Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease

The connexins are a family of homologous integral membrane proteins that fo rm channels that provide a low resistance pathway for the transmission of e lectrical signals and the diffusion of small ions and non-electrolytes betw een coupled cells. Individuals carrying mutations in the gene encoding conn exin 32 (Cx32), a gap junction protein expressed in the paranodal loops and Schmidt-Lantermann incisures of myelinating Schwann cells, develop a perip heral neuropathy - the X-linked form of Charcot-Marie-Tooth disease (CMTX). Over 160 different mutations in Cx32 associated with CMTX have been identi fied. Some mutations will lead to complete loss of function with no possibi lity of expression of functional channels. Some mutations in Cx32 lead to t he abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus; CMTX may arise due to incorrect trafficking of Cx32 o r to interference with trafficking of other proteins. On the other hand, ma ny mutant forms of Cx32 can form functional channels. Some functional mutan ts have conductance voltage relationships that are disrupted to a degree wh ich would lead to a substantial reduction in the available g-V relations. I n one of these cases (Ser26Leu), junction mediated communication pathway. O thers have essentially normal steady-state g-V relations. In one of these c ases (Ser26Leu), the only change introduced by the mutation is a reduction in the pore diameter from 7 Angstrom for the wild-type channel to less than 3 Angstrom tor Ser26Leu. This reduction in pore diameter may restrict the passage of important signaling molecules. These findings suggest that in so me, if not all cases of CMTX, loss of function of normal Cx32 is sufficient to cause CMTX, (C) 2000 Elsevier Science B.V. All rights reserved.