Visuttijai, KittichateHedberg-Oldfors, CarolaThomsen, ChristerGlamuzina, EmmaKornblum, CorneliaTasca, GiorgioHernandez-Lain, AurelioSandstedt, JoakimDellgren, GöranRoach, PeterOldfors, Anders2020-04-132020-04-132020-02-01Visuttijai, K., Hedberg-Oldfors, C., Thomsen, C., Glamuzina, E., Kornblum, C., Tasca, G., Hernandez-Lain, A., Sandstedt, J., Dellgren, G., Roach, P., & Oldfors, A. (2020). Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage. The Journal of clinical endocrinology and metabolism, 105(2), 557–566. https://doi.org/10.1210/clinem/dgz075https://hdl.handle.net/1805/22545Glycogenin is considered to be an essential primer for glycogen biosynthesis. Nevertheless, patients with glycogenin-1 deficiency due to biallelic GYG1 (NM_004130.3) mutations can store glycogen in muscle. Glycogenin-2 has been suggested as an alternative primer for glycogen synthesis in patients with glycogenin-1 deficiency. OBJECTIVE: The objective of this article is to investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle. DESIGN, SETTING, AND PATIENTS: Glycogenin-1 and glycogenin-2 expression was analyzed by Western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency. RESULTS: Glycogenin-1 and glycogenin-2 both were found to be expressed in the liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, nonfunctional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 colocalized with the storage of glycogen and polyglucosan in cardiomyocytes. CONCLUSIONS: Glycogen can be synthesized in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to the focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy.en-USAttribution 4.0 InternationalGlycogenin-1 deficiencyGlycogenin-1Glycogenin-2Glycogen synthesisSkeletal muscle fibersArticle