To elucidate the mechanism underlying transport and processing defects from the 
viewpoint of enzyme folding, we constructed three-dimensional models of human 
acid alpha-glucosidase encompassing 27 relevant amino acid substitutions by 
means of homology modeling. Then, we determined in each separate case the number 
of affected atoms, the root-mean-square distance value and the 
solvent-accessible surface area value. The analysis revealed that the amino acid 
substitutions causing a processing or transport defect responsible for Pompe 
disease were widely spread over all of the five domains comprising the acid 
alpha-glucosidase. They were distributed from the core to the surface of the 
enzyme molecule, and the predicted structural changes varied from large to very 
small. Among the structural changes, we paid particular attention to G377R and 
G483R. These two substitutions are predicted to cause electrostatic changes in 
neighboring small regions on the molecular surface. The quality control system 
of the endoplasmic reticulum apparently detects these very small structural 
changes and degrades the mutant enzyme precursor (G377R), but also the cellular 
sorting system might be misled by these minor changes whereby the precursor is 
secreted instead of being transported to lysosomes (G483R).