Type I Glycogen Storage Diseases: Disorders of the Glucose-6- Phosphatase Complex

Abstract

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.

Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer

“…However, patients continue to suffer from hyperlipidemia, hyperuricemia, hypercalciuria, hypocitraturia, and lactic acidemia, which facilitate the slow progression of kidney disease. 1,2 This is typified by renal stones, nephrocalcinosis, nephrolithiasis, and progressive renal disease that become a frequent and life-threatening complication for older patients. The success of a kidney transduction by rAAV1 in mice offers hope that a similar strategy in humans might also prove of value in gene therapy of renal diseases.…”

“…1,2 Over the last 25 years, dietary therapy consisting of nocturnal nasogastric infusion of glucose 3 or frequent oral administration of uncooked cornstarch 4 has significantly alleviated the metabolic abnormalities of GSD-Ia and greatly improved the prognosis. However, the underlying disease remains untreated and patients continue to suffer from hyperlipidemia, hyperuricemia, hypercalciuria, hypocitraturia, and lactic acidemia.…”

“…As a result, long-term complications including kidney diseases and hepatocellular adenoma with malignant potential occur even in metabolically compensated GSD-Ia patients. 1,2 G6Pase-a is a highly hydrophobic glycoprotein 5,6 that is expressed primarily in the liver, kidney, and intestine. 7,8 It contains nine transmembrane domains that anchor it in the endoplasmic reticulum (ER) membrane.…”

“…9,10 Therefore, G6P hydrolysis is dependent upon transport of the cytoplasmic G6P across the ER membrane by a G6P transporter (G6PT). 1,2,11 To be functional, both G6Pase-a and G6PT must be coexpressed and embedded correctly in the ER membrane. 12 While protein replacement therapy is not an option, somatic gene therapy, targeting G6Pase-a to the liver and the kidney, is an attractive possibility.…”

Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

“…Hepatic glucose-6-phosphatase activity is critical for maintaining plasma glucose levels between meals. Mutations in the gene encoding the glucose-6-phosphatase catalytic subunit (G6PC) result in glycogen storage disease type 1a (von Gierke's disease), which is characterised by life-threatening hypoglycaemia, growth retardation, renal dysfunction and hepatomegaly [2]. In contrast, increased G6PC mRNA and G6PC activity are thought to contribute to the elevated hepatic glucose production (HGP) characteristic of type 1 and type 2 diabetes [3,4].…”