Samples of plasma from patients wit

Samples of plasma from patients with the disease
were observed to contain very high activities of lysosomal enzymes; this suggested that the enzymes were
being synthesized but were failing to reach their proper
intracellular destination and were instead being secreted. Cultured cells from patients with the disease
were noted to take up exogenously added lysosomal enzymes obtained from normal subjects, indicating that
the cells contained a normal receptor on their surfaces
for endocytic uptake of lysosomal enzymes. In addition,
this finding suggested that lysosomal enzymes from patients with I-cell disease might lack a recognition
marker. Further studies revealed that lysosomal enzymes from normal individuals carried the Man 6-P
recognition marker described above, which interacted
with a specific intracellular protein, the Man 6-P receptor. Cultured cells from patients with I-cell disease were
then found to be deficient in the activity of the cis
Golgi-located GlcNAc phosphotransferase, explaining
how their lysosomal enzymes failed to acquire the Man
6-P marker. It is now known that there are two Man
6-P receptor proteins, one of high (275 kDa) and one
of low (46 kDa) molecular mass. These proteins are
lectins, recognizing Man 6-P. The former is cationindependent and also binds IGF-II (hence it is named
the Man 6-P–IGF-II receptor), whereas the latter is
cation-dependent in some species and does not bind
IGF-II. It appears that both receptors function in the
intracellular sorting of lysosomal enzymes into clathrincoated vesicles, which occurs in the trans Golgi subsequent to synthesis of Man 6-P in the cis Golgi. These
vesicles then leave the Golgi and fuse with a prelysosomal compartment. The low pH in this compartment
causes the lysosomal enzymes to dissociate from their
receptors and subsequently enter into lysosomes. The
receptors are recycled and reused. Only the smaller receptor functions in the endocytosis of extracellular lysosomal enzymes, which is a minor pathway for lysosomal
location. Not all cells employ the Man 6-P receptor to
target their lysosomal enzymes (eg, hepatocytes use a
different but undefined pathway); furthermore, not all
lysosomal enzymes are targeted by this mechanism.
Thus, biochemical investigations of I-cell disease not
only led to elucidation of its basis but also contributed
significantly to knowledge of how newly synthesized
proteins are targeted to specific organelles, in this case
the lysosome. Figure 47–14 summarizes the causation
of I-cell disease