Disease relevance of Otc

• Activities of monoamine oxidases, MAOA and MAOB, were measured using radiometric assays in different brain regions of the sparse-fur (spf/Y) mouse, a model of congenital hyperammonemia resulting from an X-chromosomal defect of ornithine transcarbamylase [1].
• The enhancer of the rat ornithine transcarbamylase gene is located 11 kilobases upstream from the transcription start site and has been shown to be hepatoma cell-specific [2].
• We have characterized a lambda phage recombinant, isolated from a mouse genomic library, that spans the first two exons of the mouse OTCase gene [3].
• The gene encoding the mouse urea cycle enzyme, ornithine transcarbamylase has been isolated on five partially overlapping bacteriophage lambda clones [4].
• Correction of ornithine transcarbamylase deficiency in adult spf(ash) mice and in OTC-deficient human hepatocytes with recombinant adenoviruses bearing the CAG promoter [5].

Psychiatry related information on Otc

• Congenital ornithine transcarbamylase (OTC) deficiency in humans is associated with seizures and mental retardation [6].
• Although there was no protection with the control LacZ virus, the ornithine transcarbamylase (OTC)-containing vector provided partial protection from both behavioral symptoms (ataxia, seizures, and abnormal response to sound) and biochemical abnormalities (ammonium, aspartate, alanine, and glutamine) within 24 h and complete protection by 48 h [7].

High impact information on Otc

• The ornithine transcarbamylase-deficient sparse fur mouse is an excellent model to study the most common human urea cycle disorder [8].
• The ornithine transcarbamylase gene in the sparse fur mouse contains a C to A transversion that alters a histidine residue to an asparagine residue at amino acid 117 [8].
• Biogenesis of ornithine transcarbamylase in spfash mutant mice: two cytoplasmic precursors, one mitochondrial enzyme [9].
• The spfash mouse: a missense mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing [10].
• We show here that the spfash mutation is a guanine to adenine transition of the last nucleotide of the fourth exon of the ornithine transcarbamylase gene [10].

Chemical compound and disease context of Otc

• In children with Reye's syndrome, liver specimens exhibit the following characteristics: mitochondrial dysfiguration, fatty infiltration, decreased activity of carbamyl phosphate synthetase and of ornithine transcarbamylase, histochemically reduced activity of succinic dehydrogenase and cytochrome oxidase, and depletion of glycogen [11].
• Ornithine carbamoyltransferase deficiency, an X-linked trait, leads to toxic hyperammonemia in sparse fur (spf/Y) mice [12].
• BWTG3 hepatoma cells can acquire phenylalanine hydroxylase, cystathionine synthase and CPS-I without genetic manipulation, but activation of the silent OTC gene requires cell fusion with hepatocytes [13].
• Herein we examine the effects of sodium benzoate and sodium phenylacetate on feeding and central serotonin turnover in a child with citrullinemia and in an animal model of congenital hyperammonemia, the ornithine transcarbamylase-deficient sparse-fur (spf/y) mouse [14].
• Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia [15].

Biological context of Otc

• Analysis of selected recombinants from 108 Mus musculus x Mus spretus backcross progeny with the same clone confirmed that the homologous murine locus (Gf-1) lies between Otc and the centromere of the mouse X Chr [16].
• Mosaicism of ornithine transcarbamylase (OTC) expression in hepatocytes was quantitatively analyzed during liver development of the spf(ash)-heterozygous female mouse [17].
• The ornithine transcarbamylase gene and four anonymous DNA sequences map within band Xp21, flanking the presumed locus for Duchenne muscular dystrophy [18].
• The gene encoding OTCase is located on the X chromosome and expression of OTCase is limited almost exclusively to hepatocytes [3].
• Sequence analysis revealed the presence of two putative HNF4alpha-binding sites in the mouse OTC promoter region [19].

Anatomical context of Otc

• Sizes of patches, which were aggregates of OTC-positive or -negative hepatocytes, increased during development [17].
• We conclude that this 800-bp fragment contains sufficient information to control OTCase gene expression in a tissue-specific manner, probably by interacting with trans-acting factor(s) which are not present in the other cell line [3].
• Correction of mouse ornithine transcarbamylase deficiency by gene transfer into the germ line [20].
• Using microinjection, we introduced a construction containing rat OTC cDNA linked to the SV40 early promoter into fertilized eggs of Spf-ash mice [20].
• CONCLUSIONS: Taken together, we conclude that newly synthesized mouse OTC enzyme was efficiently imported into mitochondria following vector-mediated gene delivery in spf(ash) mice, correcting secondary metabolic alterations [21].

Associations of Otc with chemical compounds

• Complementary expression of glutamine synthetase and carbamoylphosphate synthetase I in ornithine carbamoyltransferase-deficient mouse liver (spf-ash mouse) [22].
• An 800-bp fragment containing the 5' flanking region of the OTCase gene was fused upstream to the coding sequence of the chloramphenicol acetyltransferase gene to assay promoter activity [3].
• Hepatic carbamyl phosphate synthetase and ornithine transcarbamylase in mouse influenze A and influenze B infection [23].
• Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet [24].
• Sparse-fur (spf) mice with a deficiency of hepatic ornithine transcarbamylase (OTC) are congenitally hyperammonemic, showing elevated cerebral ammonia and glutamine and depleted levels of energy metabolites [25].

Physical interactions of Otc

• In the present study, densities of the M1 and M2 subclasses of muscarinic cholinergic binding sites were assessed using quantitative receptor autoradiography in the brains of sparse-fur (spf) mice with congenital OTC deficiency and in age-matched CD-1 controls [26].

Other interactions of Otc

• As in humans, the mRpgr gene maps within 50 kilobases from the 5'-end of the Otc gene [27].
• Breeding experiments were conducted to combine the X-linked sparse-fur (spf) mutation with ornithine transcarbamylase deficiency and the autosomal recessive deficiency of short-chain acyl CoA dehydrogenase (SCAD) in BALB/cByJ mice [28].
• Determination of tissue specificity of the enhancer by combinatorial operation of tissue-enriched transcription factors. Both HNF-4 and C/EBP beta are required for liver-specific activity of the ornithine transcarbamylase enhancer [2].
• Densities of binding sites for the predominantly postsynaptic muscarinic M2 subtype ligand 3H-AFDX 384 were increased by up to 60% (p < 0.01) in cerebral cortex, hippocampus, globus pallidus, as well as thalamic and hypothalamic structures of OTC-deficient mice [26].
• These findings suggest that the pronounced reduction of CPS and OTC activities reported in Reye's syndrome in man are not a general manifestation of the severity of influenza infection [23].

Analytical, diagnostic and therapeutic context of Otc

• Each was tested in adult spf(ash) mice, an animal model of human OTC deficiency, and in primary human hepatocytes with OTC deficiency [5].
• Thus, the adenoviral vector with an efficient promoter such as CAG, can be given further consideration for possible gene therapy in humans with OTC deficiency [5].
• Western blot analysis confirmed hepatic OTC expression and normalization of orotic aciduria was evident for 60 days [5].
• Correction of ureagenesis after gene transfer in an animal model and after liver transplantation in humans with ornithine transcarbamylase deficiency [29].
• Prenatal diagnosis of ornithine transcarbamylase deficiency: results in Spfash mice [30].

References