Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.9 (glucose-6-phosphatase)
3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious factors, the pathogenesis of clinical and experimental hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease (glucose-6-phosphatase deficiency) may exemplify this general mechanism, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.
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PMID:Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis. 839 60

Microsomal glucose-6-phosphatase (EC 3.1.3.9) is an enzyme system traditionally thought to be present only in gluconeogenic tissues. We have used microassay techniques, immunohistochemistry using monospecific antibodies to the liver enzyme, and specific DNA probes and primers to examine whether glucose-6-phosphatase is present in human and rat testis. Microsomal glucose-6-phosphatase activities in human fetal testis (weeks 15-20 of gestation) are approximately 25% of corresponding liver values. Localization is predominantly in Leydig cells, with variable and weak immunoreactivity in developing seminiferous tubules. Kinetic analysis of glucose-6-phosphatase in intact and disrupted microsomes and Southern blot analysis of polymerase chain reaction products indicated that the specific glucose-6-phosphatase enzyme system was also present in rat testis. We have shown for the first time that specific microsomal glucose-6-phosphatase activity, protein, and mRNA are present in testis, and that the predominant site of expression is the Leydig cell in human fetal testis.
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PMID:Human fetal testis endoplasmic reticulum glucose-6-phosphatase enzyme protein. 882 32

Glycogen storage disease type 1a (GSD 1a), a severe metabolic disorder, is caused by the absence of glucose-6-phosphatase (G6Pase) activity. Diagnosis is currently established by demonstrating the lack of G6Pase activity in the patient's liver specimen. Enzymatic diagnosis cannot be performed in chorionic villi or amniocytes as G6Pase is active only in the liver, kidney, and intestinal mucosa. Recent cloning of the G6Pase gene and subsequent identification of the mutations causing GSD 1a have led to the possibility of performing DNA-based diagnosis in chorionic villus samples (CVS) or amniocytes. Here we report the first DNA-based prenatal diagnosis in two families in whom GSD 1a patients were diagnosed. In one Jewish family with a previously identified R83C mutation, single-stranded conformation polymorphism (SSCP) analysis of the DNA extracted from CVS showed a homozygous R83C mutant pattern. As a result, the pregnancy was terminated and the diagnosis was confirmed on DNA analysis of the aborted fetus. In another family of Arabic extraction in which a V166G mutation has been identified in one of the siblings, SSCP analysis performed on DNA extracted from CVS presented the pattern of a normal control. The pregnancy was carried to term and a healthy baby was born. Thus, once mutations causing the disease are identified, prenatal diagnosis of GSD 1a is possible. SSCP analysis of DNA prepared from CVS is reliable, simple and fast, making it a suitable method for prenatal diagnosis.
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PMID:Prenatal diagnosis of glycogen storage disease type 1a by single stranded conformation polymorphism (SSCP). 890 2

Type Ia glycogen storage disease (GSD), an autosomal recessive metabolic disorder, is caused by a deficiency in glucose-6-phosphatase (G6Pase). We had previously identified the nature of the causative mutations in a Chinese family whose first two children were affected with type Ia GSD. Two different point mutations in the G6Pase gene, a guanine to adenine substitution at base position 327 in exon 2 and a thymine to adenine substitution at base position 1101 in exon 5, change the restriction sites for the enzymes Fok I and Hinc II. Family study revealed that both parents were heterozygous carriers: the father with a mutant G6Pase allele at exon 2 and the mother with another mutant G6Pase allele at exon 5. This paper deals with a prenatal diagnosis on the fetus of this family who is at risk of type Ia GSD. Genomic DNA was extracted from a chorionic villus biopsy sampled at the tenth week of gestation. Exons 2 and 5 of the G6Pase gene were amplified by the polymerase chain reaction (PCR) followed by restriction enzyme digestion and direct sequence analysis. DNA analysis indicated that the fetus was a heterozygous carrier of type Ia GSD with a mutant G6Pase allele at exon 2 and a normal G6Pase allele at exon 5. The diagnosis was further confirmed by the same method with cultured amniocytes and with a blood sample after the baby was born. This is the first report of prenatal carrier detection of type Ia GSD at the gene level.
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PMID:Prenatal diagnosis in a Chinese family with type Ia glycogen storage disease by PCR-based genetic analysis. 895 36

