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

17 Citations (Scopus)

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

Fingerprint

Glycogen Storage Disease Type III
Glycogen
Knockout Mice
Hepatomegaly
Glucosidases
Glycogen Storage Disease
Kyphosis
Muscular Diseases
Respiratory Rate
Diaphragm
Hyperlipidemias
Cardiomyopathies
Tongue
Hypoglycemia
Adenoma
Electron Microscopy
Fibrosis
Central Nervous System
Exercise
Growth

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Glycogen storage disease type III : A novel Agl knockout mouse model. / Pagliarani, Serena; Lucchiari, Sabrina; Ulzi, Gianna; Violano, Raffaella; Ripolone, Michela; Bordoni, Andreina; Nizzardo, Monica; Gatti, Stefano; Corti, Stefania; Moggio, Maurizio; Bresolin, Nereo; Comi, Giacomo P.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 11, 2014, p. 2318-2328.

Research output: Contribution to journalArticle

Pagliarani, Serena ; Lucchiari, Sabrina ; Ulzi, Gianna ; Violano, Raffaella ; Ripolone, Michela ; Bordoni, Andreina ; Nizzardo, Monica ; Gatti, Stefano ; Corti, Stefania ; Moggio, Maurizio ; Bresolin, Nereo ; Comi, Giacomo P. / Glycogen storage disease type III : A novel Agl knockout mouse model. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2014 ; Vol. 1842, No. 11. pp. 2318-2328.
@article{11775560f14d47dba9a7796ebb7e8e9c,
title = "Glycogen storage disease type III: A novel Agl knockout mouse model",
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.",
keywords = "Glycogen debranching enzyme, Glycogen storage disease type III, Glycogenosis, Metabolic disease, Mouse model",
author = "Serena Pagliarani and Sabrina Lucchiari and Gianna Ulzi and Raffaella Violano and Michela Ripolone and Andreina Bordoni and Monica Nizzardo and Stefano Gatti and Stefania Corti and Maurizio Moggio and Nereo Bresolin and Comi, {Giacomo P.}",
year = "2014",
doi = "10.1016/j.bbadis.2014.07.029",
language = "English",
volume = "1842",
pages = "2318--2328",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
issn = "0925-4439",
publisher = "Elsevier",
number = "11",

}

TY - JOUR

T1 - Glycogen storage disease type III

T2 - A novel Agl knockout mouse model

AU - Pagliarani, Serena

AU - Lucchiari, Sabrina

AU - Ulzi, Gianna

AU - Violano, Raffaella

AU - Ripolone, Michela

AU - Bordoni, Andreina

AU - Nizzardo, Monica

AU - Gatti, Stefano

AU - Corti, Stefania

AU - Moggio, Maurizio

AU - Bresolin, Nereo

AU - Comi, Giacomo P.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Glycogen debranching enzyme

KW - Glycogen storage disease type III

KW - Glycogenosis

KW - Metabolic disease

KW - Mouse model

UR - http://www.scopus.com/inward/record.url?scp=84908032896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908032896&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2014.07.029

DO - 10.1016/j.bbadis.2014.07.029

M3 - Article

AN - SCOPUS:84908032896

VL - 1842

SP - 2318

EP - 2328

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 11

ER -