title: Surprises of genetic engineering: a possible model of polyglucosan body disease.
abstract: BACKGROUND
  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.
  
  
  METHODS
  GAA-/- mice were crossed to transgenic mice overexpressing GSase or GlutI in skeletal muscle.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. rabenn@arb.niams.nih.gov
authors: N
authors: N
authors: Raben
authors: M
authors: M
authors: Danon
authors: N
authors: N
authors: Lu
authors: E
authors: E
authors: Lee
authors: L
authors: L
authors: Shliselfeld
authors: A V
authors: AV
authors: Skurat
authors: P J
authors: PJ
authors: Roach
authors: J C
authors: JC
authors: Lawrence
authors: O
authors: O
authors: Musumeci
authors: S
authors: S
authors: Shanske
authors: S
authors: S
authors: DiMauro
authors: P
authors: P
authors: Plotz
mesh_terms: D015061:1,4-alpha-Glucan Branching Enzyme / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005818:Genetic Engineering; D005936:Glucans / Q000235:genetics*; D006011:Glycogen Storage Disease Type IV / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006006:Glycogen Synthase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009132:Muscles / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D005936:Glucans; C083094:polyglucosan; D006006:Glycogen Synthase; D015061:1,4-alpha-Glucan Branching Enzyme