Connexin channels in Schwann cells and the development of the X-linked form of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease comprises a group of genetically heterogenous d isorders of the peripheral nervous system. The X-linked form of Charcot-Mar ie-Tooth (CMTX) is associated with mutations in the gene encoding the gap j unction protein connexin32 (Cx32), which is expressed in Schwann cells. Imm unocytochemical evidence suggests that Cx32 is localized to the incisures o f Schmidt-Lanterman and the paranodes of myelinating Schwann cells, where i t appears to form reflexive gap junctions. It is currently thought that thi s cytoplasmic continuity provides a much shorter diffusion pathway for the transport of ions, metabolites and second messenger molecules through intra cellular channels between the adaxonal and peri-nuclear regions of Schwann cells, across the myelin sheath. This review summarizes our current underst anding of the role of connexins in Schwann cells and focuses on the lessons for channel function and disease pathophysiology derived from the function al analysis of Cx32 mutations. One of the most intriguing aspects emerging from this work is that several mutations retain functional competence, alth ough the mutated channels exhibit altered Sating properties. This suggests that partial and/or selective disruption of the radial communication pathwa y formed by Cx32 is sufficient to cause a functional deficit and lead to th e development of CMTX. The next challenge will be to define, at the molecul ar level, the sequence of events involved in the disease process. The prese nce of a group of functional mutations should help understand the cellular basis of CMTX, by allowing the identification of the specific molecules tha t need to be exchanged through Cx32 channels, but are excluded from the mut ated ones. (C) 2000 Elsevier Science B.V. All rights reserved.