Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Deficiency of argininosuccinate synthetase causes arginine auxotrophy in lower organisms and causes citrullinemia in humans and cattle. Previously, seven missense mutations, four mutations associated with an absence of an exon in mRNA, and one splicing mutation have been identified in human neonatal citrullinemia. Reverse transcription of mRNA, amplification of cDNA and sequencing of cDNA clones were used to identify two additional missense mutations causing citrullinemia. One mutation involves substitution of leucine for serine at position 18 (S18L) and the other a substitution of cysteine for arginine at position 86 (R86C). Both of these mutations represent C----T transitions in CpG dinucleotides, and eight of nine missense mutations causing human citrullinemia involve similar transitions in CpG dinucleotides. The nucleotide coding sequence and deduced amino acid analysis are available for four mammalian species, yeast and three bacterial species. Six of nine missense mutations in humans occur in amino acid positions that are completely conserved in these organisms. Mutations causing human citrullinemia are extremely heterogeneous, and all non-consanguineous individuals studied to date are compound heterozygotes.
Mol Biol Med 1991 Feb
PMID:Additional mutations in argininosuccinate synthetase causing citrullinemia. 194 92

Heritable deficiency of the enzyme argininosuccinate synthetase results in the autosomal recessive disease citrullinemia. RNA was isolated from cultured fibroblasts from citrullinemic patients for synthesis of complementary DNA (cDNA). The mutant mRNAs were reverse transcribed, amplified and cloned for sequencing. The cDNA sequence from one mutant allele revealed the absence of exon 5 sequences, while the sequence from a second mutant allele revealed the absence of exon 6. Genomic DNA from 25 citrullinemic patients was analyzed using intron probes derived from the argininosuccinate synthetase gene. One polymorphic probe located between exons 5 and 6 identified two novel alleles amongst 48 citrullinemia chromosomes examined. Each of these alleles appears to involve deletion of genomic DNA from this region. These two mutations, which were detected as alterations of the gene structure, are the same two mutations that result in deletion of exon 5 or 6, respectively, from the mRNA. These two mutations account for approximately 10% of the chromosomes carrying mutations that cause citrullinemia.
Mol Biol Med 1989 Apr
PMID:Analysis of deletions at the human argininosuccinate synthetase locus. 261 45

Argininosuccinate synthetase (ASS) is a urea cycle enzyme that forms argininosuccinate from citrulline and aspartate. Mutations at the ASS locus in man cause the inherited disease, citrullinemia. Citrullinemia is inherited as an autosomal recessive trait and is characterized, biochemically, by elevated levels of blood citrulline and ammonia and often results in early neonatal death if untreated. We have used homologous recombination in embryonic stem cells to generate a line of mice having a targeted disruption of the Ass gene. Homozygous mutant animals develop high levels of blood citrulline, become hyperammonemic, and die within one or two days after birth. Because the phenotype of the mutant mice closely resembles that of humans who lack the ASS enzyme, we expect that these mice will serve as a useful model for exploring new treatments for citrullinemia including somatic gene therapy.
Somat Cell Mol Genet 1994 Jan
PMID:Generation of a mouse model for citrullinemia by targeted disruption of the argininosuccinate synthetase gene. 819 77

Plasma levels of glutamine (456 determinations), alanine (434 determinations), and asparagine (431 determinations) and corresponding ammonia levels (260 determinations) were retrospectively analyzed in 30 patients with hyperammonemia secondary to urea cycle disorders (including 3 patients with amino acid transport defects) and 5 patients with propionic acidemia (PA). All patients had elevated glutamine levels on one or more testing except for 2 patients with severe PA and 1 patient with a mild urea cycle disorder. All but 4 patients with urea cycle disorders showed a maximal glutamine level higher than 100 micromol/dl, and 3 patients had a maximal glutamine level of higher than 200 micromol/dl. The only exceptions were 2 asymptomatic ornithine transcarbamylase (OTC)-deficient females, 1 male with mild OTC deficiency, and 1 patient with citrullinemia (CIT) whose plasma glutamine levels were never above 100 micromol/L. Patients with CIT and argininosuccinic aciduria (ASA) showed statistically significant lower levels of glutamine than patients with other urea cycle disorders. However, the maximal glutamine level did not directly correlate with severity of the disorder and within disorders correlated inversely with severity of outcome. Patients with PA showed statistically significant lower glutamine, alanine, and asparagine levels than patients with urea cycle disorders and the severity of this disorder correlated inversely with plasma glutamine levels. Plasma ammonia levels showed a positive correlation with glutamine in patients with carbamyl phosphate synthetase I and OTC deficiency and a negative correlation in patients with PA. Although, most patients also showed elevated levels of alanine and asparagine, their levels generally did not show a good correlation with glutamine (R2 = 0.25 and 0.34, respectively).
Mol Genet Metab 1999 Jan
PMID:Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia. 997 42

