title: Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene.
abstract: Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid alpha-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid alpha-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 alpha-glucosidase deficiency on a 129xC57BL/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/6xFVB 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.
authors.affiliation: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10/9N244, 9000 Rockville Pike, Bethesda, MD 20892, USA. rabenn@arb.niams.nih.gov
authors.forename: N
authors.initials: N
authors.lastname: Raben
authors.forename: K
authors.initials: K
authors.lastname: Nagaraju
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Plotz
mesh_terms: D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D016296:Mutagenesis / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000172:deficiency* / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D000520:alpha-Glucosidases