Hereditary disorders of the urea cycle in man: Biochemical and molecular approaches

Saheki, Takeyori; Kobayashi, Keiko; Inoue, Ituro

doi:10.1007/bfb0034071

Cited by 85 publications

(75 citation statements)

References 189 publications

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“…Patients with CTLN2 show hyperammonemia and neuropsychiatric symptoms such as disorientation, delirium, aberrant behavior, delusion, and disturbance of consciousness, often leading to rapid death (Saheki et al 1987b;Kobayashi et al 2000). The onset is sudden, usually between the ages of 20 and 40.…”

Section: Clinical Features Of Ctln2mentioning

confidence: 99%

“…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).…”

Section: Questions To Be Answeredmentioning

confidence: 99%

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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)

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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Section: Clinical Features Of Ctln2mentioning

confidence: 99%

Section: Questions To Be Answeredmentioning

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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“…Saheki et al (10) originally described three clinical forms of citrullinemia based on argininosuccinate synthetase enzyme abnormalities; these forms have subsequently been re-classified into classical citrullinemia (CTLN1; OMIM TM number 215700) caused by mutations in the argininosuccinate synthetase gene (11,12), and CTLN2 caused by mutations in SLC25A13 (3). CTLN2 is characterized by a liver-specific decrease in argininosuccinate synthetase protein (13) without any detectable abnormalities in the argininosuccinate synthetase gene or hepatic argininosuccinate synthetase mRNA levels (14,15). The causal link between citrin deficiency and the hepatic loss of argininosuccinate synthetase in CTLN2 patients still remains to be clarified (16).…”

mentioning

confidence: 99%

“…The causal link between citrin deficiency and the hepatic loss of argininosuccinate synthetase in CTLN2 patients still remains to be clarified (16). Patients with CTLN2 suffer from recurring neuropsychiatric symptoms associated with hyperammonemia, including disorientation, delirium, seizures, and coma that can lead to death from brain edema (13). 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).…”

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confidence: 99%

“…Clinically, one of the most distinct features of CTLN2 are reports of patients having a peculiar fondness for foods high in protein and fat such as beans and nuts, and a dislike of foods high in carbohydrates such as rice and sweets (1,2,13,27). Patients with CTLN1 or other urea cycle enzyme deficiencies typically are given restricted protein diets to minimize episodes of hyperammonemia resulting from protein degradation.…”

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confidence: 99%

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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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Mutations and DNA diagnoses of classical citrullinemia

et al. 1997

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Hereditary disorders of the urea cycle in man: Biochemical and molecular approaches

Cited by 85 publications

References 189 publications

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

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

Mutations and DNA diagnoses of classical citrullinemia

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