Glycogen storage disease type III: A novel Agl knockout mouse model

Serena Pagliarani, Sabrina Lucchiari, Gianna Ulzi, Raffaella Violano, Michela Ripolone, Andreina Bordoni, Monica Nizzardo, Stefano Gatti, Stefania Corti, Maurizio Moggio, Nereo Bresolin, Giacomo P. Comi

Research output: Contribution to journalArticle

Abstract

Glycogen storage disease type III is an autosomal recessive disease characterized by a deficiency in the glycogen debranching enzyme, encoded by AGL. Essential features of this disease are hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Progressive skeletal myopathy, neuropathy, and/or cardiomyopathy become prominent in adults. Currently, there is no available cure. We generated an Agl knockout mouse model by deletion of the carboxy terminus of the protein, including the carboxy end of the glucosidase domain and the glycogen-binding domain. Agl knockout mice presented serious hepatomegaly, but we did not observe signs of cirrhosis or adenomas. In affected tissues, glycogen storage was higher than in wild-type mice, even in the central nervous system which has never been tested in GSDIII patients. The biochemical findings were in accordance with histological data, which clearly documented tissue impairment due to glycogen accumulation. Indeed, electron microscopy revealed the disruption of contractile units due to glycogen infiltrations. Furthermore, adult Agl knockout animals appeared less prompt to move, and they exhibited kyphosis. Three-mo-old Agl knockout mice could not run, and adult mice showed exercise intolerance. In addition, older affected animals exhibited an accelerated respiratory rate even at basal conditions. This observation was correlated with severe glycogen accumulation in the diaphragm. Diffuse glycogen deposition was observed in the tongues of affected mice. Our results demonstrate that this Agl knockout mouse is a reliable model for human glycogenosis type III, as it recapitulates the essential phenotypic features of the disease.

Original languageEnglish
Pages (from-to)2318-2328
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number11
DOIs
Publication statusPublished - 2014

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Keywords

  • Glycogen debranching enzyme
  • Glycogen storage disease type III
  • Glycogenosis
  • Metabolic disease
  • Mouse model

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

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