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The Journal of Neuroscience, June 1, 1998, 18(11):4063-4075
Connexin32 Mutations Associated with X-Linked
Charcot-Marie-Tooth Disease Show Two Distinct Behaviors: Loss of
Function and Altered Gating Properties
Catherine
Ressot1, 2,
Danielle
Gomès1,
André
Dautigny2,
Danielle
Pham-Dinh2, and
Roberto
Bruzzone1
1 Unité de Neurovirologie et
Régénération du Système Nerveux, Institut
Pasteur, F-75724 Paris Cedex 15, France, and 2 Laboratoire
de Neurogénétique Moléculaire, Unité de
Recherche Associée 1488, Centre National de la Recherche
Scientifique, Institut des Neurosciences, Université de Paris VI,
F-75252 Paris Cedex 05, France
The X-linked form of Charcot-Marie-Tooth disease (CMTX) is
associated with mutations in the gene encoding connexin32 (Cx32), which
is expressed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by
testing their ability to form intercellular channels in the paired
oocyte expression system. Although seven mutations were functionally
incompetent, four others were able to generate intercellular currents
of the same order of magnitude as those induced by wild-type Cx32
(Cx32wt). In homotypic oocyte pairs, CMTX mutations retaining functional activity induced the development of junctional currents that
exhibited changes in the sensitivity and kinetics of voltage dependence
with respect to that of Cx32wt. The four mutations were also capable of
interacting in heterotypic configuration with the wild-type protein,
and in one case the result was a marked rectification of junctional
currents in response to voltage steps of opposite polarity. In
addition, the functional CMTX mutations displayed the same selective
pattern of compatibility as Cx32wt, interacting with Cx26, Cx46, and
Cx50 but failing to do so with Cx40. Although the functional mutations
exhibited sensitivity to cytoplasmic acidification, which induced a
 80% decrease in junctional currents, both the rate and extent of
channel closure were enhanced markedly for two of them. Together, these
results indicate that the functional consequences of CMTX mutations of Cx32 are of two drastically distinct kinds. The presence of a functional group of mutations suggests that a selective deficit of Cx32
channels may be sufficient to impair the homeostasis of Schwann cells
and lead to the development of CMTX.
Key words:
gap junction; channel; myelin; Schwann cell; neuropathy; peripheral nervous system
Copyright © 1998 Society for Neuroscience 0270-6474/98/18114063-13$05.00/0
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