GYS2

GYS2 is the gene that encodes the liver isoform of glycogen synthase, an enzyme central to the biosynthesis of glycogen in mammals. In humans, the liver form of glycogen synthase produced by GYS2 is the primary glycogen synthase variant in the liver, while a separate gene, GYS1, encodes the muscle isoform. The GYS2 gene is expressed mainly in the liver, with lower levels detected in other tissues.

Glycogen synthase catalyzes a key step in glycogen production, forming α-1,4-glycosidic bonds to extend the core glycogen chain by adding glucose units from UDP-glucose. The liver isoform is regulated to support systemic glucose homeostasis, particularly during fasting and feeding.

Regulation of GYS2 activity involves both allosteric and covalent mechanisms. The enzyme is activated allosterically by glucose-6-phosphate and is regulated by phosphorylation: dephosphorylation by protein phosphatase 1 activates the enzyme, while phosphorylation by kinases such as glycogen synthase kinase-3 and others inhibits it. Hormonal signals, notably insulin, promote dephosphorylation and activation in the liver, aligning glycogen synthesis with nutritional status.

Clinical significance: pathogenic variants in GYS2 have been associated with hepatic glycogen storage disease type 0, a deficiency of hepatic glycogen synthesis. This condition can lead to fasting hypoglycemia, low hepatic glycogen stores, and metabolic consequences related to impaired glucose storage. Diagnosis and management typically involve metabolic assessment and dietary strategies to maintain euglycemia. Research continues to clarify the spectrum of GYS2-related disorders and their optimal treatment approaches.