Glycogen Storage Disease Type lb: Genetic Disorder
Involving the Transport System of Intracellular Membrane

Narisawa, Kuniaki; Igarashi, Yutaka; Tada, Keiya

doi:10.1159/000469203

Cited by 9 publications

(5 citation statements)

References 4 publications

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“…Decreased respiratory burst activity is not uniform in GSD 1b PMN; some patients have relatively normal values, though methods vary (32)(33)(34)(35)(36). These defects are postulated to be caused by variably decreased rates of NADPH biosynthesis in GSD 1b PMN (6). Hexose monophosphate shunt abnormalities have been associated with G6P transport defects (35).…”

Section: Discussionmentioning

confidence: 99%

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Glucose-6-Phosphatase Mutation G188R Confers an Atypical Glycogen Storage Disease Type 1b Phenotype

et al. 2000

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Glycogen storage disease type 1a (GSD 1a) is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase). A variant (GSD 1b) is caused by a defect in the transport of glucose-6-phosphate (G6P) into the microsome and is associated with chronic neutropenia and neutrophil dysfunction. Mutually exclusive mutations in the G6Pase gene and the G6P transport gene establish GSD la and GSD 1b as independent molecular processes and are consistent with a multicomponent translocase catalytic model. A modified translocase/catalytic unit model based on biochemical data in a G6Pase knockout mouse has also been proposed for G6Pase catalysis. This model suggests coupling of G6Pase activity and G6P transport. A 5-mo-old girl with hypoglycemia, hepatomegaly, and lactic acidemia was diagnosed with GSD 1a. She also developed neutropenia, neutrophil dysfunction, and recurrent infections characteristic of GSD 1b. Homozygous G188R mutations of the G6Pase gene were identified, but no mutations in the G6P translocase gene were found. We have subsequently identified a sibling and two unrelated patients with similar genotypic/phenotypic characteristics. The unusual association of neutrophil abnormalities in patients with homozygous G188R mutations in the G6Pase gene supports a modified translocase/catalytic unit model.

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Section: Discussionmentioning

confidence: 99%

“…A variant subgroup, GSD 1b, is caused by a defect in the transport of the substrate G6P into the microsome. GSD 1b is associated with normal G6Pase catalytic activity in disrupted microsomes, chronic neutropenia, and neutrophil dysfunction (5,6) in addition to the aforementioned clinical manifestations of GSD 1a.…”

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confidence: 99%

Glucose-6-Phosphatase Mutation G188R Confers an Atypical Glycogen Storage Disease Type 1b Phenotype

et al. 2000

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“…Type 1b glycogen storage disease is characterized by an absence of glucose-6-phosphatase enzymatic activity in intact liver microsomes but normal or elevated activity in detergentdisrupted preparations (12). The biochemical phenotype of type 1b glycogen storage disease patients lends support to the substrate-transport model for the glucose-6-phosphatase complex, in which the role of P46 is suggested to be as an ER-localized transporter for glucose 6-phosphate, allowing the luminally oriented Glc-6-Pase catalytic subunit to gain access to its substrate (2).…”

Section: Discussionmentioning

confidence: 99%

“…Patients with type Ia glycogen storage disease have mutations in the P36 gene (5) and a complete deficiency of glucose-6-phosphatase enzymatic activity, regardless of whether the assay is performed in intact or detergent-disrupted microsomal preparations (12). Patients with type Ib glycogen storage disease have mutations in the P46 gene (11) and have absent or reduced glucose-6-phosphatase enzymatic activity in intact microsomes but normal or increased activity in detergent-disrupted preparations (13).…”

mentioning

confidence: 99%

Overexpression of the P46 (T1) Translocase Component of the Glucose-6-phosphatase Complex in Hepatocytes Impairs Glycogen Accumulation via Hydrolysis of Glucose 1-Phosphate

