CHARACTERIZATION OF A MUTANT ALPHA-GALACTOSIDASE GENE-PRODUCT FOR THE LATE-ONSET CARDIAC FORM OF FABRY DISEASE

The expression product of a mutant α-galactosidase gene, Q279E (279Gln→Glu), found in an atypical variant (cardiac form) of Fabry disease, was purified and characterized. It had kinetic properties similar to those of normal α-galactosidase, but was markedly thermolabile at neutral pH. Galactose and melibiose at high concentrations stabilized the mutant enzyme in vitro. Its catalytic activity was 15% of that for the normal enzyme, when it was expressed in COS-1 cells at 37°C. The activity increased at 30°C or in the presence of galactose at 37°C. An increase was also observed in lymphoblasts from a patient with this mutation in the presence of galactose or melibiose. We conclude that this mutant protein is posttranslationally inactivated under the neutral conditions in the cells. The possibility of anew therapeutic approach is suggested. © 1993 Academic Press, Inc.