Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c.

Lei, Ke-Jian; Shelly, Leslie L.; Lin, Baochuan; Sidbury, James; Chen, Y T; Nordlie, Robert C.; Chou, Janice Y.

doi:10.1172/jci117645

Cited by 109 publications

(87 citation statements)

References 19 publications

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“…(ii) Family studies in GSD subtype 1b (29) indicate that the genes associated with glucose-6-phosphate transport are not located on human chromosome 17, the location of the glucose-6-phosphatase enzyme gene. (iii) No mutations were found in the glucose-6-phosphatase enzyme gene in GSD 1b (28). (iv) In liver microsomes from a patient with GSD subtype 1b, glucose-6-phosphate transport could not be detected by lightscattering technique despite the presence of the enzyme.…”

Section: Discussionmentioning

confidence: 90%

“…Liver glucose-6-phosphatase enzyme cDNAs have been cloned in humans, rats, and mice (8,9,25,26), and a number of point mutations of the gene have been shown to underlie GSD 1a (27). In contrast, no mutations of this gene have been found in patients with deficiencies of microsomal glucose-6-phosphate transport (28). This indicates that the enzyme protein does not have transport function and that other loci (and proteins) are also needed for glucose-6-phosphate hydrolysis in native (intact) microsomes (2,12,16).…”

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confidence: 98%

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Demonstration of a Metabolically Active Glucose-6-phosphate Pool in the Lumen of Liver Microsomal Vesicles

Bánhegyi

Marcolongo

Fulceri

et al. 1997

Journal of Biological Chemistry

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Glucose-6-phosphate transport was investigated in rat or human liver microsomal vesicles using rapid filtration and light-scattering methods. Upon addition of glucose-6-phosphate, rat liver microsomes accumulated the radioactive tracer, reaching a steady-state level of uptake. In this phase, the majority of the accumulated tracer was glucose, but a significant intraluminal glucose-6-phosphate pool could also be observed. The extent of the intravesicular glucose pool was proportional with glucose-6-phosphatase activity. The relative size of the intravesicular glucose-6-phosphate pool (irrespective of the concentration of the extravesicular concentration of added glucose-6-phosphate) expressed as the apparent intravesicular space of the hexose phosphate was inversely dependent on glucose-6-phosphatase activity. The increase of hydrolysis by elevating the extravesicular glucose-6-phosphate concentration or temperature resulted in lower apparent intravesicular glucose-6-phosphate spaces and, thus, in a higher transmembrane gradient of glucose-6-phosphate concentrations. In contrast, inhibition of glucose-6-phosphate hydrolysis by vanadate, inactivation of glucose-6-phosphatase by acidic pH, or genetically determined low or absent glucose-6-phosphatase activity in human hepatic microsomes of patients suffering from glycogen storage disease type 1a led to relatively high intravesicular glucose-6-phosphate levels. Glucose-6-phosphate transport investigated by light-scattering technique resulted in similar traces in control and vanadate-treated rat microsomes as well as in microsomes from human patients with glycogen storage disease type 1a. It is concluded that liver microsomes take up glucose-6-phosphate, constituting a pool directly accessible to intraluminal glucose-6-phosphatase activity. In addition, normal glucose-6-phosphate uptake can take place in the absence of the glucose-6-phosphatase enzyme protein, confirming the existence of separate transport proteins.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 98%

Demonstration of a Metabolically Active Glucose-6-phosphate Pool in the Lumen of Liver Microsomal Vesicles

Bánhegyi

Marcolongo

Fulceri

et al. 1997

Journal of Biological Chemistry

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“…It alters Arg 83 , an amino acid residue that contributes to the active center of the enzyme. The stringent structural requirement of codon 83 suggests that this amino acid residue in G6Pase may also be involved in positioning the phosphate (Lei et al 1995). The mutation Q347X, which converts a glutamine at position 347 to a stop codon, inactivates G6Pase activity, because it causes truncation of the carboxy terminal 11 amino acid residues in human G6Pase (Lei et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Glycogen storage disease type Ia: molecular study in Brazilian patients

et al. 2001

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Mutations in the glucose-6-phosphatase (G6Pase) gene are responsible for glycogen storage disease type Ia (GSDIa). This disease is characterized by growth retardation, hepatomegaly, hypoglycemia, hyperlipidemia, and lactic acidosis. In this study, we report mutations in the G6Pase gene in 8 of 25 Brazilian patients with clinical symptoms of GSDIa. Five previously described mutations (R83C, Q347X, V338F, D38V, and G68R) were detected. The two most common mutations identified were R83C and Q347X, accounting for 8 of 14 (57.14%) mutant alleles. A 1176 single-nucleotide polymorphism and two intronic mutations (IVS3-58TϾA and IVS4ϩ10GϾA) were also analyzed. We used the minigene strategy in order to verify the effect of these intronic mutations on the splicing mechanism. This study emphasizes that molecular genetic analysis is a reliable and convenient alternative to the assay of enzyme activity in a fresh liver biopsy specimen for diagnosing GSDIa.

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“…The V166G mutation was introduced into the G6Pase cDNA by site-directed mutagenesis and both the mutated and the wild-type constructs were tested for enzymatic activity after transient expression in COS-1 cells as described by Lei et al [1995b].…”

Section: Methodsmentioning

confidence: 99%

Glycogen storage disease type 1a in Israel: Biochemical, clinical, and mutational studies

et al. 1997

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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 Ashkenazi 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. Am. J. Med. Genet. 72:286-290, 1997.

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Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c.

Cited by 109 publications

References 19 publications

Demonstration of a Metabolically Active Glucose-6-phosphate Pool in the Lumen of Liver Microsomal Vesicles

Demonstration of a Metabolically Active Glucose-6-phosphate Pool in the Lumen of Liver Microsomal Vesicles

Glycogen storage disease type Ia: molecular study in Brazilian patients

Glycogen storage disease type 1a in Israel: Biochemical, clinical, and mutational studies

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