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Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes

  • Glycogenoses
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Disorders of the glucose-6-phosphatase (G6Pase)/glucose-6-phosphate transporter (G6PT) complexes consist of three subtypes: glycogen storage disease type Ia (GSD-Ia), deficient in the liver/kidney/intestine-restricted G6Pase-α (or G6PC); GSD-Ib, deficient in a ubiquitously expressed G6PT (or SLC37A4); and G6Pase-β deficiency or severe congenital neutropenia syndrome type 4 (SCN4), deficient in the ubiquitously expressed G6Pase-β (or G6PC3). G6Pase-α and G6Pase-β are glucose-6-phosphate (G6P) hydrolases with active sites lying inside the endoplasmic reticulum (ER) lumen and as such are dependent upon the G6PT to translocate G6P from the cytoplasm into the lumen. The tissue expression profiles of the G6Pase enzymes dictate the disease's phenotype. A functional G6Pase-α/G6PT complex maintains interprandial glucose homeostasis, while a functional G6Pase-β/G6PT complex maintains neutrophil/macrophage energy homeostasis and functionality. G6Pase-β deficiency is not a glycogen storage disease but biochemically it is a GSD-I related syndrome (GSD-Irs). GSD-Ia and GSD-Ib patients manifest a common metabolic phenotype of impaired blood glucose homeostasis not shared by GSD-Irs. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and neutrophil/macrophage dysfunction not shared by GSD-Ia. While a disruption of the activity of the G6Pase-α/G6PT complex readily explains why GSD-Ia and GSD-Ib patients exhibit impaired glucose homeostasis, the basis for neutropenia and myeloid dysfunction in GSD-Ib and GSD-Irs are only now starting to be understood. Animal models of all three disorders are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy.

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Acknowledgement

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

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Conflict of Interest

Janice Y. Chou, Hyun Sik Jun, and Brian C. Mansfield declare that they have no conflict of interest.

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This article does not contain any studies with human subjects performed by any of the authors.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

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Authors and Affiliations

  1. Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Janice Y. Chou, Hyun Sik Jun & Brian C. Mansfield

  2. Foundation Fighting Blindness, Columbia, MD, 21046, USA

    Brian C. Mansfield

  3. Building 10, Room 9D42, NIH, 10 Center Drive, Bethesda, MD, 20892-1830, USA

    Janice Y. Chou

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  1. Janice Y. Chou
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  2. Hyun Sik Jun
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Correspondence to Janice Y. Chou.

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Communicated by: Alberto B Burlina

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Chou, J.Y., Jun, H.S. & Mansfield, B.C. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J Inherit Metab Dis 38, 511–519 (2015). https://doi.org/10.1007/s10545-014-9772-x

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  • DOI: https://doi.org/10.1007/s10545-014-9772-x

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