Effective insulin-stimulated storage of excess glucose after a meal, and its rapid mobilisation in the fasting state provide basis of glucose homeostasis. Glycogen is the macromolecular storage form of glucose and glycogen synthase (GS) is the rate-limiting enzyme in glycogen synthesis. Skeletal muscle and liver are the major depots of glycogen. The present studies were undertaken to isolate and characterise the human skeletal muscle and liver GS genes (GYS1 and GYS2) and to study their role in diabetic insulin resistance and in severe childhood hypoglycaemia associated with glycogen storage disease type 0 (GSD-0). The GYS1 and GYS2 genes were composed of 16 exons and had identical exon-intron structures but differed in the size of the intronic regions. In a paired sibling analysis, the A2 allele of the XbaI polymorphism in the GYS1 gene conferred an increased susceptibility to different features of the metabolic syndrome and to type 2 diabetes. Several naturally occurring variants were identified in the GYS1 gene, but only the rare Pro442Ala mutation resulted in significantly decreased capability to synthesise glycogen when expressed in COS cells. Suggestive linkage of GSD-0 to the GYS2 gene was established in five families with 9 affected children. Mutation screening of the GYS2 gene revealed unique mutations in each family including a premature stop codon in exon 5, a 5´-donor splice site mutation of intron 6, and six missense mutations in exons 1, 7, 11 and 12. These mutations were not found in 200 healthy control subjects, and expression of the mutated enzymes in COS cells indicated severely impaired GS activity. In spite of extremely low or nil hepatic GS activity, the glycogen content in the liver was only moderately decreased in children with GSD-0. Conclusions: As the association between the XbaI polymorphism and type 2 diabetes could not be related to mutations in the GYS1 gene, it seems likely that the polymorphism is in linkage disequilibrium with another gene in the chromosome 19q13.3 region. The Pro442Ala is the first naturally occurring mutation in the GYS1 gene with functional consequences but it remains unclear whether it is enough to cause type 2 diabetes. The results demonstrate that GSD-0 is caused by different mutations in the GYS2 gene. The findings of only moderately decreased liver glycogen stores may point at a GS-independent pathway for glycogen formation in the liver. Finally, the inactivating missense mutations in the highly conserved exons 7, 11 and 12 pinpoint new sites and regions of importance for GS function
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