Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease

Massimiliano Bicego, Sabina Morassutto, Victor H. Hernandez, Marcello Morgutti, Fabio Mammano, Paola D'Andrea, Roberto Bruzzone

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Δ111-116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.

Original languageEnglish
Pages (from-to)607-617
Number of pages11
JournalNeurobiology of Disease
Volume21
Issue number3
DOIs
Publication statusPublished - Mar 2006

Fingerprint

Charcot-Marie-Tooth Disease
Permeability
Mutation
Coloring Agents
Connexins
Schwann Cells
Myelin Sheath
Ions
Injections

Keywords

  • Connexin
  • Dye coupling
  • Gap junction
  • Genetic disease
  • Human
  • PNS

ASJC Scopus subject areas

  • Neurology

Cite this

Bicego, M., Morassutto, S., Hernandez, V. H., Morgutti, M., Mammano, F., D'Andrea, P., & Bruzzone, R. (2006). Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease. Neurobiology of Disease, 21(3), 607-617. https://doi.org/10.1016/j.nbd.2005.09.005

Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease. / Bicego, Massimiliano; Morassutto, Sabina; Hernandez, Victor H.; Morgutti, Marcello; Mammano, Fabio; D'Andrea, Paola; Bruzzone, Roberto.

In: Neurobiology of Disease, Vol. 21, No. 3, 03.2006, p. 607-617.

Research output: Contribution to journalArticle

Bicego, M, Morassutto, S, Hernandez, VH, Morgutti, M, Mammano, F, D'Andrea, P & Bruzzone, R 2006, 'Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease', Neurobiology of Disease, vol. 21, no. 3, pp. 607-617. https://doi.org/10.1016/j.nbd.2005.09.005
Bicego, Massimiliano ; Morassutto, Sabina ; Hernandez, Victor H. ; Morgutti, Marcello ; Mammano, Fabio ; D'Andrea, Paola ; Bruzzone, Roberto. / Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease. In: Neurobiology of Disease. 2006 ; Vol. 21, No. 3. pp. 607-617.
@article{3f0f0b0bf67b4adea7b00aaa183734f3,
title = "Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease",
abstract = "The X-linked form of Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Δ111-116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.",
keywords = "Connexin, Dye coupling, Gap junction, Genetic disease, Human, PNS",
author = "Massimiliano Bicego and Sabina Morassutto and Hernandez, {Victor H.} and Marcello Morgutti and Fabio Mammano and Paola D'Andrea and Roberto Bruzzone",
year = "2006",
month = "3",
doi = "10.1016/j.nbd.2005.09.005",
language = "English",
volume = "21",
pages = "607--617",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease

AU - Bicego, Massimiliano

AU - Morassutto, Sabina

AU - Hernandez, Victor H.

AU - Morgutti, Marcello

AU - Mammano, Fabio

AU - D'Andrea, Paola

AU - Bruzzone, Roberto

PY - 2006/3

Y1 - 2006/3

N2 - The X-linked form of Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Δ111-116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.

AB - The X-linked form of Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Δ111-116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.

KW - Connexin

KW - Dye coupling

KW - Gap junction

KW - Genetic disease

KW - Human

KW - PNS

UR - http://www.scopus.com/inward/record.url?scp=33244478285&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33244478285&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2005.09.005

DO - 10.1016/j.nbd.2005.09.005

M3 - Article

C2 - 16442804

AN - SCOPUS:33244478285

VL - 21

SP - 607

EP - 617

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -