Glycogen is a large, branched polysaccharide that is present in all tissues but mainly in the liver, skeletal muscle, and heart, and is a readily available source of energy. In the liver, glycogen is used to keep blood glucose at physiological levels, whereas in muscle glycogen is used as an energy source for muscle cells. Formation of glycogen (glycogenesis) from glucose is a multistep process regulated by various enzymes (1, 2). The enzyme glycogenin is considered to be essential for initiating de novo glycogen synthesis. By autoglucosylation, glycogenin generates an oligosaccharide chain of approximately 7 to 12 glucose residues, which are linearly linked by α1,4-glycosidic bonds and covalently linked to the glycogenin apoprotein by a tyrosine-O-glucose binding. Glycogen synthase adds further glucose molecules to the priming oligosaccharide chain by formation of more α1,4-glycosidic linkages. Branching enzyme adds glucose molecules by α1,6-glycosidic linkages, which leads to branching of the molecule. By this process, the glycogen molecule grows to form the glycogen β particle, consisting of approximately 30 000 glucose molecules, and these β particles can be linked together to form even larger α particles. Glycogenin is found in 2 isoforms, glycogenin-1 and glycogenin-2, which are encoded by 2 separate genes, GYG1 and GYG2, respectively. Glycogenin-1 is a 39-kDa protein (the GN1L-isoform) that is ubiquitously expressed. Functional glycogenin-2, a 55-kDa protein (the α-isoform) that resembles glycogenin-1 structurally and functionally, is also expressed in the liver (3, 4). In glycogenin-1, the tyrosine-O-glucose bond is at position Tyr195, whereas in glycogenin-2 the glucose is attached to Tyr228.
Glycogen storage disease type XV/polyglucosan body myopathy 2 (OMIM#613507/#616199) is caused by biallelic mutations in the GYG1 gene. Since the first report in 2010 (5), more than 30 patients with glycogenin-1 deficiency have been described. Most of these patients had adult-onset, slowly progressive myopathy and muscle weakness without cardiomyopathy (6-14), but there have also been reports of patients presenting with cardiomyopathy without muscle weakness, leading to severe cardiac failure (5, 15). Patients with GYG1 mutations are characterized by either the absence of glycogenin-1 or the expression of nonfunctional glycogenin-1, and there is storage of glycogen and polyglucosan in the affected tissues.
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Despite the fact that glycogenin is considered to be essential for de novo glycogen synthesis (16), glycogen is present in the skeletal muscle of glycogenin-1-deficient patients. This finding challenges the generally accepted concept that glycogenin is required for glycogen synthesis, and it has been speculated that glycogenin-2 may act as an alternative primer for glycogen synthesis (5). In 1 study, Western blot analysis of glycogenin-2 was performed on muscle from 2 patients with glycogenin-1 deficiency, and bands believed to be glycogenin-2 were identified in the patients, but no functional glycogenin-2 was demonstrated (12).
To further investigate the hypothesis that upregulation of expression of functional glycogenin-2 may substitute for glycogenin-1 deficiency in cardiac and skeletal muscle, we investigated the expression of glycogenin-1 and glycogenin-2 by immunohistochemistry and Western blot analysis in liver, heart, and skeletal muscle from controls and in heart and skeletal muscle from patients with biallelic GYG1 mutations.
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