A novel role for glycogenin in the regulation of glycogen metabolism

Abstract

Glycogen synthesis is crucial for storing glucose residues that are released in case of energy demand. The mechanism needs to be tightly regulated because a lack or an overload of glycogen can lead to severe systemic problems. Aberrant glycogen storage can lead to certain pathological conditions that are grouped under different types of glycogen storage diseases (GSDs) or glycogenosis.

It is generally accepted that glycogenin is an indispensable component of the glycogen synthesis machinery participating as both primer of the glucose chain and enzyme that catalyzes the linkages between the initial residues.

Further chain elongation is performed by glycogen synthase (GS) and branches are introduced by glycogen branching enzyme 1 (GBE1). There are two type of interactions between GS and glycogenin: GS interacts directly with the glycosyl-primer chain through an active site during catalysis, and 33 conserved amino acids of glycogenin’s c-terminal domain mediate the protein interaction between GS and glycogenin. Because of these two mechanisms, it is thought that the interaction between GS and glycogenin is crucial for glycogen synthesis. It was generally accepted that the depletion of one of the two proteins was incompatible with glycogen production, except some rare cases of GSD 0 characterized by MGS loss of function.

On the other hand glycogenin has been always considered an essential component of the synthesis complex due to its roles as priming molecule for glucose residues and enzymatic activity of self-glucosylation. Rodents, on the other hand, only carry a single Gyg gene. For this characteristic, mus musculus match all the parameters to be a perfect model to study the impact of glycogenin on the entire metabolism. Therefore, we generated a transgenic constitutive Gyg mouse using gene trap technology for the loss of function of the gene. We expected a model completely void of glycogen and possibly incompatible with life. The study of the heterozygous of Gyg would have elucidated the impact to have just one allele of the gene, and it was expected that only half of the glycogen was synthetized. This could have been a very powerful tool for the regulation of glycogen storage especially in those GSDs accumulating high levels of the polysaccharide.

To our surprise, Gyg transgenic mouse revealed a completely different picture. Despite the high lethality (90%), surviving Gyg KO embryos and adults show, not only maintain their ability to synthesize glycogen, but also carry the accumulation of high levels of the polysaccharide especially in skeletal and cardiac muscle.

Along the study the first clinical case of a patient affected by a mutation in glycogenin1’s catalytic site was reported. Recently, Malfatti et al. reported 7 clinical cases of the newly described GSD XV, in which patients, with GYG1 loss of function, are affected by high glycogen storage in muscle fibers. These results support the hypothesis of a regulatory role of glycogenin in glycogen metabolism.