Glycogen storage disease type Ib without neutropenia generated by a novel splice-site mutation in the glucose-6-phosphate translocase gene

Angaroni, Celia J.; Labrune, Philippe; Petit, François; Sastre, Darío; Capra, Ana E.; Kremer, Raquel Dodelson de; Argaraña, Carlos E.

doi:10.1016/j.ymgme.2005.12.011

Cited by 13 publications

(11 citation statements)

References 11 publications

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“…41 notably, not all patients with GSD-Ib seem to develop neutropenia, as shown by case reports of at least seven patients with deleterious SLC37A4 mutations who did not develop this complica- tion. 41–44 Together, these data suggest that, as with G6PC mutations, yet unidentified factors can compensate or stabilize low level expression of G6PT in vivo .…”

Section: Genotypementioning

confidence: 85%

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Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

2010

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Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6- phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.

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Section: Genotypementioning

confidence: 85%

“…63,85 However, this triage may not be effective for all patients. neutropenia is not a clinical presentation of all patients with GSD-Ib, 41–44 and individuals with GSD-Ia who carry the homozygous Gly188Arg muta- tion display mild neutropenia. 35 A definitive diagnosis should, therefore, be confirmed by mutational analysis of both genes.…”

Section: Diagnosismentioning

confidence: 98%

Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

2010

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“…Therefore, flowcharts have been presented for the diagnosis of GSD-Ia in which the presence or absence of myeloid dysfunction determines whether to perform mutation analysis of the G6PC gene [Rake et al, 2000a]. However, neutropenia is not manifest by all GSD-Ib patients [Galli et al, 1999; Kure et al, 2000; Melis et al, 2005; Angaroni et al, 2006; Martens et al, 2006] and some GSD-Ia patients suffer from mild neutropenia [Weston et al, 2000]. Therefore, a clear diagnosis may still warrant mutational analysis of both G6PC and G6PT genes.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the glucose-6-phosphatase-α (G6PC) gene that cause type Ia glycogen storage disease

2008

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“…Of the 160 patients studied to date, 7 patients carrying deleterious G6PT mutations are not reported to have manifested either neutropenia or frequent infections [27–30]. A genotype-phenotype study with a cohort of 22 GSD-Ib patients carrying 16 different G6PT mutations, including 9 patients homozygous or compound heterozygous for nonsense mutations failed to show any correlation between individual mutations and the presence of neutropenia, bacterial infections and systemic complications [28].…”

Section: Geneticsmentioning

confidence: 99%

Neutropenia in type Ib glycogen storage disease

Chou

Jun

Mansfield

2010

Current Opinion in Hematology

104

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Purpose of review Glycogen storage disease type Ib (GSD-Ib), characterized by disturbed glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in a ubiquitously expressed glucose-6-phosphate transporter (G6PT). G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the endoplasmic reticulum, where it is hydrolyzed to glucose either by a liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α) or by a ubiquitously expressed G6Pase-β. The role of the G6PT/G6Pase-α complex is well established and readily explains why G6PT disruptions disturb interprandial blood glucose homeostasis. However, the basis for neutropenia and neutrophil dysfunction in GSD-Ib are poorly understood. Recent studies that are now starting to unveil the mechanisms are presented in this review. Recent Findings Characterization of G6Pase-β and generation of mice lacking either G6PT or G6Pase-β have shown that neutrophils express the G6PT/G6Pase-β complex capable of producing endogenous glucose. Loss of G6PT activity leads to enhanced ER stress, oxidative stress, and apoptosis that underlie neutropenia and neutrophil dysfunction in GSD-Ib. Summary Neutrophil function is intimately linked to the regulation of glucose and G6P metabolism by the G6PT/G6Pase-β complex. Understanding the molecular mechanisms that govern energy homeostasis in neutrophils has revealed a previously unrecognized pathway of intracellular G6P metabolism in neutrophils.

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Glycogen storage disease type Ib without neutropenia generated by a novel splice-site mutation in the glucose-6-phosphate translocase gene

Cited by 13 publications

References 11 publications

Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

Mutations in the glucose-6-phosphatase-α (G6PC) gene that cause type Ia glycogen storage disease

Neutropenia in type Ib glycogen storage disease

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