Heterozygosity for phosphodiester glycosidase deficiency: a novel human mutation of lysosomal enzyme processing

We have carried out studies on the fibroblasts of III-3, a clinically normal Lebanese individual previously reported to have abnormally high plasma lysosomal enzyme levels. Mannose-6-phosphate (man-6-P) receptors in III-3 fibroblasts were found to be functioning normally, but the cells had only half normal levels of phosphodiester glycosidase activity. Pinocytosis of III-3 fibroblast secreted beta-hexosaminidase B (hex B) into Sandhoff disease fibroblasts was 18% of control, and the apparent KD for binding of III-3 hex B to man-6-P receptors was 3.7 X 10(-9) M compared to 1.25 X 10(-9) M for control enzyme. Hex B secreted by III-3 fibroblasts included an enzyme pool less electro-negative than control enzyme which had a very low affinity for man-6-P receptors and which did not bind to DEAE-Sephadex. Treatment of this abnormal hex B with exogenous placental phosphodiester glycosidase increased its binding to man-6-P receptors three-fold. Secretion rates of seven lysosomal enzymes from III-3 fibroblasts were, on average, twice as great as rates measured for two I-cell disease heterozygote fibroblast lines. The results suggest that III-3 fibroblasts are heterozygous for phosphodiester glycosidase deficiency. The possibility that an individual homozygous for this enzyme deficiency would develop I-cell disease is discussed.