INVITRO MUTAGENESIS HELPS TO UNRAVEL THE BIOLOGICAL CONSEQUENCES OF ASPARTYLGLUCOSAMINURIA MUTATION

Aspartylglucosaminuria (AGU) is a lysosomal storage disease resulting in severe mental retardation. We have recently reported that mutations in the aspartylglucosaminidase (AGA) locus are responsible for this disease. About 90% of reported AGU cases are found in Finland, and we have shown that the vast majority (98%) of AGU alleles in this isolated population contain two point mutations located 5 bp apart. We expressed these Arg161 → Gln and Cys163 → Ser mutations separately in vitro and demonstrated that deficient enzyme activity is caused by the Cys163 → Ser mutation, whereas the Arg161 → Gln substitution represents a rare polymorphism. Further analyses of in vitro expressed AGA proteins and the enzyme purified from an AGU patient revealed that Cys163 participates in an S-S bridge. The absence of this covalent cross-link in the mutated protein most probably results in disturbed folding of the polypeptide chain and a consequent decrease in its intracellular stability. © 1991.