Mutations in the Liver Glycogen Phosphorylase Gene (PYGL) Underlying Glycogenosis Type VI (Hers Disease)

Abstract

Deficiency of glycogen phosphorylase in the liver gives rise to glycogen-storage disease type VI (Hers disease; MIM 232700). We report the identification of the first mutations in PYGL, the gene encoding the liver isoform of glycogen phosphorylase, in three patients with Hers disease. These are two splice-site mutations and two missense mutations. A mutation of the 5' splice-site consensus of intron 14 causes the retention of intron 14 and the utilization of two illegitimate 5' splice sites, whereas a mutation of the 3' splice-site consensus of intron 4 causes the skipping of exon 5. Two missense mutations, N338S and N376K, both cause nonconservative replacements of amino acids that are absolutely conserved even in yeast and bacterial phosphorylases. We also report corrections of the PYGL coding sequence, sequence polymorphisms, and a partial PYGL gene structure with introns in the same positions as in PYGM, the gene of the muscle isoform of phosphorylase. Our findings demonstrate that PYGL mutations cause Hers disease, and they may improve laboratory diagnosis of deficiencies of the liver phosphorylase system.

The Cellular Fate of Glucose and Its Relevance in Type 2 Diabetes

“…Deficiency of glycogen phosphorylase in liver is responsible for glycogen storage disease type VI, characterized by hepatomegaly and growth retardation (250). Muscle glycogen phosphorylase deficiency leads to glycogen storage disease type V, characterized by exercise intolerance (251).…”

Glycogen Phosphorylase, the Product of the glgP Gene, Catalyzes Glycogen Breakdown by Removing Glucose Units from the Nonreducing Ends in Escherichia coli

“…The highly regulated muscle and liver glycogen phosphorylases are by far the best understood and most extensively studied members of the glucan phosphorylases group, their involvement in mammalian glycogen breakdown being well documented (6,9,10,16,40,42). By contrast, despite the fact that plant glucan phosphorylases are assumed to be involved in generating G1P, some of them have been shown to play a pivotal role in processes such as tolerance to abiotic stress, flowering, and seed growth (28,50,52,56).…”

Predicting Cross-Reactivity from Computational Studies for Pre-evaluation of Specific Hepatic Glycogen Phosphorylase Inhibitors

“…Glycogen phosphorylase (GP) is a phosphorylase enzyme (EC 2.4.1.1) implicated in disease conditions such as type-2 diabetes, McArdle's disease [1], Hers' disease [2] and has been further proposed as a biomarker in gastric cancer [3]. In both liver and muscle, GP catalyzes the rate-limiting breakdown of glycogen to glucose-1-phosphate upon phosphorolytic cleavage of the R-1,4-linked glycosyl units.…”