Citrullinemia is an autosomal recessive disease due to the mutations in the argininosuccinate synthetase (ASS) gene. Mutation analysis was performed on three Korean patients with citrullinemia. All of the three patients had the splicing mutation previously reported as IVS6-2A>G mutation. Two had Gly324Ser mutation and the other patient had a 67-bp insertion mutation in exon 15. The IVS6-2A>G mutation was reported to be found frequently in Japanese patients with citrullinemia, but Caucasian patients showed the extreme mutational heterogeneity. Although a limited number of Korean patients were studied, the IVS6-2A>G mutation appears to be one of the most frequent mutant alleles in Korean patients with citrullinemia. The Gly324Ser mutation identified in two patients also suggests the possible high frequency of this mutation in Korean patients as well.
Mol Cells 2000 Aug 31
PMID:Mutation analysis of Korean patients with citrullinemia. 1098 46

DNA prenatal diagnosis was successfully performed on a family with citrullinemia. The father carried the G324S mutation and the mother carried the IVS6-2A > G mutation in the argininosuccinate synthase gene. They had a previous child with citrullinemia who died in the week after birth owing to complicated hyperammonemia. The lost child turned out to be a compound heterozygote. DNA was extracted from the cultured amniotic cells after amniocentesis done at 18-week gestation. For the detection of the G324S mutation, the PCR and restriction fragment length polymorphism method was used, and for the IVS6-2A > G mutation, allele-specific PCR was performed. The fetus was found to carry G324S but not IVS6-2A > G, suggesting a heterozygote carrier. Pregnancy was continued and a healthy boy was born. Plasma amino acid analysis performed on the third day after birth was normal and the serial ammonia level was in the normal range. A molecular study on his genomic DNA after birth also agreed with the previous fetal DNA analysis. He is now 2-months old with normal growth and development.
Mol Cells 2000 Dec 31
PMID:The first successful prenatal diagnosis on a Korean family with citrullinemia. 1121 75

We summarize the diagnosis, outcome, and molecular studies of five Mediterranean patients with citrullinemia: four neonatal classical forms and one subacute form, who also suffers from Down syndrome and presented with severe hepatic encephalopathy at age 7. Mutational analysis revealed three alleles with a common mutation and five new mutations: two Moroccan siblings are homozygous for G390R, the subacute form is compound heterozygous for G390R/G117D (new mutation), and the two other neonatal forms are compound heterozygous for four new mutations: V69A/E270Q and T119I(R108L)/?.
Mol Genet Metab 2001 Nov
PMID:Phenotype and genotype heterogeneity in Mediterranean citrullinemia. 1170 71

Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation.
Mol Genet Metab
PMID:Pyruvate carboxylase deficiency--insights from liver transplantation. 1235 42

Citrullinemia is caused by either deficiency of argininosuccinate synthetase (ASS, citrullinemia type 1) or a defect of the SLC25A13 gene encoding a mitochondrial aspartate-glutamate transporter (citrullinemia type II). Citrullinemia type 1-referred to as classical citrullinemia-is characterized by largely elevated concentrations of citrulline, manifesting with acute hyperammonemic crises predominantly early in life and occurs panethnically. Citrullinemia type II is a rare multisystem-disorder nearly exclusively observed in the Japanese population and characterized by less pronounced elevations of plasma citrulline and mainly a late onset of clinical symptoms. Here, we investigated 21 citrullinemic patients (mean peak plasma citrulline 1023 micromol/l, range 152-3360), all of whom remained asymptomatic during the observation period (6-156 months). These patients were referred to as mild citrullinemia due to less striking peak citrulline concentrations or absent clinical symptoms. Extended newborn screening using tandem mass spectrometry detected 15/21 patients, 4/21 patients were identified by investigation of siblings, 2/21 during metabolic work-up of unspecific neurological symptoms. We characterized the genetic defects in all affected families and found all patients affected by citrullinemia type 1 due to mutations of the ASS gene. We identified 15 different mutations, 14/15 missense and 1/15 nonsense, 6/15 were novel mutations. This is the first genetic study in a series of patients with hitherto asymptomatic citrullinemia. According to the mutations found in this study, mild citrullinemia seems to be primarily related to the human ASS gene, at least in patients of caucasian origin.
Mol Genet Metab 2003 Nov
PMID:Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). 1468 Sep 76

Deficiency of citrin encoded by SLC25A13 causes adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). So far we have diagnosed 126 (3) CTLN2 and 103 (4) NICCD patients in Japan (and other countries). From preliminary population analysis of the known nine SLC25A13 mutations, we found that the carrier frequency is high in China (1/79), Taiwan (1/98), and Korea (1/50) as well as Japan (1/69), suggesting that many patients with citrin deficiency exist in East Asia.
Mol Genet Metab 2003 Nov
PMID:Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. 1468 Sep 84


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