Elsevier

Brain Research Reviews

Volume 32, Issue 1, 24 March 2000, Pages 203-214
Brain Research Reviews

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

https://doi.org/10.1016/S0165-0173(99)00082-XGet rights and content

Abstract

The connexins are a family of homologous integral membrane proteins that form channels that provide a low resistance pathway for the transmission of electrical signals and the diffusion of small ions and non-electrolytes between coupled cells. Individuals carrying mutations in the gene encoding connexin 32 (Cx32), a gap junction protein expressed in the paranodal loops and Schmidt–Lantermann incisures of myelinating Schwann cells, develop a peripheral neuropathy — the X-linked form of Charcot–Marie–Tooth disease (CMTX). Over 160 different mutations in Cx32 associated with CMTX have been identified. Some mutations will lead to complete loss of function with no possibility of expression of functional channels. Some mutations in Cx32 lead to the abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus; CMTX may arise due to incorrect trafficking of Cx32 or to interference with trafficking of other proteins. On the other hand, many mutant forms of Cx32 can form functional channels. Some functional mutants have conductance voltage relationships that are disrupted to a degree which would lead to a substantial reduction in the available gap junction mediated communication pathway. Others have essentially normal steady-state g–V relations. In one of these cases (Ser26Leu), the only change introduced by the mutation is a reduction in the pore diameter from 7 Å for the wild-type channel to less than 3 Å for Ser26Leu. This reduction in pore diameter may restrict the passage of important signaling molecules. These findings suggest that in some, if not all cases of CMTX, loss of function of normal Cx32 is sufficient to cause CMTX.

Introduction

The connexins are a family of homologous integral membrane proteins that form channels that provide a low resistance pathway for the transmission of electrical signals and the diffusion of small ions and non-electrolytes between coupled cells [30]. Normal cellular signaling pathways may be dependent on the pathways provided by the connexins, and several human diseases arise in patients carrying mutations in connexin genes. Individuals carrying mutations in the gene encoding Cx32 (Cx32) develop a peripheral neuropathy, the X-linked form of Charcot–Marie–Tooth disease (CMTX) [7]. Mutations in the gap junction protein connexin 26 (Cx26) cause non-syndromic deafness in humans [27]. Mutations in human connexin 46 or 50 lead to hereditary cataracts 34, 57. The presence of heterozygous mutations in human connexin 31.1 leads to erythrokeratodermia [50]or deafness [64]. In addition, mice with targeted deletion of any one of several connexins develop pathology as well. The loss of connexin 37 function leads to infertility in female mice [58], while connexin 43 knockout mice die of cardiopulmonary anomalies shortly after birth [47]. In addition, homozygous connexin 46 knockout mice develop nuclear cataracts in later life [19]. Mice lacking Cx32 develop a demyelinating peripheral neuropathy 2, 56. Targeted deletion of connexin 40 in mice leads to cardiac conduction abnormalities 28, 59. Thus, the ion channel forming gap junction proteins join a rapidly expanding list of ion channels, which, when mutated, lead to disease. This paper will review the clinical manifestations and pathophysiology of CMTX, the most well studied of the gap junction diseases.

Section snippets

CMTX is an inherited peripheral neuropathy with unique features.

CMT disease is a group of inherited chronic progressive conditions affecting peripheral nerves. As a group, these diseases are fairly common with a population frequency of 1 in 3000 [36]. Some forms are characterized by demyelination of peripheral nerves with secondary axonal loss (CMT1 and Dejerine–Sotas). Other forms (CMT2) show only axonal loss [15]. In the last few years, the genetic bases for several forms of CMT have been elucidated [39]. CMT1A, the most common form of CMT, usually arises

Mutations in Cx32 underlie the X-linked form of CMTX

Since the first mutations were reported in 1993 [7], over 160 different mutations in Cx32 associated with CMTX have been identified [39]. These include missense, frameshift, deletion and non-sense mutations. However, missense mutations predominate by far.

Cx32 forms gap junction channels that allow the passage of molecules smaller than ∼7 Å in radius 30, 43. Second messengers such as cAMP and Ca2+ permeate wild-type Cx32 junctions [8]. As with all connexins, the complete cell–cell channel is

Several mechanisms have been proposed to explain the pathogenesis of CMTX

Mutations in Cx32 may give rise to CMTX through one of several proposed mechanisms. Some mutations will lead to loss of function with no possibility of expression of functional channels. One non-sense mutation (ARG22STOP) is at a very upstream site [25]and would likely lead to the expression of no functional protein. Ainsworth et al. [1]recently described a family with complete absence of the coding region of the gene for Cx32. Interestingly, based on the clinical descriptions in this paper,

Summary

This brief review serves to emphasize the current gaps in our understanding of the role of mutations in Cx32 in promoting Schwann cell dysfunction and the neuropathy CMTX. The hypothesis is that CMTX mutations lead to a loss of normal cellular communication, which in turn may lead to Schwann cell dysfunction and peripheral neuropathy. Many questions still need to be investigated. Do all mutations that allow for formation of functional channels lead to gap junction channels with altered

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