Two populations of β-hexosaminidase isozymes in mucolipidosis II and III fibroblasts: Only one is segregated to lysosomes

I-cell disease (mucolipidosis II; ML II) is an autosomal recessive neurodegenerative disorder of childhood partially characterized in vitro by an enhanced excretion of many lysosomal hydrolases from cultured skin fibroblasts. ML III is a milder form of the disease. Both the intra- and extracellular forms of several of these enzymes have abnormal electrophoretic patterns. It has been determined for the enzyme β-hexosaminidase, that two distinct intracellular pools of isozymes exist in ML II cells. One pool is rapidly turning over and destined for excretion, while the other presumably is transported to lysosomes. We have now determined by free flow electrophoresis of isolated lysosomes that the two populations of β-hexosaminidase isozymes in ML II and ML III cells are in distinct subcellular compartments, one of which is the lysosomes. No distinct pools or subcompartmental distribution of β-hexosaminidase isozymes were apparent in normal cells. The targeting mechanism by which distinct isozyme pools are directed to individual compartments in ML II and ML III is unknown and may not depend on the fibroblast phosphomannosyl recognition system.