Surprises of genetic engineering

A possible model of polyglucosan body disease

Nina Raben, M. Danon, N. Lu, E. Lee, L. Shliselfeld, Alexander Skurat, Peter Roach, J. C. Lawrence, O. Musumeci, S. Shanske, S. DiMauro, P. Plotz

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1739-1745
Number of pages7
JournalNeurology
Volume56
Issue number12
StatePublished - Jun 26 2001

Fingerprint

Genetic Engineering
Glycogen Synthase
1,4-alpha-Glucan Branching Enzyme
Knockout Mice
alpha-Glucosidases
Transgenes
Polysaccharides
Glycogen Storage Disease Type IV
Lafora Disease
Glycogen Storage Disease Type II
Glycogen Storage Disease
Periodic Acid
Acids
Facilitative Glucose Transport Proteins
Muscular Diseases
polyglucosan
Glycogen
Age of Onset
Transgenic Mice
Skeletal Muscle

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Raben, N., Danon, M., Lu, N., Lee, E., Shliselfeld, L., Skurat, A., ... Plotz, P. (2001). Surprises of genetic engineering: A possible model of polyglucosan body disease. Neurology, 56(12), 1739-1745.

Surprises of genetic engineering : A possible model of polyglucosan body disease. / Raben, Nina; Danon, M.; Lu, N.; Lee, E.; Shliselfeld, L.; Skurat, Alexander; Roach, Peter; Lawrence, J. C.; Musumeci, O.; Shanske, S.; DiMauro, S.; Plotz, P.

In: Neurology, Vol. 56, No. 12, 26.06.2001, p. 1739-1745.

Research output: Contribution to journalArticle

Raben, N, Danon, M, Lu, N, Lee, E, Shliselfeld, L, Skurat, A, Roach, P, Lawrence, JC, Musumeci, O, Shanske, S, DiMauro, S & Plotz, P 2001, 'Surprises of genetic engineering: A possible model of polyglucosan body disease', Neurology, vol. 56, no. 12, pp. 1739-1745.
Raben N, Danon M, Lu N, Lee E, Shliselfeld L, Skurat A et al. Surprises of genetic engineering: A possible model of polyglucosan body disease. Neurology. 2001 Jun 26;56(12):1739-1745.
Raben, Nina ; Danon, M. ; Lu, N. ; Lee, E. ; Shliselfeld, L. ; Skurat, Alexander ; Roach, Peter ; Lawrence, J. C. ; Musumeci, O. ; Shanske, S. ; DiMauro, S. ; Plotz, P. / Surprises of genetic engineering : A possible model of polyglucosan body disease. In: Neurology. 2001 ; Vol. 56, No. 12. pp. 1739-1745.
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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.",
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AU - Skurat, Alexander

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AU - Lawrence, J. C.

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AU - Plotz, P.

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