Qualitative and quantitative abnormalities of argininosuccinate synthetase in citrullinemia

Saheki, Takeyori; Ueda, Atsushi; Hosoya, Masakazu; Kusumi, Kimiko; Takada, Shigeo; Tsuda, Michio; Katsunuma, Tsunehiko

doi:10.1016/0009-8981(81)90318-1

Cited by 92 publications

(62 citation statements)

References 12 publications

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“…Determination of Urea Cycle Enzyme Activities-Liver extracts were prepared as described previously (46). The urea cycle enzyme activities were determined using the methods of Schimke (47) Quantification of Liver TG and Asp-Total lipid was extracted from the liver with 20 volumes of chloroform/methanol solution (v/v, 1:2) as described previously (51).…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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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“…Miyakoshi et al (1968) reported that blood citrulline levels were increased in adult hyperammonemic patients with a specific type of chronic recurrent hepatocerebral degeneration described by Inose (1952). Later, Saheki et al (1980Saheki et al ( , 1981 reported that the enzyme abnormalities of citrullinemia can be classified as qualitative (type I) or quantitative (type II), and that in type I, ASS is affected not only in the liver but also in the kidney and in cultured fibroblast cells, and is kinetically abnormal, while in type II, ASS is affected only in the liver (Saheki et al 1982(Saheki et al , 1983a, where it is deficient but kinetically normal and has the same specific activity as the control. Further research showed that type I citrullinemia, together with type III, in which ASS is almost completely absent in every cell where the ASS gene is expressed (Saheki et al 1985a(Saheki et al , 1987aImamura et al 1987), is caused by mutations in the ASS gene (Kobayashi et al , 1990(Kobayashi et al , 1991(Kobayashi et al , 1994(Kobayashi et al , 1995aKakinoki et al 1997;Vilaseca et al 2001).…”

Section: Introductionmentioning

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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“…Antiserum raised against rat liver ASS (5) and further purified to give an immunoglobulin fraction reacted with human liver ASS as well as with rat. liver ASS (7). With this immunoglobulin, we were able to demonstrate for the first time that ASS was located only in the cytoplasm of the hepatocytes of control liver, but not in the bile duct.…”

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confidence: 67%

“…reported a unique quantitative type of citrullinemia which is different from the classical, qualitative type with abnormal kinetic properties. In the quantitative type of citrullinemia, a decrease in ASS activity in the liver is caused by a decrease in the amount of ASS protein with normal kinetic properties (6,7). The question has been raised whether ASS protein is decreased uniformly in all the hepatocytes or unevenly in particular hepatocytes of the citrullinemic liver whose histology usually shows only fatty infiltration.…”

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confidence: 99%

<b>Immunohistochemical localization of argininosuccinate synthetase in the liver of control and citrullinemic </b><b>patients </b>

et al. 1983

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In order to clarify the pathogenesis of a quantitative reduction of argininosuccinate synthetase (ASS) protein in a specific type of citrullinemia. in Japan, immunohistochemical techniques were used to locate ASS in the liver of control and citrullinemic patients whose enzymatic analysis had already been performed. In the controls, ASS was located only in the cytoplasm of hepatocytes, but not in bile duct cells or endothelial cells, and was distributed almost homogeneously in the lobulus with slightly denser staining in the periportal region than in the pericentral region. Staining of the liver from patients with the quantitative type of citrullinemia indicated the presence of two types of abnormality. In the first group, the liver was stained more weakly than in the controls, but homogeneously in the lobulus. In the second group, the liver was stained heterogeneously in the lobulus showing a mixture of densely

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Qualitative and quantitative abnormalities of argininosuccinate synthetase in citrullinemia

Cited by 92 publications

References 12 publications

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

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

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

<b>Immunohistochemical localization of argininosuccinate synthetase in the liver of control and citrullinemic </b><b>patients </b>

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