Glycogen storage disease type 1a (GSD 1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase (G6Pase). We analyzed the G6Pase gene of two unrelated Japanese families with GSD 1a. DNA sequencing of all five exons and exon-intron junctions revealed a G-to-T transversion at nucleotide 727 (G727T) in exon 5, which has been previously reported to cause abnormal splicing. Family studies using mismatch PCR showed that three patients were homozygous for the G727T mutation, while the parents were heterozygous. To investigate allele frequencies, we screened 216 Japanese healthy volunteers and found one asymptomatic carrier. Our findings suggest that the G727T mutation may be prevalent in Japan.
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PMID:Identification of a point mutation (G727T) in the glucose-6-phosphatase gene in Japanese patients with glycogen storage disease type 1a, and carrier screening in healthy volunteers. 913 83

Two Maltese puppies with massive hepatomegaly and failure to thrive had isolated deficient glucose-6-phosphatase (G-6-Pase) activity in liver and kidney and pathological findings compatible with GSD-Ia. To identify the mutation, we cloned G-6-Pase canine cDNA by RT-PCR with primers from the murine G-6-Pase gene sequence. The canine G-6-Pase cDNA is 2346 bp, with a 5' untranslated region of 87 bp, a coding region of 1071 bp, and a 3' untranslated region of 1185 bp. The difference between the canine and human sequences is in the 3' untranslated region. A greater than 90% amino acid sequence homology was seen with canine, human, murine, and rat G-6-Pase. G-6-Pase cDNA from affected and control puppies revealed complete homology except at nt position 450, which showed a guanine to cytosine (G to C) transversion resulting in substitution of a methionine by isoleucine at codon 121 (M121I) in all five clones studied. The loss of an NcoI restriction site on genomic DNA amplified with primers flanking the mutation allowed us to prove that affected puppies were homozygous for the mutation and parents were heterozygous carriers. The mutant G-6-Pase cDNA had 15 times less enzyme activity than wild-type cDNA following transient transfection. Northern blot analysis of puppies with GSD-Ia revealed increased G-6-Pase mRNA, compared to normal controls. Increased G-6-Pase mRNA was also seen in normal fasted puppies compared to littermates in the fed state, suggesting that the increased G-6-Pase mRNA is a physiologic response to fasting. This is the first report of a molecularly confirmed naturally occurring animal model of GSD-Ia. The establishment of a breeding colony of this dog strain will facilitate studies on the role of G-6-Pase gene in glucose homeostasis, in pathophysiology of disease, and development of novel therapeutic approaches such as gene therapy.
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PMID:Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. 925 82

We have assessed the effect of the oral ingestion of thioacetamide on small intestine structure and function. Thioacetamide-treated rats showed diminished mucosa weight; protein, DNA, and RNA content; and leucine aminopeptidase activity as compared to controls in both jejunum and ileum. In the jejunum, there was a reduction in the activities of alkaline phosphatase, ATPase, glucose-6-phosphatase, and myeloperoxidase, whereas in the ileum, maltase, lactase, and gamma-glutamyltranspeptidase were reduced. In both jejunum and ileum we found enlarged intercellular spaces, dark epithelial enterocytes, and lymphocyte infiltration. Enterocytes showed lobulated nuclei, deranged mitochondria with loss of their cristae, dilated rough endoplasmic reticulum containing dense material, and vesiculation of the smooth endoplasmic reticulum and the Golgi apparatus. Smooth muscle cells of the intestine exhibited ultrastructural alterations. These findings indicate that chronic oral intake of thioacetamide mimics not only hepatic alterations but also small intestine alterations normally associated with human cirrhosis.
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PMID:Hepatotoxic agent thioacetamide induces biochemical and histological alterations in rat small intestine. 928 39

