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Since the main source of glycogen is glucose-6-phosphate, and G6Pase is critical for both glucogenolysis and gluconeogenesis, mutations causing a G6Pase deficiency result in the more severe symptoms experienced by patients with glycogen storage disease. The symptoms of GSD-Ia include hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic academia, hypoglycemic seizures, and coma (Kim and Bae, 2009). GSD-1b patients also suffer from neutropenia and myeloid dysfunctions, and defects in neutrophils respiratory bursts, chemotaxis, and calcium flux . The latter renders these patients susceptible to bacterial infections, inflammatory bowel disease, and aphtous stomatitis.

The major product of glycogen metabolism is glucose-1-phosphate, which is reversibly converted to glucose-6-phosphate by phosphoglucomutase (G6P; see Figure 1). G6P can then by hydrolyzed into glucose and inorganic phosphorus by the multi-component G6Pase enzymatic complex located on the luminal surface of the endoplasmic reticulum (ER) (Rake et al., 2000). The structure of the catalytic unit (G6Pase) consists of a nine-transmembrane helical structure, with the N-terminus and four loops positioned on the ER luminal surface. One of these transmembrane sections is home to 25 missense mutations that cause GSD type Ia, suggesting the resulting amino acid changes and this transmembrane section are critical to the catalytic activity of G6Pase. Another disease-linked missense mutation is located in the N-terminus and the remaining seven missense mutations that have been identified are located in two of the four loops. The only regions not linked to disease-causing mutations are the cytoplasmic loops and one luminal loop.

Overall, the majority of GSD type Ia cases are the result of just three mutations: R83C, Q347X, and 727GT (Rake et a., 2000). All other mutations individually account for less than 5% of disease prevalence and some have only been found in one patient or family. The arginine to cysteine change that occurs in patients with the R83C mutation results in a G6Pase protein without detectable phosphohydrolase activity (Lei, Shelly, Pann, Sidbury, and Chou, 1993). The Q347X mutation results in the conversion of a glutamine codon to a stop codon, which truncates the carboxy terminal by 11 residues and completely destroys the catalytic activity of G6Pase (Lei, Pan, Shelly, Liu, and Chou, 1994). The 727GT mutation affects the splicing of exons 4 and 5, despite the retention of the wild-type splice sites, and results in a G6Pase protein truncated by 146 amino acids (Kajihara et al., 1995). Other mutations similarly have been shown to abolish or significantly diminish G6Pase