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

Glycogen storage disease type II (GSDII) is a recessively inherited disorde r caused by defects in lysosomal acid cr-glucosidase. In an attempt to repr oduce the range of clinical manifestations of the human illness we have cre ated null alleles at the acid ol-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was complete ly abolished and glycogen accumulated at indistinguishable rates. The pheno types, however, differed strikingly. Acid or-glucosidase deficiency on a 12 9 x C57BL1/6 background resulted in a severe phenotype with progressive car diomyopathy and profound muscle wasting similar to that in patients with gl ycogen storage disease type IL. On a 129/C57BL/6 x FVB background, homozygo us mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in hum ans with glycogen storage disease type II, therefore, other genetic loci af fect the phenotypic expression of a single gene mutation. Published by Else vier Science B.V.