Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult‐onset type II citrullinemia

Kobayashi, Keiko; Nakata, Masao; Terazono, Hiroki; Shinsato, Takuro; Saheki, Takeyori

doi:10.1016/0014-5793(95)00948-9

Cited by 28 publications

(18 citation statements)

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“…In CTLN2 patients, ASS protein is quantitatively reduced in the liver while ASS mRNA levels appear to be normal (17,18). Furthermore, hepatic mRNA levels of the PSTI gene are upregulated in CTLN2 (16). An examination of the mice showed alterations in the expression patterns of ASS protein (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Furthermore, CTLN2 patients exhibit an increase in their plasma threonine-to-serine (Thr/Ser) ratio (13,37) as well as elevated levels of pancreatic secretory trypsin inhibitor (PSTI) in serum, the latter resulting from its up-regulated transcriptional expression in the liver (13,16). The most characteristic feature of CTLN2 is the late onset of serious and recurring symptoms of hyperammonemia and neuropsychiatric symptoms, often leading to rapid death (14,34,35).…”

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confidence: 99%

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Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

Sinasac

Moriyama

Jalil

et al. 2004

Molecular and Cellular Biology

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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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Section: Resultsmentioning

confidence: 94%

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confidence: 99%

Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

Sinasac

Moriyama

Jalil

et al. 2004

Molecular and Cellular Biology

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“…The remaining mechanisms to be clarified are the enhanced expression of the pancreatic secretory trypsin inhibitor (PSTI) gene in the liver (Kobayashi et al 1995b and the unique uneven distribution of the ASS protein in the liver lobulus (Saheki et al 1983b(Saheki et al , 1987bYagi et al 1988) of CTLN2 patients. These phenomena are useful for diagnosis of CTLN2 Tsuboi et al 2001;Ikeda et al 2001;Maruyama et al 2001;Oshiro et al 2002) and to determine the prognosis of the patients (Yagi et al 1988), and may be related to the finding that about 10% of the patients with CTLN2 suffer from hepatoma without liver cirrhosis at relatively young ages (Tsujii et al 1976;Kobayashi et al 2000).…”

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confidence: 99%

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

2002

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Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) Abstract 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. So far, we have reported nine mutations, most of which cause loss of citrin, and we have established several methods for DNA diagnosis. These methods have shown that more than 90% of the patients diagnosed as suffering from CTLN2 by enzymatic analysis carry SLC25A13 mutations in both alleles, indicating that CTLN2 is caused by citrin deficiency. Furthermore, by using the same DNA diagnosis methods, we discovered that 70 neonates or infants suffering from a particular type of neonatal hepatitis carry the same SLC25A13 mutations. Since the symptoms of the neonates are different from those of the more severe CTLN2 and usually ameliorate without special treatment, we designated the neonatal disease neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). We conclude that citrin deficiency causes NICCD in neonates and CTLN2 in adults through the additional effects of genetic or environmental modifiers. 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. It is, however, still difficult to understand the cause of the hepatic deficiency of argininosuccinate synthetase protein in CTLN2.Received

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“…Laboratory findings of CTLN2 patients show moderately elevated plasma Cit and arginine (Arg) levels, an elevated plasma threonine to serine (Thr/Ser) ratio, a decreased Fischer ratio (branched-chain amino acids to aromatic amino acid ratio; BCAA/AAA) (17), an elevated serum level of pancreatic secretory trypsin inhibitor (18), and fatty liver (19). The elevated pancreatic secretory trypsin inhibitor in CTLN2 patients results from its up-regulated transcriptional expression in the liver (20). Finally, CTLN2 patients also have an increased incidence of hepatocellular carcinoma, pancreatitis, and hyperlipidemia (1,2,8,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

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Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Saheki

Iijima

et al. 2007

Journal of Biological Chemistry

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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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Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult‐onset type II citrullinemia

Cited by 28 publications

References 50 publications

Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

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

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

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