Intracellular processing and maturation of mutant gene products in hereditary ?-galactosidase deficiency (?-galactosidosis)

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Abstract
Heterogeneous patterns of biosynthesis, post-translational processing, and degradation were demonstrated for mutant enzymes in three clinical forms of β-galactosidase deficiency (β-galactosidosis): juvenile GM1-gangliosidosis, adult GM1-gangliosidosis, and Morquio B disease. The precursor of the mutant enzyme in adult GM1-gangliosidosis was not phosphorylated, and only a small portion of the gene product reached the lysosomes. The enzyme in Morquio B disease was normally processed and transported to lysosomes, but its catalytic activity was low. A common gene mutation in juvenile GM1-gangliosidosis (R201C) produced an enzyme protein that did not aggregate with protective protein in the lysosome, and was rapidly degraded by thiol proteases. This abnormal turnover was similar to that for the normal but dissociated β-galactosidase in galactosialidosis. Protease inhibitors restored the enzyme acitivity in fibroblasts of this clinical form. A possible therapeutic approach is discussed for this specific type of enzyme deficiency.