Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histochemical assay for ornithine transcarbamylase (OTC) activity in fixed frozen hepatic sections from a woman heterozygous for OTC deficiency revealed two populations of hepatocytes: those with normal activity and those with no activity. This observation, in conjunction with data from previous family studies, confirms the hypothesis that the gene for OTC is X-linked. It also provides the first cytologic demonstration of cellular mosaicism for a liver-specific cell product.
 ...
PMID:X-chromosome inactivation in human liver: confirmation of X-linkage of ornithine transcarbamylase. 94

Assay of urea-cycle enzymes in liver tissue showed ornithine transcarbamylase activities of 18 to 72 per cent of the normal mean in eight patients with Reye's syndrome, below the range of normal in seven of eight, and, in six cases, as low as those in females with X-linked deficiency of this enzyme. Carbamyl phosphate synthetase activities were less than 32 per cent of controls in two patients. Argininosuccinate synthetase and lyase activities were normal in seven patients. Arginase was normal in two biopsy specimens, but below normal in four of five autopsy specimens. The Km's for ornithine and carbamyl phosphate, pH optimum, and heat lability of ornithine transcarbamylase were normal. Two patients excreted 0.64 and 0.58 g per kilogram per day of urinary nitrogen at the peak of hyperammonemia, in spite of peritoneal dialysis. The hyperammonemia of Reye's syndrome apparently results from excess waste nitrogen that overwhelms the ability of reduced ornithine transcarbamylase (and occasionally carbamyl phosphate synthetase) to detoxify the ammonia load.
 ...
PMID:Urea-cycle enzyme deficiencies and an increased nitrogen load producing hyperammonemia in Reye's syndrome. 125 Mar 13

The sparse fur (spf) and the sparse fur/abnormal skin and hair (spf-ash) mice are two murine models of the human X-linked disorder ornithine transcarbamylase (OTC) deficiency. A defective recombinant retrovirus, delta N2OTC was used to transduce primary hepatocytes derived from these mutant animals. Transduction of the primary cultures was highly efficient, with an average proviral copy number of 0.5-2 per cell in the population of transduced hepatocytes. Northern analysis and slot blots of total RNA isolated from transduced cells showed levels of human OTC mRNA to be equivalent to that present in normal human liver. Enzymatic assays demonstrated that a partial biochemical correction of the defect was achieved. After retroviral transduction, the hepatocytes were trypsinized and replated for long-term culture. Viability after replating exceeded 90%, indicating that the transduced cells might be useful for transplantation. The successful in vitro correction of OTC deficiency by this vector suggests that it will also be useful in somatic gene therapy experiments.
 ...
PMID:Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice. 156 38

Sparse-fur (spf) mutant mice with X-linked ornithine transcarbamylase (OTC) deficiency were examined for hyperammonemia and its effect on energy metabolism. We compared the levels of ammonia, glutamine, glutamate and some of the intermediates of energy metabolism in the brain and liver of spf mice with those of control mice. In spf mice we observed significant increases in ammonia, glutamine, alpha-ketoglutarate and glucose with a significant decrease in ATP, glutamate and pyruvate in both brain and liver. The redox states of the brain and liver were also altered in spf mice. The results suggest that many of the metabolic alterations seen in spf mice could be due to the elevated ammonia levels. The spf mouse may, therefore, be an ideal model for the study of the neurotoxic effects of ammonia in chronic hyperammonemic syndromes.
 ...
PMID:Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice. 157 47

Since the cloning of the cDNA for X-linked ornithine transcarbamylase (OTC) in 1984, diagnostic accuracy of OTC deficiency for prenatal and carrier detection has been greatly improved by the use of linkage analysis. However, the use of RFLP-based diagnosis is limited in this and in other new mutation diseases. Here we report both the use of direct mutation detection by new PCR-based techniques and our experience with linkage-based diagnosis in 18 families. We have previously reported the use of chemical mismatch cleavage to detect mutations first in amplified mRNA and then in genomic DNA of patients. This technique has now been utilized for prenatal diagnosis. Primers for specific amplification of OTC exons 1, 3, 5, 9, and 10 have been developed and been employed to map deletions of the OTC gene in two families. These primers also have been used to detect alterations in the TaqI sites found in exons 1, 3, 5, and 9. Four novel mutations of the OTC gene leading to abolition of a TaqI site in the OTC cDNA were discovered. One of these mutations is in exon 1; two lie in exon 3; and one is in exon 9. In addition, we have used the PCR products as probes to identify the exon-specific bands seen on Southern blots and to map the polymorphic BamHI and MspI sites, which are commonly used for linkage analysis. This information will facilitate the interpretation of altered band patterns seen in deletion cases and in cases of point mutations affecting restriction sites. Utilization of the appropriate combination of these molecular techniques permitted accurate diagnostic evaluations in 17 of 18 families.
 ...
PMID:Improved molecular diagnostics for ornithine transcarbamylase deficiency. 167 17

