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)

The clinical manifestations of type 1 glycogen storage disease (GSD-1) in patients deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are shared by Hnf1alpha(-/-) mice deficient of a transcriptional activator, hepatocyte nuclear factor 1alpha (HNF1alpha). However, the molecular mechanism is unknown. The G6Pase system, essential for the maintenance of glucose homeostasis, is comprised of glucose 6-phosphate transporter (G6PT) and G6Pase. G6PT translocates G6P from the cytoplasm to the lumen of the endoplasmic reticulum where it is metabolized by G6Pase to glucose and phosphate. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Hnf1alpha(-/-) mice also develop noninsulin-dependent diabetes mellitus caused by defective insulin secretion. In this study, we sought to determine whether there is a molecular link between HNF1alpha deficiency and function of the G6Pase system. Transactivation studies revealed that HNF1alpha is required for transcription of the G6PT gene. Hepatic G6PT mRNA levels and microsomal G6P transport activity are also markedly reduced in Hnf1alpha(-/-) mice as compared with Hnf1alpha(+/+) and Hnf1alpha(+/-) littermates. On the other hand, hepatic G6Pase mRNA expression and activity are up-regulated in Hnf1alpha(-/-) mice, consistent with observations that G6Pase expression is increased in diabetic animals. Taken together, the results strongly suggest that metabolic abnormalities in HNF1alpha-null mice are caused in part by G6PT deficiency and by perturbations of the G6Pase system.
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PMID:A molecular link between the common phenotypes of type 1 glycogen storage disease and HNF1alpha-null mice. 1112 25

A canine model of glycogen storage disease Ia (GSD Ia), similar clinically, biochemically, and pathologically to the human disease, was established by crossbreeding Maltese and Beagle dogs carrying a mutated, defective glucose-6-phosphatase (G-6-Pase) gene. Ten puppies were born in three litters from these crossbreedings. Six were homozygous for the previously described M121I GSD Ia mutation. Of these six affecteds, two were stillborn, and one died at 2, 32, and 60 days of life, respectively (puppies A, B, C, D, E), while one is alive at age 15 months (puppy F). Affected puppies exhibited tremors, weakness, and neurologic signs when hypoglycemic. They had postnatal growth retardation and progressive hepatomegaly. Biochemical abnormalities included fasting hypoglycemia, hyperlactacidemia, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia. Microscopic examination of tissues from affected puppies showed diffuse, marked hepatocellular vacuolation, with distended clear hepatocytes and central to marginally located rounded nuclei. In the kidneys of puppies D and E, there was segmental glomerular sclerosis and vacuolation of proximal convoluted tubular epithelium. Biochemical analysis revealed increased liver glycogen content and isolated markedly reduced G-6-Pase enzyme activity in liver and kidney. The canine G-6-Pase gene was characterized by screening a canine genomic library. It spans approximately 11.8 kb and consists of five exons with >90% amino acid sequence homology to the derived human sequence. The first 1.5 kb of the 5' region was sequenced and contains several putative response element motifs homologous to the human 5' region. Establishment of this canine colony of GSD Ia that closely resembles human disease and isolation of the canine genomic gene provides an excellent model for studying pathophysiology and long-term complications and an opportunity to develop novel therapeutic approaches such as drug and gene therapy.
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PMID:Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). 1119 68

Glycogen storage disease type 1 (GSD 1) comprises a group of autosomal recessive inherited metabolic disorders caused by deficiency of the microsomal multicomponent glucose-6-phosphatase system. Of the two known transmembrane proteins of the system, malfunction of the catalytic subunit (G6Pase) characterizes GSD 1a. GSD 1 non-a is characterized by defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport due to mutations in G6PT (glucose-6-phosphate translocase gene) encoding a microsomal transporter protein. Mutations in G6Pase and G6PT account for approximately 80 and approximately 20% of GSD 1 cases, respectively. G6Pase and G6PT work in concert to maintain glucose homeostasis in gluconeogenic organs. Whereas G6Pase is exclusively expressed in gluconeogenic cells, G6PT is ubiquitously expressed and its deficiency generally causes a more severe phenotype. Rapid confirmation of clinically suspected diagnosis of GSD 1, reliable carrier testing, and prenatal diagnosis are facilitated by mutation analyses of the chromosome 11-bound G6PT gene as well as the chromosome 17-bound G6Pase gene.
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PMID:Molecular genetics of type 1 glycogen storage disease. 1138 47

Deficiencies in the glucose-6-phosphate transporter (G6PT) cause glycogen storage disease type 1b (GSD-1b), a heritable metabolic disorder. The G6PT protein translocates glucose-6-phosphate from the cytoplasm to the lumen of the endoplasmic reticulum, where glucose-6-phosphatase metabolizes it to glucose and phosphate. Therefore, G6PT and glucose-6-phosphatase work in concert to maintain glucose homeostasis. To delineate the control of G6PT gene expression, we first demonstrated that transcription of the gene requires hepatocyte nuclear factor 1alpha. Consequently, hepatocyte nuclear factor 1alpha-null mice manifest a G6PT deficiency like that of GSD-1b patients. In this study, we delineated the role of glucocorticoids in the transcription of the G6PT gene. We showed that the basal G6PT promoter is contained within nucleotides -369 to -1 upstream of the translation start site, which contains three activation elements. Further, we demonstrated that glucocorticoids activate G6PT transcription and that glucocorticoid action is mediated through a glucocorticoid response element within activation element-2 of the promoter. Taken together, the results suggest that glucocorticoids play a pivotal role in regulating the G6PT gene.
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PMID:Glucocorticoids activate transcription of the gene for the glucose-6-phosphate transporter, deficient in glycogen storage disease type 1b. 1156 Jul 76

