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.
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pagliarani
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lucchiari
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Gianna
authors.initials: G
authors.lastname: Ulzi
authors.affiliation: Neuromuscular Unit - Fondazione I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, University of Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Violano
authors.affiliation: Neuromuscular Unit - Fondazione I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, University of Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Ripolone
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.affiliation: Center for Surgical Research, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gatti
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.affiliation: Neuromuscular Unit - Fondazione I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, University of Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: giacomo.comi@unimi.it.
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
keywords: Glycogen debranching enzyme; Glycogen storage disease type III; Glycogenosis; Metabolic disease; Mouse model