Ornithine transcarbamylase (OTC) is one of 5 enzymes in the detoxification of ammonia to urea, and its deficiency, an X-linked disease, is the most common inborn error of urea genesis in humans. Because of the devastating nature of the disease there is a strong demand for reliable and rapid molecular analyses in OTC families in order to offer carrier detection and prenatal diagnosis. This paper presents the efficiency of direct and indirect mutation analyses in 22 OTC families using Southern blotting and polymerase chain reaction (PCR) amplification. For 89% of the mothers with an affected child, at least 1 RFLP of the OTC locus was informative concerning prenatal diagnosis. 100% informativity was reached by using the additional flanking markers 754 and LI.28. In total, 3 deletions (14%) and 1 TaqI site mutation (4.5%) in exon 3 were detected. 13 (60%) of our 22 mothers were found to be carriers, 9 of them being obligate carriers and 4 detected by biochemical testing. 4 mothers were excluded as carriers by DNA analyses, and in 5 mothers the carrier status could not be assessed positively. DNA analyses permitted carrier detection in 32% and carrier exclusion in 55% of 22 female relatives. Prenatal diagnosis was performed in 4 families: in 1 family by direct mutation detection and in 3 families by linkage analyses. It was possible to determine the mutation origin in 6 families, all of them with male probands. In 4 families the mutation had occurred during grandpaternal spermiogenesis, suggesting higher mutation rates in males, but in 2 cases it was the result of an event during maternal oogenesis, proving that new mutations in the OTC gene do also occur in eggs. Our recommended strategy for carrier detection and prenatal diagnosis in OTC deficiency is to examine routinely Southern blots of BamHI, EcoRI, HindIII, MspI, PstI and TaqI digestions using the OTCcDNA probe pH0731 and the flanking markers 754 and LI.28, as well as the TaqI-digested PCR products of exons 3, 5 and 9.
 ...
PMID:Direct and indirect mutation analyses in patients with ornithine transcarbamylase deficiency. 180 71

Ornithine transcarbamylase (OTC) (EC 2.1.3.3) is an hepatic mitochondrial enzyme involved in the detoxication of ammonia; it catalyzes the second step of the urea cycle, and is X-linked in human beings. Deficiency of OTC results in ammonia intoxication and, often, in early infant death, especially in males. This report describes the use of a nearly full-length cloned human cDNA for OTC for Southern blot analysis of genomic DNA. The pattern of MspI, TaqI, HindIII and EcoRI restriction endonuclease sites from 28 control individuals of Chinese backgrounds is reported. A Southern blot by Msp I reveals invariant bands of 19.5, 5.2 and 1.9 kb respectively, as well as one set of polymorphic bands 6.6/6.2 kb. By TaqI, invariant bands are 4.8, 2.7, 1.9, 1.7 and 1.4 kb respectively, while polymorphic bands are found at 4.1/3.9 kb. By HindIII, 3.2 kb is invariant but 4.0/2.9 kb polymorphic. By EcoR I, invariant bands are 9.0, 3.6, 3.4 and 1.45 kb respectively, but 2.5 kb is polymorphic. Combined with study of the alteration of restriction sites in the informative pedigrees, this information is expected to allow accurate heterozygote detection and prenatal diagnosis of OTC deficiency.
 ...
PMID:Restriction fragment length polymorphisms at the ornithine transcarbamylase locus in normal Chinese. 197 99