Werve

et al. 2001

Journal of Biological Chemistry

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The final step of gluconeogenesis and glycogenolysis is catalyzed by the glucose-6-phosphatase (Glc-6-Pase) enzyme complex, located in the endoplasmic reticulum. The complex consists of a 36-kDa catalytic subunit (P36), a 46-kDa glucose 6-phosphate translocase (P46), and putative glucose and inorganic phosphate transporters. Mutations in the genes encoding P36 or P46 have been linked to glycogen storage diseases type Ia and type Ib, respectively. However, the relative roles of these two proteins in control of the rate of glucose 6-phosphate hydrolysis have not been defined. To gain insight into this area, we have constructed a recombinant adenovirus containing the cDNA encoding human P46 (AdCMV-P46) and treated rat hepatocytes with this virus, or a virus encoding P36 (AdCMV-P36), or the combination of both viruses, resulting in large and equivalent increases in expression of the transgenes within 8 -24 h of viral treatment. The overexpressed P46 protein was appropriately targeted to hepatocyte microsomes and caused a 58% increase in glucose 6-phosphate hydrolysis in nondetergent-treated (intact) microsomal preparations relative to controls, whereas overexpression of P36 caused a 3.6-fold increase. Overexpression of P46 caused a 50% inhibition of glycogen accumulation in hepatocytes from fasted rats incubated at 25 mM glucose relative to cells treated with a control virus (AdCMV-␤GAL). Furthermore, in hepatocytes from fed rats cultured at 25 mM glucose and then exposed to 15 mM glucose, AdCMV-P46 treatment activated glycogenolysis, as indicated by a 50% reduction in glycogen content relative to AdCMV-␤GAL-treated controls. In contrast, overexpression of P46 had only small effects on glycolysis, whereas overexpression of P36 had large effects on both glycogen metabolism and glycolysis, even in the presence of cooverexpressed glucokinase. Finally, P46 overexpression enhanced glucose 1-phosphate but not fructose 6-phosphate hydrolysis in intact microsomes, providing a mechanism by which P46 overexpression may exert its preferential effects on glycogen metabolism.The glucose-6-phosphatase enzyme complex catalyzes the final step of gluconeogenesis. The complex is composed of a catalytic subunit of 36 kDa (P36) 1 sequestered within the endoplasmic reticulum (ER), a 46-kDa glucose-6-phosphate translocase known as P46 or T1 that delivers glucose 6-phosphate to the catalytic subunit, and putative ER glucose and inorganic phosphate (P i ) transporters (T2 and T3) that move the reaction products back into the cytosol (1-3). However, only P36 and P46 have been clearly identified and cloned (4 -7). It remains uncertain whether P i transport is embodied in the function of P46 or encoded by a separate protein (8). Furthermore, an earlier report describing an ER-localized glucose transporter, GLUT-7 (9), has recently been retracted (10).Mutations in P36 and P46 have both been linked to glycogen storage diseases in human subjects (5, 11). Patients with type Ia glycogen storage disease have mutations in the P36 gene (5) and a comp...

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“…(2) Inactive glucose-6-phosphate (G6P) translocase in GSD Ib (Schaub and Heyne, 1983;Narisawa et al, 1987); and…”

Section: A Methods For the Diagnosis Of Glycogen Storage Disease Type mentioning

confidence: 99%

A Method for the Diagnosis of Glycogen Storage Disease Type Ib using Polymorphonuclear Leukocytes

Bashan¹,

Potashnik²,

Phillip³

et al. 1989

Studies in Inherited Metabolic Disease

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Glycogen Storage Disease Type lb: Genetic Disorder Involving the Transport System of Intracellular Membrane

Cited by 9 publications

References 4 publications

Glucose-6-Phosphatase Mutation G188R Confers an Atypical Glycogen Storage Disease Type 1b Phenotype

Glucose-6-Phosphatase Mutation G188R Confers an Atypical Glycogen Storage Disease Type 1b Phenotype

Overexpression of the P46 (T1) Translocase Component of the Glucose-6-phosphatase Complex in Hepatocytes Impairs Glycogen Accumulation via Hydrolysis of Glucose 1-Phosphate

A Method for the Diagnosis of Glycogen Storage Disease Type Ib using Polymorphonuclear Leukocytes

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