Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene for ornithine transcarbamylase (OTC; EC 2.1.3.3), a urea cycle enzyme, is expressed almost exclusively in the liver and small intestine. To identify DNA elements regulating transcription of the OTC gene in the liver, transient expression analysis was carried out by using hepatoma (HepG2) and nonhepatic (CHO) cell lines. The 1.3-kilobase 5'-flanking region of the rat OTC gene directed expression of the fused chloramphenicol acetyltransferase gene in HepG2 cells much more efficiently than in CHO cells. Analysis of deletion mutants of the 5'-flanking region in HepG2 cells revealed that there are at least one negative and two positive regulatory elements within the about 220-base-pair immediate 5'-flanking region. DNase I footprint analysis showed the presence of factors binding to these regulatory elements in nuclear extracts of rat liver and brain, and footprint profiles at the two positive elements exhibited liver-specific features. Transient expression analysis also revealed the existence of an enhancer region located 11 kilobases upstream of the transcription start site. The OTC enhancer was able to activate both its own and heterologous promoters in HepG2 but not in CHO cells. The enhancer was delimited to an about 230-base-pair region, and footprint analysis of this region revealed four protected areas. Footprint profiles at two of the four areas exhibited liver-specific features, and gel shift competition analysis showed that a factor(s) binding to the two liver-specific sites is related to C/EBP. These results suggest that both liver-specific promoter and enhancer elements regulate expression of the OTC gene through interaction with liver-specific factors binding to these elements.
Mol Cell Biol 1990 Mar
PMID:Promoter and 11-kilobase upstream enhancer elements responsible for hepatoma cell-specific expression of the rat ornithine transcarbamylase gene. 230 62

We have investigated mitochondrial import and processing of the precursor for human ornithine transcarbamylase (OTC; carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3) in HeLa cells stably transformed with cDNA sequences encoding OTC precursors carrying mutations in their leader peptides. The mutant precursors studied included two with amino acid substitutions in the 32-amino-acid leader peptide (glycine for arginine at position 23, designated gly23; glycines for arginines at positions 15, 23, and 26, designated gly15,23,26) and two with deletions (deletion of residues 8 to 22, designated d8-22; deletion of residues 17 to 32, designated N16). Specific immunoprecipitation with anti-OTC antiserum of extracts of L-[35S]methionine-labeled cells expressing these mutations yielded only precursor species; neither mature nor intermediate-size OTC subunits were observed. Fractionation of radiolabeled cells, however, revealed important differences among the various mutants: the gly23 precursor was associated with mitochondria and was not detected in the cytosol; the d8-22 and N16 precursors were found with both the mitochondrial fraction and the cytosol; only the gly15,23,26 precursor was detected exclusively in the cytosol. A large fraction of each of the mitochondrially associated OTC species was in a trypsin-protected compartment. In particular, the gly23 precursor behaved in trypsin protection and mitochondrial fractionation studies in a manner consistent with its translocation into the mitochondrial matrix. On the other hand, the lack of binding of the gly23 protein to a delta-N-phosphonoacetyl-L-ornithine affinity column, which specifically recognizes active OTC enzyme, indicated that, despite its intramitochondrial location, the mutant protein did not assemble into the normal, active trimer. Further, the gly23 mutant precursor was unstable within the mitochondria and was degraded with a t1/2 of less further than 4 h. Thus, we have shown that, in intact HeLa cells, cleavage of the OTC leader peptide is not required for translocation into mitochondria, but is required for assembly into active enzyme.
Mol Cell Biol 1988 Dec
PMID:Mitochondrial import and processing of mutant human ornithine transcarbamylase precursors in cultured cells. 324 50

X-linked retinitis pigmentosa (XLRP) is characterized by retinal degeneration with night blindness and progressive reduction of the visual fields. By linkage and deletion analysis a gene locus (RP3) has been mapped to the short arm of the X chromosome between the genes CYBB and OTC. Analysis of transcript in this region has revealed a gene which is abundantly expressed in human retina and encodes a putative membrane protein with significant homologies to short consensus repeat (SCR/sushi) domains known from selections and complement proteins. The gene termed SRPX (sushi-repeat-containing protein, x chromosome) is deleted in an RP patient who also suffers from chronic granulomatous disease and McLeod syndrome. A 75 kb deletion removing exon 1 of the gene was also found in two brothers of a second XLRP family. However, no further functionally significant mutations were detected by SSCP screening of all 10 exons in 34 unrelated XLRP patients nor by full length RT-PCR sequencing in two RP3 families. The role of this highly conserved retinal gene in the pathogenesis of RP therefore remains to be determined.
Hum Mol Genet 1995 Dec
PMID:A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa. 863 8

