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×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×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.