Modulation of disease severity in mice with targeted disruption of the acid α-glucosidase gene

Nina Raben, Kanneboyina Nagaraju, Eunice Lee, Paul Plotz

Research output: Contribution to journalArticle

Abstract

Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid α-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid α-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was completely abolished and glycogen accumulated at indistinguishable rates. The phenotypes, however, differed strikingly. Acid α-glucosidase deficiency on a 129 x C57BL/6 background resulted in a severe phenotype with progressive cardiomyopathy and profound muscle wasting similar to that in patients with glycogen storage disease type II. On a 129/C57BL/6 x FVB background, homozygous mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in humans with glycogen storage disease type II, therefore, other genetic loci affect the phenotypic expression of a single gene mutation. (C) 2000 Published by Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)283-291
Number of pages9
JournalNeuromuscular Disorders
Volume10
Issue number4-5
DOIs
StatePublished - Jun 1 2000
Externally publishedYes

Fingerprint

Glycogen Storage Disease Type II
Glucosidases
Phenotype
Acids
Genes
Genetic Loci
Gene Targeting
Glycogen
Cardiomyopathies
Age of Onset
Alleles
Muscles
Mutation
Enzymes

Keywords

  • Acid α-glucosidase
  • Gene targeting
  • Glycogen storage disease type II
  • Phenotype

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Neurology

Cite this

Modulation of disease severity in mice with targeted disruption of the acid α-glucosidase gene. / Raben, Nina; Nagaraju, Kanneboyina; Lee, Eunice; Plotz, Paul.

In: Neuromuscular Disorders, Vol. 10, No. 4-5, 01.06.2000, p. 283-291.

Research output: Contribution to journalArticle

Raben, Nina ; Nagaraju, Kanneboyina ; Lee, Eunice ; Plotz, Paul. / Modulation of disease severity in mice with targeted disruption of the acid α-glucosidase gene. In: Neuromuscular Disorders. 2000 ; Vol. 10, No. 4-5. pp. 283-291.
@article{99db3316e2c44e38b537b1c21aba68c3,
title = "Modulation of disease severity in mice with targeted disruption of the acid α-glucosidase gene",
abstract = "Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid α-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid α-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was completely abolished and glycogen accumulated at indistinguishable rates. The phenotypes, however, differed strikingly. Acid α-glucosidase deficiency on a 129 x C57BL/6 background resulted in a severe phenotype with progressive cardiomyopathy and profound muscle wasting similar to that in patients with glycogen storage disease type II. On a 129/C57BL/6 x FVB background, homozygous mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in humans with glycogen storage disease type II, therefore, other genetic loci affect the phenotypic expression of a single gene mutation. (C) 2000 Published by Elsevier Science B.V.",
keywords = "Acid α-glucosidase, Gene targeting, Glycogen storage disease type II, Phenotype",
author = "Nina Raben and Kanneboyina Nagaraju and Eunice Lee and Paul Plotz",
year = "2000",
month = "6",
day = "1",
doi = "10.1016/S0960-8966(99)00117-0",
language = "English (US)",
volume = "10",
pages = "283--291",
journal = "Neuromuscular Disorders",
issn = "0960-8966",
publisher = "Elsevier Limited",
number = "4-5",

}

TY - JOUR

T1 - Modulation of disease severity in mice with targeted disruption of the acid α-glucosidase gene

AU - Raben, Nina

AU - Nagaraju, Kanneboyina

AU - Lee, Eunice

AU - Plotz, Paul

PY - 2000/6/1

Y1 - 2000/6/1

N2 - Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid α-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid α-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was completely abolished and glycogen accumulated at indistinguishable rates. The phenotypes, however, differed strikingly. Acid α-glucosidase deficiency on a 129 x C57BL/6 background resulted in a severe phenotype with progressive cardiomyopathy and profound muscle wasting similar to that in patients with glycogen storage disease type II. On a 129/C57BL/6 x FVB background, homozygous mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in humans with glycogen storage disease type II, therefore, other genetic loci affect the phenotypic expression of a single gene mutation. (C) 2000 Published by Elsevier Science B.V.

AB - Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid α-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid α-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was completely abolished and glycogen accumulated at indistinguishable rates. The phenotypes, however, differed strikingly. Acid α-glucosidase deficiency on a 129 x C57BL/6 background resulted in a severe phenotype with progressive cardiomyopathy and profound muscle wasting similar to that in patients with glycogen storage disease type II. On a 129/C57BL/6 x FVB background, homozygous mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in humans with glycogen storage disease type II, therefore, other genetic loci affect the phenotypic expression of a single gene mutation. (C) 2000 Published by Elsevier Science B.V.

KW - Acid α-glucosidase

KW - Gene targeting

KW - Glycogen storage disease type II

KW - Phenotype

UR - http://www.scopus.com/inward/record.url?scp=0034212319&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034212319&partnerID=8YFLogxK

U2 - 10.1016/S0960-8966(99)00117-0

DO - 10.1016/S0960-8966(99)00117-0

M3 - Article

C2 - 10838256

AN - SCOPUS:0034212319

VL - 10

SP - 283

EP - 291

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

IS - 4-5

ER -