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide-exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.
Hum Mol Genet 1996 Jul
PMID:Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1. 881 43

The development of hepatic glutamine synthetase (GS; EC 6.3.1.2) activity and expression was studied in 1 to 112 day old sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase (OTC, EC 2.1.3.3.) deficiency. The spf/Y mutant mice were found to have a smaller body weight (p < 0.01) yet possessed a larger liver (p < 0.01-0.05) in comparison to normal male mice (+/Y). The neonatal hepatic GS activity was retarded in the spf/Y mice (p < 0.01) but reached normal values by the 28th day of age, after which it increased as compared to the control CD-I mice (p < 0.01). The spf GS activity remained constant from 28 to 56 days, whereas the CD-I GS activity decreased. A further significant increase in the spf GS activity was observed from 56 day to 112 day indicating its adaptation. The decrease of GS mRNA in the spf/Y mice from 28 to 112 days of age (3.72 +/- 0.25 vs 1.68 +/- 0.32, p < 0.01) suggests translational and post-translational modifications in the regulation of GS activity. The changes in the activity and expression patterns of GS could be due to an effect of the OTC mutation on the hepatic ammonia metabolism. This may be indicative of the adaptational processes in the spf mutant mice, which may play a specific role in this animal model to help it to survive with its hyperammonemia.
Biochem Mol Biol Int 1997 Sep
PMID:Developmental study of hepatic glutamine synthetase in a mouse model of congenital hyperammonemia. 931 91

Forty-four sequences of ornithine carbamoyltransferases (OTCases) and 33 sequences of aspartate carbamoyltransferases (ATCases) representing the three domains of life were multiply aligned and a phylogenetic tree was inferred from this multiple alignment. The global topology of the composite rooted tree (each enzyme family being used as an outgroup to root the other one) suggests that present-day genes are derived from paralogous ancestral genes which were already of the same size and argues against a mechanism of fusion of independent modules. A closer observation of the detailed topology shows that this tree could not be used to assess the actual order of organismal descent. Indeed, this tree displays a complex topology for many prokaryotic sequences, with polyphyly for Bacteria in both enzyme trees and for the Archaea in the OTCase tree. Moreover, representatives of the two prokaryotic Domains are found to be interspersed in various combinations in both enzyme trees. This complexity may be explained by assuming the occurrence of two subfamilies in the OTCase tree (OTC alpha and OTC beta) and two other ones in the ATCase tree (ATC I and ATC II). These subfamilies could have arisen from duplication and selective losses of some differentiated copies during the successive speciations. We suggest that Archaea and Eukaryotes share a common ancestor in which the ancestral copies giving the present-day ATC II/OTC beta combinations were present, whereas Bacteria comprise two classes: one containing the ATC II/OTC alpha combination and the other harboring the ATC I/OTC beta combination. Moreover, multiple horizontal gene transfers could have occurred rather recently amongst prokaryotes. Whichever the actual history of carbamoyltransferases, our data suggest that the last common ancestor to all extant life possessed differentiated copies of genes coding for both carbamoyltransferases, indicating it as a rather sophisticated organism.
J Mol Evol 1999 Oct
PMID:The evolutionary history of carbamoyltransferases: A complex set of paralogous genes was already present in the last universal common ancestor. 1048 4

Ornithine transcarbamylase (OTC, EC 2.1.3.3) deficiency (OTCD; OMIM #311250) is known to be genetically very heterogeneous, with many cases occurring de novo, due to an exceptional instability of the OTC gene. We report a new G > T substitution in the first nucleotide of intron 2 and we describe also a novel SNP (IVS8 + 35 nt: G > T) with very convenient frequencies (62%/38%) for its use as an extra tool for OTCD diagnosis in cases of suspected deletions.
Mol Genet Metab 2002 May
PMID:Ornithine transcarbamylase deficiency: a novel splice site mutation in a family with meiotic recombination and a new useful SNP for diagnosis. 1217 83