Ornithine transcarbamylase (OTC) is an X-linked, liver-specific enzyme that catalyzes the second step of the urea cycle. In humans, inherited deficiency of OTC in hemizygous affected males usually results in severe ammonia intoxication and early death. To characterize mutations responsible for OTC deficiency, we used the PCR to amplify cDNAs prepared from patient livers which demonstrated no OTC enzyme activity and no OTC cross-reacting material on western blots. In three of seven cases, smaller than normal products were observed. Sequencing of these cDNAs revealed that two were missing exon 7 of the OTC gene and that the other was missing the first 12 bp of exon 5. Sequencing of genomic DNA from these three patients revealed that one mutant missing exon 7 had a T-to-C substitution in the 5' splice donor site of intron 7. The other mutant missing exon 7 had an A-to-G change in the third position of intron 7. It is interesting that both of these mutations resulted in skipping the preceding exon rather than in inclusion of some or all of the affected intron. In the third mutant, an A-to-T substitution was found in the 3' splice acceptor site at the end of intron 4. Here, a cryptic splice acceptor site within exon 5 was used. Northern blotting of liver RNA from these patients demonstrated (a) reduced, but significant, amounts of OTC mRNA in one of the patients who had a deleted exon 7 but (b) very little OTC mRNA in the other two patients. We propose that these point mutations, which result in aberrant splicing of the OTC pre-mRNAs, lead to OTC deficiency through either decreased efficiency of mRNA export from the nucleus to the cytosol or synthesis of enzyme subunits that are unstable and rapidly degraded. We speculate that abnormal mRNA splicing may represent a relatively common mechanism in the pathogenesis of this disease.
 ...
PMID:Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency. 203 31

Ornithine transcarbamylase (OTC) deficiency is an X-linked disease responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes (15%). Increased orotic acid excretion occurs in both symptomatic and asymptomatic carriers, especially under protein loading tests. The disease is therefore partially dominant with neonatal lethality in the hemizygous male; the fraction of new mutations has previously been estimated to be low in males (point estimation = 0, upper bound of the confidence interval = 0.16) and 57% in females. Genetic counseling in this disease is difficult because it is not clear whether a negative protein loading test rules out carrier status. In an attempt to determine how reliable the test is for carrier detection, we investigated ten obligate carriers for orotic acid excretion; considering all data available, we concluded that the test is rarely negative in obligate carriers (8%). Consequently, a negative test in a mother decreases the minimum risk of being a carrier from 84% a priori to 30% if she had an affected son and from 43% a priori to 5% if she had a heterozygous daughter. Finally, the diagnosis of a new mutation in the germ cells of the maternal grandfather in one particular family could be ascertained by extensive DNA analysis.
 ...
PMID:Carrier detection in a partially dominant X-linked disease: ornithine transcarbamylase deficiency. 229 53

Ornithine carbamoyltransferase is an X-linked mitochondrial enzyme expressed in hepatocytes and enterocytes. A deficiency of this enzyme results in central nervous system dysfunction, which may be fatal in newborn boys. Milder forms are seen in older boys and girls and in adults. Establishing the carrier status of women at risk for ornithine carbamoyltransferase deficiency is important for determining reproductive and medical risks for affected women. We report a test to establish the carrier status of women at risk for ornithine carbamoyltransferase deficiency. This test relies on the allopurinol-induced accumulation of orotidine, whose synthesis is stimulated by carbamoyl phosphate, a substrate that accumulates in ornithine carbamoyltransferase deficiency. We used anion-exchange, high-performance liquid chromatography to measure urinary orotidine and orotic acid excretion after the administration of a 300-mg oral dose of allopurinol in 25 [corrected] women who were obligate heterozygotes, 13 who were probable heterozygotes, 15 mothers of affected boys from monoplex families (families with only one affected member), 12 mothers of affected girls from monoplex families, and 21 [corrected] normal, unrelated women who were not carriers. Urinary orotidine excretion was increased 3 SD or more above the mean value for the normal women in 95.8 percent of the obligate heterozygotes, 84.6 percent of the probable heterozygotes, 73.3 percent of the mothers of affected boys in monoplex families, and 33.3 percent of the mothers of affected girls in monoplex families, thus establishing that these women were carriers of a mutant ornithine carbamoyltransferase allele. The presence of allopurinol-induced orotic aciduria was not as sensitive or specific an indicator of carrier status as the presence of orotidinuria. We conclude that measurement of urinary orotidine excretion after the administration of allopurinol is a simple and reliable test for the identification of women who are heterozygous for ornithine carbamoyltransferase deficiency.
 ...
PMID:Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. 234 27


1 2 3 4 5 6 7 8 9 10 Next >>