A 23-year-old woman was admitted to our hospital with recurrent gouty arthritis. Laboratory findings showed hypoglycemia, lactic acidosis, hyperlipidemia, and hyperuricemia, with normal values of serum alfa-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA-II). A diagnosis of glycogen storage disease type I (GSD-type I) was made on the basis of the laboratory data, liver biopsy findings, and partially deficient thrombocyte glucose-6-phosphatase (G-6-Pase) activity. Ultrasonography and computed tomography revealed multiple focal hepatic masses. Biopsied specimens of the lesion demonstrated a hepatic adenoma, which changed in appearance in the relatively short period between echography and computed tomography. This interesting phenomenon may highlight the importance for careful follow-up of hepatic adenomas, because of the potential of rupture, hemorrhage, or malignant transformation. During follow-up, the present patient received hemodialysis due to renal failure, and the adenoma regressed spontaneously after 8 years. Included are diagnostic images, demonstrating the association of hepatic adenoma and GSD-type I.
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PMID:Spontaneous regression of hepatic adenoma in a patient with glycogen storage disease type I after hemodialysis: ultrasonographic and CT findings. 1157 51

Glycogen storage disease type 1 (GSD-1), also known as von Gierke disease, is a group of autosomal recessive metabolic disorders caused by deficiencies in the activity of the glucose-6-phosphatase (G6Pase) system that consists of at least two membrane proteins, glucose-6-phosphate transporter (G6PT) and G6Pase. G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum (ER) and G6Pase catalyzes the hydrolysis of G6P to produce glucose and phosphate. Therefore, G6PT and G6Pase work in concert to maintain glucose homeostasis. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Both manifest functional G6Pase deficiency characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD-1b patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa. The G6Pase gene maps to chromosome 17q21 and encodes a 36-kDa glycoprotein that is anchored to the ER by 9 transmembrane helices with its active site facing the lumen. Animal models of GSD-1a have been developed and are being exploited to delineate the disease more precisely and to develop new therapies. The G6PT gene maps to chromosome 11q23 and encodes a 37-kDa protein that is anchored to the ER by 10 transmembrane helices. A functional assay for the recombinant G6PT protein has been established, which showed that G6PT functions as a G6P transporter in the absence of G6Pase. However, microsomal G6P uptake activity was markedly enhanced in the simultaneous presence of G6PT and G6Pase. The cloning of the G6PT gene now permits animal models of GSD-1b to be generated. These recent developments are increasing our understanding of the GSD-l disorders and the G6Pase system, knowledge that will facilitate the development of novel therapeutic approaches for these disorders.
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PMID:The molecular basis of type 1 glycogen storage diseases. 1189 41

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients' genotype. While the molecular basis for the GSD-I disorders are now known and symptomatic therapies are available, many aspects of the diseases are still poorly understood, and there are no cures. Recently developed animal models of the disorders are now being exploited to delineate the disease more precisely and develop new, more causative therapies.
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PMID:Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. 1194 31

Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the potential of intravenously delivered adeno-associated virus (AAV) vectors for gene therapy. In three affected canines, liver glycogen was reduced following hepatic expression of canine glucose-6-phosphatase (G6Pase). Two months after AAV vector administration, one affected dog had normalization of fasting glucose, cholesterol, triglycerides, and lactic acid. Concatamerized AAV vector DNA was confirmed by Southern blot analysis of liver DNA isolated from treated dogs, as head-to-tail, head-to-head, and tail-to-tail concatamers. Six weeks after vector administration, the level of vector DNA signal in each dog varied from one to five copies per cell, consistent with variation in the efficiency of transduction within the liver. AAV vector administration in the canine model for GSD Ia resulted in sustained G6Pase expression and improvement in liver histology and in biochemical parameters.
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PMID:Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. 1210 32

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility. Previously, we reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia. Using neonatal GSD-Ia mice, we now demonstrate that a combined adeno virus and adeno-associated virus vector-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and corrects the murine GSD-Ia disease for at least 12 months. Our results suggest that human GSD-Ia would be treatable by gene therapy.
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PMID:Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice. 1218 68

Glycogen storage disease type I (GSD I) (McKusick 232200) is caused by inherited defects of the glucose-6-phosphatase complex. Patients with GSD Ia as well as patients with GSD lb may suffer from intermittent diarrhoea, which seems to worsen with age. The cause of this diarrhoea is unknown. This study describes the results of investigations of intestinal functions and morphology in patients with GSD Ia and GSD lb, which were performed to detect a common cause for chronic diarrhoea in GSD I. The following were investigated: faecal fat excretion, faecal alpha1-antitrypsin and faecal chymotrypsin, expiratory H2 concentrations, persorption of cornstarch in urine and colonic biopsies. With the investigations presented in this study, no common cause for diarrhoea in GSD I was found. In GSD lb loss of mucosal barrier function due to inflammation, documented by increased faecal alpha1-antitrypsin excretion (3.5-9.6 mg/g dry faeces) and inflammation in the colonic biopsies, seems to be the main cause. The inflammation is most likely related to disturbed neutrophil function, which is often found in GSD lb. Whether another cause is involved in GSD Ia and in GSD Ib, related to the disturbed function of glucose-6-phosphatase in the enterocyte, remains to be investigated.
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PMID:Intestinal function in glycogen storage disease type I. 1222 56


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