al., 1997).