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

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.
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PMID:Urea-cycle enzyme deficiencies and an increased nitrogen load producing hyperammonemia in Reye's syndrome. 125 Mar 13

A new large Danish family with X-linked retinitis pigmentosa was studied for linkage analysis. Carrier diagnosis was performed using full-field electro-retinogram combined with a careful fundus examination. Multipoint linkage analysis, employing DNA markers from the proximal short arm of the X chromosome and the cytogenetic centromere marker, revealed the highest location score distally to DXS255 and proximal to the ornithine carbamoyl transferase locus. In comparison with the first Danish family that we studied, the pericentromeric recombination fraction was increased; it is speculated that the observed difference in genetic distances from the centromere in the 2 Danish families is correlated with a difference in the size and location of the centromeric heterochromatin.
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PMID:X-linked retinitis pigmentosa: new map studies of XLRP2, and a possible human centromere effect. 155 73

The pathogenetic basis of the Rett syndrome (RS) is unknown: an X-linked dominant, male-lethal gene defect is thought likely. We present a girl with RS who has defects both of the urea cycle and of carbohydrate metabolism resulting in fasting hypoglycaemia, post-prandial hyperlactataemia and excess urinary orotic acid excretion after alanine load. Her sister has a similar clinical picture, but less marked metabolic anomalies. The mother of these sisters has abnormal urinary orotic acid excretion; she transmitted opposite ornithine carbomoyltransferase (OCT) alleles to the two girls. Another girl with RS has similar metabolic responses to fasting and to carbohydrate load. We conclude that RS may be an aetiologically homogeneous condition, but that it includes a variable pattern of metabolic anomalies, and that the gene defect is distinct from the OCT locus.
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PMID:Abnormalities of carbohydrate metabolism and of OCT gene function in the Rett syndrome. 234 6

Ornithine-delta-aminotransferase (OAT) is a nuclear-encoded, mitochondrial matrix enzyme which, in rat, is expressed as basal levels in most tissues but is induced in liver by high dietary protein and in kidney by estrogen and thyroxine administration. In man, the hereditary deficiency of OAT results in ornithine accumulation and the blinding disease gyrate atrophy of the choroid and retina. We cloned near full length rat and human liver OAT cDNAs and demonstrated OAT expression in a variety of tissues from each species. We mapped the human OAT structural gene to chromosome 10, cloned 40 kilobase pairs of genomic DNA containing the complete OAT structural gene, and determined its organization. It is 21 kilobase pairs in length, and contains 11 exons. Exon 2 has been absent from all cDNAs studied and was detected by homology to X-linked processed OAT pseudogenes. The 5'-flanking region of the OAT gene has features of housekeeping genes (GC enrichment and three Sp1 binding consensus sequences) and tissue-specific, inducible genes (TATA box-like element and two CCAAT boxes). A 22-base pair region of partial dyad symmetry containing homology to estrogen responsive elements overlaps the OAT transcription site. Another 5' sequence, GTATCCTGCCCTC, is homologous to sequences in the promoter regions of the genes of three urea cycle enzymes.
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PMID:Human ornithine-delta-aminotransferase. cDNA cloning and analysis of the structural gene. 317 May 46

X-linked retinitis pigmentosa (XLRP) is a series of hereditary dystrophic diseases of the retina that occur in three clinically distinguishable variants: the classic form (McK31360), a type known as choroidoretinal dystrophy (McK30330), and a variant with golden-metallic or "tapetal" reflex in the heterozygote (McK30320). Controversy exists as to whether these phenotypic differences are due to clinical variability in disease expression, heterogeneity in disease alleles at a single locus, or a multiplicity of loci for XLRP. We have studied a single large kindred segregating for XLRP with the metallic fundus reflex in the heterozygote with restriction fragment length polymorphisms (RFLPs) from the short arm of the human X chromosome, and found measurable linkage to DXS7 (theta = 12.5 cMorgans at LOD = 2.5), the same RFLP previously shown by others to be tightly linked to the other forms of XLRP at theta = 3 cM. Although these estimates appeared to be different, each fell just within the 95% probability interval of the other and, therefore, were insufficient to prove or disprove that the metallic sheen form of XLRP is allelic with other forms of XLRP. Additional RFLPs at the DXS43 and the ornithine transcarbamoylase loci provided three-point crosses for determining the relative positions of DXS7 and XLRP, and supported an order that placed this form of XLRP distal to DXS7 on the Xp. Until the question of genetic heterogeneity is resolved, careful phenotypic characterization of the clinical type of XLRP present in families being used for linkage analyses is advisable.
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PMID:Mapping X-linked ophthalmic diseases: II. Linkage relationship of X-linked retinitis pigmentosa to X chromosomal short arm markers. 385 18

