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

Abstract

Glucose-6-phosphatase-alpha (G6PC) is a key enzyme in glucose homeostasis that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis. Mutations in the G6PC gene, located on chromosome 17q21, result in glycogen storage disease type Ia (GSD-Ia), an autosomal recessive metabolic disorder. GSD-Ia patients manifest a disturbed glucose homeostasis, characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. G6PC is a highly hydrophobic glycoprotein, anchored in the membrane of the endoplasmic reticulum with the active center facing into the lumen. To date, 54 missense, 10 nonsense, 17 insertion/deletion, and three splicing mutations in the G6PC gene have been identified in more than 550 patients. Of these, 50 missense, two nonsense, and two insertion/deletion mutations have been functionally characterized for their effects on enzymatic activity and stability. While GSD-Ia is not more prevalent in any ethnic group, mutations unique to Caucasian, Oriental, and Jewish populations have been described. Despite this, GSD-Ia patients exhibit phenotypic heterogeneity and a stringent genotype-phenotype relationship does not exist.

Fig. 1

G6PC is anchored in the membrane of the ER by 9 transmembrane helices. The amino-terminus is located in the ER lumen and the carboxyl-terminus in the cellular cytoplasm. Missense and the p.F327del mutations identified in the G6PC gene of GSD-Ia patients are marked in black. Arg-83, His-119, Arg-170, and His-176, which contribute to the active center, are denoted by large circles. The phosphate acceptor His-176 is denoted by an arrow.

Fig. 2

Proposed roles of Arg-83, His-119, Arg-170, and His-176 in the G6PC reaction mechanism. The single thick line represents the general backbone of the protein, which lies within the ER membrane.

Fig. 3

Mutations identified in the G6PC gene of GSD-Ia patients. The G6PC gene is shown as a line diagram with the 5 exons marked as boxes I to V. Black boxes represent coding regions, white boxes the 5′ and 3′ untranslated regions of the G6PC transcript. The positions of all known mutations are listed from left to right as insertion/deletion, nonsense, splicing, and missense mutations.

Fig. 4

A summary of mutations of G6PC that affect phosphohydrolase activity. The G6PC protein is represented by a line diagram, with the 9 helical transmembrane domains marked as boxes H1 to H9. Protein mutations that destroy G6PC activity are listed. Mutants retaining some residual activity are listed with the percent of wild-type enzymatic activity retained in parentheses. The active site mutant H176A, show in italic, is not naturally occurring.