A group of genetic disorders termed lysosomal storage diseases are caused by the absence of one or more lysosomal enzymes. As a result, undigested glycolipids and extracellular components that would normally be degraded by lysosomal enzymes accumulate in lysosomes as large inclusions. Patients with lysosomal storage diseases can have a variety of developmental, physiological, and neurological abnormalities depending on the type and severity of the storage defect. I-cell disease is a particularly severe type of lysosomal storage disease in which multiple enzymes are missing from the lysosomes. Cells from affected individuals lack the N-acetylglucosamine phosphotransferase that is required for formation of M6P residues on lysosomal enzymes in the cis-Golgi (see Figure 14-21). Biochemical comparison of lysosomal enzymes from normal individuals with those from patients with I-cell disease led to the initial discovery of M6P as the lysosomal sorting signal. Lacking this signal, the lysosomal enzymes of affected individuals are secreted rather than being sorted to and sequestered in lysosomes.

When fibroblasts from patients with I-cell disease are grown in a medium containing lysosomal enzymes bearing M6P residues, the diseased cells acquire a nearly normal intracellular content of lysosomal enzymes. This finding indicates that the plasma membrane of these cells contains M6P receptors, which can internalize extracellular phosphorylated lysosomal enzymes by receptor-mediated endocytosis. This process, used by many cell-surface receptors to bring bound proteins or particles into the cell, is discussed in detail in the next section. It is now known that even in normal cells, some M6P receptors are transported to the plasma membrane and some phosphorylated lysosomal enzymes are secreted (see Figure 14-22). The secreted enzymes can be retrieved by receptor-mediated endocytosis and directed to lysosomes. This pathway thus scavenges any lysosomal enzymes that escape the usual M6P sorting pathway.

Hepatocytes from patients with I-cell disease contain a normal complement of lysosomal enzymes and no inclusions, even though these cells are defective in mannose phosphorylation. This finding implies that hepatocytes (the most abundant type of liver cell) employ an M6P-independent pathway for sorting lysosomal enzymes. The nature of this pathway, which may also operate in other cell types, is unknown.