Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is 
required for myelin formation in the peripheral nervous system. Many PMP22 
mutants accumulate in excess in the endoplasmic reticulum (ER) and lead to the 
inherited neuropathies of Charcot-Marie-Tooth (CMT) disease. However, the 
mechanism through which PMP22 mutants accumulate in the ER is unknown. Here, we 
studied the quality control mechanisms for the PMP22 mutants L16P and G150D, 
which were originally identified in mice and patients with CMT. We found that 
the ER-localised ubiquitin ligase Hrd1/SYVN1 mediates ER-associated degradation 
(ERAD) of PMP22(L16P) and PMP22(G150D), and another ubiquitin ligase, gp78/AMFR, 
mediates ERAD of PMP22(G150D) as well. We also found that PMP22(L16P), but not 
PMP22(G150D), is partly released from the ER by loss of Rer1, which is a 
Golgi-localised sorting receptor for ER retrieval. Rer1 interacts with the 
wild-type and mutant forms of PMP22. Interestingly, release of PMP22(L16P) from 
the ER was more prominent with simultaneous knockdown of Rer1 and the 
ER-localised chaperone calnexin than with the knockdown of each gene. These 
results suggest that CMT disease-related PMP22(L16P) is trapped in the ER by 
calnexin-dependent ER retention and Rer1-mediated early Golgi retrieval systems 
and partly degraded by the Hrd1-mediated ERAD system.