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Vol. 11, Issue 6, 1933-1946, June 2000
and
*Vollum Institute for Advanced Biomedical Research and
More than 130 different mutations in the gap junction integral
plasma membrane protein connexin32 (Cx32) have been linked to the human
peripheral neuropathy X-linked Charcot-Marie-Tooth disease (CMTX).
How these various mutants are processed by the cell and the
mechanism(s) by which they cause CMTX are unknown. To address these
issues, we have studied the intracellular transport, assembly, and
degradation of three CMTX-linked Cx32 mutants stably expressed in PC12
cells. Each mutant had a distinct fate: E208K Cx32 appeared to be
retained in the endoplasmic reticulum (ER), whereas both the E186K and
R142W mutants were transported to perinuclear compartments from which
they trafficked either to lysosomes (R142W Cx32) or back to the ER
(E186K Cx32). Despite these differences, each mutant was soluble in
nonionic detergent but unable to assemble into homomeric connexons.
Degradation of both mutant and wild-type connexins was rapid
(t1/2 < 3 h) and took place at least in
part in the ER by a process sensitive to proteasome inhibitors. The mutants studied are therefore unlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared
from the cell by quality control processes that prevent abnormal
connexin molecules from traversing the secretory pathway.
Department of Molecular and Medical Genetics, Oregon
Health Sciences University, Portland, Oregon 97201
Corresponding author. E-mail address:
Musill{at}OHSU.edu.
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