Sparse-fur mutant mice have an X-linked deficiency of liver ornithine transcarbamylase (OTC), similar to congenital hyperammonemia type II seen in children. The purpose of the present study was to see whether the expression of enzyme deficiency in the small intestine and colon was similar to that in the liver. Our results show that the level of residual OTC activity in duodenal, jejunal, and ileal mucosa is not significantly different from that of the liver, both in mutant heterozygous female and hemizygous male mice. A highly significant (p less than 0.001) positive correlation was seen between the enzyme activity from all segments of the normal and mutant intestine and that of the liver. pH dependence of mucosal OTC was similar to liver enzyme, when compared within normal or hemizygous mutant mice. Apparent Km (ornithine) of the enzyme from normal or mutant small intestine did not show any significant differences when compared with OTC from normal or mutant livers, respectively. Apparent Km (carbamyl phosphate) from both organs of normal mice was also similar. However, Km (carbamyl phosphate) of mutant intestine and liver gave variable results on statistical comparisons. The specific activity in the proximal and distal colon of mutant mice was significantly lower (p less than 0.001) than normal mice, and showed a similar expression of enzyme deficiency as seen in the small intestine. The similarity of OTC deficiency in the intestine and liver of sparse-fur mice would provide a basis for investigating the use of mucosal biopsies in the confirmation and characterization of human disease.
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PMID:Expression of ornithine transcarbamylase deficiency in the small intestine and colon of sparse-fur mutant mice. 398 56

The clonal origin of tumors was studied in a large series of liver cell tumors in mice. Tumors were induced with phenobarbitone alone or following N-nitroso-diethylamine administration in female mice heterozygous for the sparse-fur strain. In this strain, a histochemical technique can be used in heterozygotes to differentiate clearly between liver cells expressing the histochemically positive normal or the histochemically negative abnormal form of the X-linked enzyme ornithine carbamoyl transferase. Three hundred twenty-seven liver tumors in heterozygous female Spf mice were studied: 157 (48%) were uniformly negative, and 160 (49%) were positive (some with partial enzyme loss). One hundred fifty-four liver tumors in normal mice were studied; all were positive, with a frequency of partial enzyme loss similar to that seen in the heterozygotes. Ten (3%) of the tumors in the heterozygotes contained some separate groups of positive and negative cells, but no tumor was made up exclusively of such groups. Even the smallest recognizable tumors were made up of single-phenotype cells, which suggested that a polyclonal origin followed at a later stage by clonal selection was unlikely. It is concluded that at least 97% of the tumors were of single-cell origin, and that convincing evidence of a polyclonal origin was completely lacking. It is also concluded that the histochemical demonstration of an X-linked enzyme in tumors induced in female animals heterozygous for an abnormal form of that enzyme provides an extremely useful technique for the study of the origins of neoplasia.
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PMID:Clonal origin of mouse liver cell tumors. 407 17