Glycogen storage disease type 1a (von Gierke disease, GSD 1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity which catalyzes the final common step of glycogenolysis and gluconeogenesis. The recent cloning of the G6Pase cDNA and characterization of the human G6Pase gene enabled the characterization of the mutations causing GSD 1a. This, in turn, allows the introduction of a noninvasive DNA-based diagnosis that provides reliable carrier testing and prenatal diagnosis. In this study, we report the biochemical and clinical characteristics as well as mutational analyses of 12 Israeli GSD 1a patients of different families, who represent most GSD 1a patients in Israel. The mutations, G6Pase activity, and glycogen content of 7 of these patients were reported previously. The biochemical data and clinical findings of all patients were similar and compatible with those described in other reports. All 9 Jewish patients, as well as one Muslim Arab patient, presented the R83C mutation. Two Muslim Arab patients had the V166G mutation which was not found in other patients' populations. The V166G mutation, which was introduced into the G6Pase cDNA by site-directed mutagenesis following transient expression in COS-1 cells, was shown to cause complete inactivation of the G6Pase. The characterization of all GSD 1a mutations in the Israeli population lends itself to carrier testing in these families as well as to prenatal diagnosis, which was carried out in 2 families. Since all Ashkenzai Jewish patients harbor the same mutation, our study suggests that DNA-based diagnosis may be used as an initial diagnostic step in Ashkenazi Jews suspected of having GSD 1a, thereby avoiding liver biopsy.
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PMID:Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies. 933 55

Glycogen storage disease type 1a (von Gierke disease, GSD-1A) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity which catalyzes the final common step of glycogenolysis and gluconeogenesis. The cloning of the G6Pase cDNA and characterization of the human G6Pase gene enabled the identification of the mutations causing GSD-1a. This, in turn, allows the development of non-invasive DNA-based diagnosis that provides reliable carrier testing and prenatal diagnosis. Here we report on two new mutations E110Q and D38V causing GSD-1a in two Hungarian patients. The analyses of these mutations by site-directed mutagenesis followed by transient expression assays demonstrated that E110Q retains 17% of G6Pase enzymatic activity while the D38V abolishes the enzymatic activity. The patient with the E110Q has G222R as his other mutation. G222R was also shown to preserve about 4% of the G6Pase enzymatic activity. Nevertheless, the patient presented with the classical severe symptomatology of the GSD-1a.
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PMID:Two new mutations in the glucose-6-phosphatase gene cause glycogen storage disease in Hungarian patients. 935 38

The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expressed in a tissue-specific manner in the liver and kidney. To understand the molecular mechanisms regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays. The G6Pase promoter is active in HepG2 hepatoma cells, but inactive in JEG3 choriocarcinoma or 3T3 cells. DNA elements essential for optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3. Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs) at nucleotides -234 to -212 (AE-I), -146 to -125 (AE-II), and -124 to -71 (AE-III). AE-I contains binding sites for hepatocyte nuclear factors (HNF) 1 and 4. Electromobility shift and cotransfection assays demonstrated that HNF1alpha, but not HNF4, bound to its cognate site and transactivated G6Pase gene expression. The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174), 2 (-139/-133), 3 (-91/-85), 4 (-81/-75), and 5 (-72/-66), and all five sites bound HNF3gamma with high affinity. Transient expression and cotransfection assays showed that HNF3 site 1 is not required for basal promoter activity, but is essential for HNF3gamma-activated transcription from the G6Pase promoter. We further showed that HNF3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamma. AE-II contains, in addition to a HNF3 motif, a cAMP-response element (CRE) and a C/EBP half-site. The G6Pase(-146/-116) DNA containing AE-II formed multiple protein-DNA complexes with HepG2 nuclear extracts, including HNF3gamma, CRE-binding protein (CREB), C/EBPalpha, and C/EBPbeta. We showed that AE-II mediated transcription activation of the G6Pase gene by cAMP.
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PMID:The role of HNF1alpha, HNF3gamma, and cyclic AMP in glucose-6-phosphatase gene activation. 936 82


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