Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease 
resulting from mutations of the tyrosinase gene (TYR). To elucidate the 
molecular basis of OCA1 phenotypes, we analysed the early processing and 
maturation of several different types of mutant tyrosinase with various degrees 
of structural abnormalities (i.e. two large deletion mutants, two missense 
mutants that completely destroy catalytic function and three missense mutants 
that have a temperature-sensitive phenotype). When expressed in COS7 cells, all 
mutant tyrosinases were sensitive to endoglycosidase H digestion, and 
immunostaining showed their localization in the endoplasmic reticulum (ER) and 
their failure to be sorted further to their target organelles. Pulse-chase 
experiments showed that all mutant tyrosinases were retained by calnexin in the 
ER and that they were degraded at similarly rapid rates, which coincided with 
their dissociation from calnexin. Temperature-sensitive mutant enzymes were 
sorted more efficiently at 31 degrees C than at 37 degrees C, and their 
degradation was accelerated at 37 degrees C compared with 31 degrees C. Thus in 
contrast to the current concept that mutant tyrosinases are transported to 
melanosomes but are functionally inactive there, our results suggest that mutant 
tyrosinases may not be transported to melanosomes in the first place. We 
conclude that a significant component of mutant tyrosinase malfunction in OCA1 
results from their retention and degradation in the ER compartment. This 
quality-control process is highly sensitive to minimal changes in protein 
folding, and so even relatively minor mutations in peripheral sequences of the 
enzyme not involved with catalytic activity may result in a significant 
reduction of functional enzyme in melanosomes.