Several recent reviews describe the management of urea cycle disorders. There is much agreement on diet, alternative pathway therapy, maintenance of arginine and ornithine levels in acute and chronic management, sick-day regimens, and some aspects of monitoring. However, differences remain in several areas, and physicians at most treatment centers have relatively little experience, because these disorders are rare. Early suspicion of the diagnosis of a urea cycle disorder, and prompt referral to a tertiary center is vital. Drug treatment using chronic administration of sodium benzoate has been abandoned by some centers, but the acceptability of phenylbutyrate is an issue for many patients. Using citrulline chronically is not always successful in recommended doses, and may result in an arginine level too low for maximum control. Appetite and nutrition problems are common. One major concern is the early identification and management of chronic catabolism, theoretically easy, but hard in practice. Biochemical measurement problems complicate monitoring, and there are disagreements about the optimum way of identifying OTC carriers. It is not always clear whom to treat. Within a kindred with an early-onset phenotype, an asymptomatic newborn girl may need treatment for some undetermined time, but target values for monitoring are not clear. In late-onset phenotypes, management of asymptomatic males identified by family screening is also difficult. Most centers do not have sufficient cases to solve these conundrums, some of which require further multicenter study. This paper examines the recommendations of a consensus conference on management, outlines some remaining problems, and incorporates in the text the points raised in open discussion during a session of a symposium held in Sydney in 2003 entitled "New Developments in Urea Cycle Disorders."
Mol Genet Metab 2004 Apr
PMID:Problems in the management of urea cycle disorders. 1505 Sep 80

The present study reports on the frequency of liver tumors observed in a gene therapy study with AAV vectors in male mice of the B6C3F1 hybrid background, which are known to have a high frequency of spontaneous liver tumors. Male mice with mutations in their Otc gene and their wild-type siblings received AAV vectors expressing either the murine Otc or the LacZ gene. Untreated control animals were included in the study. All experimental groups, including wild-type and OTC-deficient animals not treated with vector, developed liver nodules, which in some cases were due to hepatocellular carcinoma. Vector DNA was lower in tumors than in adjacent normal liver. A statistical analysis of the data did not show an association between treatment with Otc vectors and formation of tumors in OTC-deficient mice. However, mice treated with LacZ vectors showed increased risks of tumor formation and hepatocellular carcinoma relative to untreated animals or animals that had received vectors with Otc as the transgene. It appears that AAV vectors alone do not contribute to the formation of tumors in these strains of mice although the expression of LacZ alone or in combination with vector may be problematic.
Mol Ther 2006 Jul
PMID:Analysis of tumors arising in male B6C3F1 mice with and without AAV vector delivery to liver. 1675 Jun 55

Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn defect of metabolism of the urea cycle, which causes hyperamonemia. Mutations of the OTC gene have been recognized as the genetic cause underlying the OTC deficiency. The severity of the disease is associated with the type of mutation, leading either to neonatal onset of hyperammonemia or to a later appearance of the disease. The mutation Thr125Met is associated with neonatal hyperammonemia. Recently, the disease-causing Thr125Met mutation in humans was reported as wild-type neutral allele in chimpanzees. Further analysis confirmed the presence of Met125 fixed in chimpanzees together with Thr135, representing the only two divergent positions between human and chimpanzee OTCs. Thr125 and Thr135 were identified as ancestral mammalian combination, so the Thr135Ala substitution occurred as human-specific event, whereas the substitution of Thr125Met was characteristic of the chimpanzee linage. Only when Met125 emerges in a background with the human-specific Ala135, a highly deleterious effect is observed, suggesting among other hypotheses the existence of a compensatory effect in chimpanzee. To explore this hypothesis, we built an in vitro cell model system to study the effect of the three distinct genetic backgrounds (Ala135-Thr125; Ala135-Met125 and Thr135-Met125) on the OTC protein function. We observed that the human Thr125Met mutant is inactive, whereas the chimp OTC shows an enzymatic activity comparable with the wild-type human OTC. We concluded that the presence of a threonine at position 135 in chimps rescues the deleterious effect of the methionine at position 125, in a mechanism of intra-locus compensation.
Hum Mol Genet 2007 Sep 15
PMID:In vitro demonstration of intra-locus compensation using the ornithine transcarbamylase protein as model. 1761 37


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