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      Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

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          Abstract

          A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase- α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

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          Glycogen storage diseases: new perspectives.

          Hasan Özen (2007)
          Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20000-43000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. Type Ia involves the liver, kidney and intestine (and Ib also leukocytes), and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type IIIa involves both the liver and muscle, and IIIb solely the liver. The liver symptoms generally improve with age. Type IV usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type VI and IX are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type XI is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type II is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types V and VII involve only the muscle.
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            Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex.

            Janice Chou, Dietrich Matern, Brian Mansfield … (2002)
            Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients' genotype. While the molecular basis for the GSD-I disorders are now known and symptomatic therapies are available, many aspects of the diseases are still poorly understood, and there are no cures. Recently developed animal models of the disorders are now being exploited to delineate the disease more precisely and develop new, more causative therapies.
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              Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a.

              K Lei, Katherine Chou, L Shelly … (1993)
              Glycogen storage disease (GSD) type 1a is caused by the deficiency of D-glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. Despite both a high incidence and morbidity, the molecular mechanisms underlying this deficiency have eluded characterization. In the present study, the molecular and biochemical characterization of the human G6Pase complementary DNA, its gene, and the expressed protein, which is indistinguishable from human microsomal G6Pase, are reported. Several mutations in the G6Pase gene of affected individuals that completely inactivate the enzyme have been identified. These results establish the molecular basis of this disease and open the way for future gene therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biomed Biotechnol
                Journal ID (publisher-id): JBB
                Title: Journal of Biomedicine and Biotechnology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1110-7243
                ISSN (Electronic): 1110-7251
                Publication date (Print): 2011
                Publication date (Electronic): 3 January 2011
                Volume: 2011
                Electronic Location Identifier: 646257
                Affiliations
                1Department of Small Animal Clinical Sciences, University of Florida, Gainesville, FL 32610, USA
                2Glycogen Storage Disease Program, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
                3Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA
                4Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL 32610, USA
                5Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
                6Animal Care Services, University of Florida, Gainesville, FL 32610, USA
                7Section on Cellular Differentiation, PDEGEN, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20892, USA
                8Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
                9Department of Pediatrics, University of Florida College of Medicine, P.O. Box 103610, Gainesville, FL 32610, USA
                Author notes
                *Thomas J. Conlon: conlon@ 123456peds.ufl.edu

                Academic Editor: Monica Fedele

                Article
                DOI: 10.1155/2011/646257
                PMC ID: 3027000
                PubMed ID: 21318173
                SO-VID: 7bcbbd41-2382-4dce-9974-42323151c5d7
                Copyright © Copyright © 2011 Andrew Specht et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 6 October 2010
                Date accepted : 24 November 2010
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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