The lysosomal storage disorders constitute greater than 30 separate entities, the majority of which result from the absence of one or more lysosomal enzymes. While many ofthese disorders are due to the failure to synthesize an active form ofthe relevant enzyme, an increasing number ofcases are being reported where the defect lies in the inability to transport an active enzyme to the lysosome. Recent work from many laboratories has greatly enhanced our understanding ofhow newly synthesized lysosomal enzymes are segregated from secretory proteins and packaged into lysosomes. Studies of patients with defects in this sorting pathway have facilitated the unraveling of this complex process while also serving to pinpoint the exact site where the targeting has gone awry. The purpose of this review is to summarize our current understanding of lysosomal enzyme targeting and to discuss the defects in this pathway that have been documented thus far.

Lysosomal enzymes, along with secretory proteins and plasma membrane proteins, are synthesized on membranebound polysomes in the rough endoplasmic reticulum (Fig. 1). Each of these proteins contains a hydrophobic amino terminal signal peptide which interacts with a signal recognition particle, an llS ribonucleoprotein, and thereby initiates the vectoral transport ofthe nascent protein across the endoplasmic reticulum membrane into the lumen of that organelle (1-3). Since lyso-somal enzymes and secretory proteins share this mechanism for membrane translocation, they are mixed together in the lumen of the endoplasmic reticulum. The lysosomal enzymes (as well as most ofthe secretory and plasma membrane proteins) undergo cotranslational glycosylation of selected Asn residues. This glycosylation step involves the en bloc transfer ofa large preformed oligosaccharide (three glucose, nine mannose, and two N-ace-tylglucosamine residues) from a lipid-linked intermediate to the nascent polypeptide (4). In the endoplasmic reticulum, the signal peptide is cleaved, and the processing of the Asn-linked oligo-saccharide begins by the excision of three glucoses and one of the mannose residues from the oligosaccharide. The proteins then move, by vesicular transport, to the Golgi stack where they undergo a variety of posttranslational modi-fications and are sorted for targeting to the proper destination, eg, lysosome, secretory granule, or plasma membrane. During passage through the Golgi, the oligosaccharides on secretory and membrane glycoproteins are processed to sialic acid-containing complex-type units. While some of the oligosaccharides on ly-sosomal enzymes undergo similar processing, most undergo a