Functional alterations in gap junction channels formed by mutant forms of connexin 32: Evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease

Charles K. Abrams, Mona M. Freidin, Vytautas Verselis, Michael V. L. Bennett, Thaddeus A. Bargiello

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Abstract

CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.

Original languageEnglish (US)
Pages (from-to)9-25
Number of pages17
JournalBrain Research
Volume900
Issue number1
DOIs
StatePublished - May 4 2001

Fingerprint

Charcot-Marie-Tooth Disease
Gap Junctions
Oocytes
Mutation
Connexins
Xenopus
Communication
connexin 32
Genes

Keywords

  • Charcot-Marie-Tooth disease
  • Conductance-Voltage relations
  • Connexin 32
  • Loss of function
  • Peripheral neuropathy
  • Xenopus oocyte expression system

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

@article{6e08767316aa438d8a71c89e68d9dfdb,
title = "Functional alterations in gap junction channels formed by mutant forms of connexin 32: Evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease",
abstract = "CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.",
keywords = "Charcot-Marie-Tooth disease, Conductance-Voltage relations, Connexin 32, Loss of function, Peripheral neuropathy, Xenopus oocyte expression system",
author = "Abrams, {Charles K.} and Freidin, {Mona M.} and Vytautas Verselis and Bennett, {Michael V. L.} and Bargiello, {Thaddeus A.}",
year = "2001",
month = "5",
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T1 - Functional alterations in gap junction channels formed by mutant forms of connexin 32

T2 - Evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease

AU - Abrams, Charles K.

AU - Freidin, Mona M.

AU - Verselis, Vytautas

AU - Bennett, Michael V. L.

AU - Bargiello, Thaddeus A.

PY - 2001/5/4

Y1 - 2001/5/4

N2 - CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.

AB - CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.

KW - Charcot-Marie-Tooth disease

KW - Conductance-Voltage relations

KW - Connexin 32

KW - Loss of function

KW - Peripheral neuropathy

KW - Xenopus oocyte expression system

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U2 - 10.1016/S0006-8993(00)03327-8

DO - 10.1016/S0006-8993(00)03327-8

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