CONNEXIN32 MUTATIONS ASSOCIATED WITH X-LINKED CHARCOT-MARIE-TOOTH DISEASE SHOW 2 DISTINCT BEHAVIORS - LOSS OF FUNCTION AND ALTERED GATING PROPERTIES

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expres sed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by testing their a bility to form intercellular channels in the paired oocyte expression system. Although seven mutations were functionally incompetent, four o thers were able to generate intercellular currents of the same order o f 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 sens itivity and kinetics of voltage dependence with respect to that of Cx3 2wt. The four mutations were also capable of interacting in heterotypi c configuration with the wild-type protein, and in one case the result was a marked rectification of junctional currents in response to volt age steps of opposite polarity. In addition, the functional CMTX mutat ions 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 greater than or equal to 80% decrease in junctional currents, both the rate and extent of channel closure we re 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 mut ations suggests that a selective deficit of Cx32 channels may be suffi cient to impair the homeostasis of Schwann cells and lead to the devel opment of CMTX.