Surprises of genetic engineering: A possible model of polyglucosan body disease

• Published in: Neurology Vol. 56; no. 12; pp. 1739 - 1745
• Main Authors: RABEN, N, DANON, M, DIMAURO, S, PLOTZ, P, LU, N, LEE, E, SHLISELFELD, L, SKURAT, A. V, ROACH, P. J, LAWRENCE, J. C, MUSUMECI, O, SHANSKE, S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 26-06-2001
• Subjects: 1,4-alpha-Glucan Branching Enzyme - metabolism; Animals; Biological and medical sciences; Carbohydrates (enzymatic deficiencies). Glycogenosis; Disease Models, Animal; Errors of metabolism; Genetic Engineering; Glucans - genetics; Glycogen Storage Disease Type IV - genetics; Glycogen Storage Disease Type IV - metabolism; Glycogen Storage Disease Type IV - pathology; Glycogen Synthase - metabolism; Medical sciences; Metabolic diseases; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Electron; Muscles - pathology; Muscles - ultrastructure; Animal model; Enzyme; Transferases; Biological transport; Glycosyltransferases; Rodentia; Transgenic animal; Gene overexpression; Metabolic diseases; Glucose; Glycogen (starch) synthase; Enzymopathy; Genetic disease; Vertebrata; Mammalia; Glycogenosis; Mouse; Evolution; Hexosyltransferases; Carbohydrate; Polysaccharide
• ISSN: 0028-3878; 1526-632X
• DOI: 10.1212/WNL.56.12.1739

The authors previously reported the generation of a knockout mouse model of Pompe disease caused by the inherited deficiency of lysosomal acid alpha-glucosidase (GAA). The disorder in the knockout mice (GAA-/-) resembles the human disease closely, except that the clinical symptoms develop late relative to the lifespan of the animals. In an attempt to accelerate the course of the disease in the knockouts, the authors increased the level of cytoplasmic glycogen by overexpressing glycogen synthase (GSase) or GlutI glucose transporter.
GAA-/- mice were crossed to transgenic mice overexpressing GSase or GlutI in skeletal muscle.
Both transgenics on a GAA knockout background (GS/GAA-/- and GlutI/GAA-/-) developed a severe muscle wasting disorder with an early age at onset. This finding, however, is not the major focus of the study. Unexpectedly, the mice bearing the GSase transgene, but not those bearing the GlutI transgene, accumulated structurally abnormal polysaccharide (polyglucosan) similar to that observed in patients with Lafora disease, glycogenosis type IV, and glycogenosis type VII. Ultrastructurally, the periodic acid-Schiff (PAS)-positive polysaccharide inclusions were composed of short, amorphous, irregular branching filaments indistinguishable from classic polyglucosan bodies. The authors show here that increased level of GSase in the presence of normal glycogen branching enzyme (GBE) activity leads to polyglucosan accumulation. The authors have further shown that inactivation of lysosomal acid alpha-glucosidase in the knockout mice does not contribute to the process of polyglucosan formation.
An imbalance between GSase and GBE activities is proposed as the mechanism involved in the production of polyglucosan bodies. The authors may have inadvertently created a "muscle polyglucosan disease" by simulating the mechanism for polyglucosan formation.