Two X-linked genes, specifying ornithine transcarbamoylase (OTC) and glucose-6-phosphate dehydrogenase (Glc-6-PD), are reversibly suppressed in certain derivatives of the rat H4-II-E hepatoma. Either gene can become reactivated spontaneously, and it is shown that both can be reactivated by azacytidine treatment. This gene reactivation has been investigated by enzyme assay and by the use of selective growth media ('ornithine-medium' to select for OTC, and medium containing diamide to select for Glc-6-PD). There is a clear tendency for both genes to be reactivated together, though either can become active alone. Since OTC is an enzyme of the urea-cycle, and Glc-6-PD is an enzyme of the hexose monophosphate shunt, and since these two pathways are normally under quite separate control, it would seem that the coupled regulation of the two genes in these hepatomas is abnormal. It is suggested that the suppression of the two genes resembles X-inactivation: in both cases, azacytidine treatment induces gene reactivation with a high frequency and results in different clones of cells expressing widely varying amounts of enzyme activity. The association between the re-expression of OTC and Glc-6-PD might indicate that some phenomenon like the position-effect is occurring.
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PMID:The associated reactivation of two X-linked genes. The spontaneous and azacytidine-induced reexpression of ornithine transcarbamoylase and glucose-6-phosphate dehydrogenase in a rat hepatoma. 608 29

Studies of X-linked enzymes provide an approach to the study of tumour and normal cellular development. We have assessed the technique for the histochemical demonstration of one such enzyme, ornithine carbamoyltransferase (EC 2.1.3.3). Various stages in the Mizutani technique for ornithine carbamoyltransferase were re-examined, and the resulting improved technique applied to normal mice and to mice of the sparse fur strain (Spf) known to have an abnormal form of ornithine carbamoyltransferase inherited as an X-linked characteristic. Positive enzyme activity was present in all hepatocytes from normal mice, the strongest reaction being present in the periportal area with a gradual reduction of activity towards the centrilobular region. No activity was demonstrable in hepatocytes from hemizygous male Spf mice. In heterozygous female Spf mice, there was a clear-cut separation of ornithine carbamoyl-transferase-positive and -negative cells. These were present in very variable proportions in different liver lobes and different animals. Preliminary studies were also carried out using a high pH reaction mixture to detect the abnormal enzyme. These studies demonstrate conclusively the X-linkage of ornithine carbamoyltransferase in mice, showing the mosaic pattern of distribution predicted by the Lyon hypothesis. They show that the Spf strain of mice can be used for studies of both development and tumorigenesis in the liver, and that histochemical study of an animal strain with an X-linked enzyme abnormality provides a powerful investigative tool.
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PMID:Studies of X-chromosome inactivation with an improved histochemical technique for ornithine carbamoyltransferase. 686 20

Ornithine transcarbamylase (OTC) deficiency is an X-linked trait and is one of the most frequent of the inherited urea cycle enzyme deficiencies. Most male patients with OTC deficiency develop a hyperammonemic crisis and die in the neonatal period or in early infancy. In contrast to those patients, in some male patients the disease first becomes overt in adolescence or during the reproductive age period. In the present report, we describe six such male patients who first developed clinical signs at ages ranging from 6 to 58 years, all of whom came from a limited area of the northern part of Kyushu Island in southern Japan. The mutation analysis disclosed a R40H mutation in exon 2 of the OTC gene in each of these patients. Transmission of this mutant gene through paternal lineage as well as through maternal lineage was documented in one family. The levels of mRNA of the mutant OTC gene expressed in transfected Cos 1 cells and in the liver tissue obtained by biopsy in one patient were both similar to those of the wild-type gene. The activity of the mutant OTC was, however, decreased to a level of 28% of the wild-type OTC, and the levels of the mutant OTC protein expressed in Cos 1 cells were decreased, as assessed by western blot analysis. Apparent Km values of the mutant enzyme for ornithine (1.1 mM) and carbamylophosphate (2.0 mM) were similar to those of the wild-type enzyme. Both enzymes gave similar pH-dependency profiles, giving a maximal activity at pH 7.8-7.9. Activity of wild-type OTC expressed in Cos 1 cells did not change after five cycles of freezing and thawing, whereas that of the mutant OTC decreased to 17% by this treatment. These results suggest that deficiency is due to inactivation of the mutant OTC under certain conditions.
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PMID:The R40H mutation in a late onset type of human ornithine transcarbamylase deficiency in male patients. 904 15


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