Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage

Kittichate Visuttijai, Carola Hedberg-Oldfors, Christer Thomsen, Emma Glamuzina, Cornelia Kornblum, Giorgio Tasca, Aurelio Hernandez-Lain, Joakim Sandstedt, Göran Dellgren, Peter Roach, Anders Oldfors

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Context: Glycogenin 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.

Original languageEnglish (US)
Article numberdgz075
JournalJournal of Clinical Endocrinology and Metabolism
Volume105
Issue number2
DOIs
StatePublished - Jan 23 2020

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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    Visuttijai, 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. Journal of Clinical Endocrinology and Metabolism, 105(2), [dgz075]. https://doi.org/10.1210/clinem/dgz075