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 language | English |
|---|---|
| Pages (from-to) | 607-617 |
| Number of pages | 11 |
| Journal | Neurobiology of Disease |
| Volume | 21 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2006 |
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Keywords
- Connexin
- Dye coupling
- Gap junction
- Genetic disease
- Human
- PNS
ASJC Scopus subject areas
- Neurology
Cite this
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 journal › Article
}
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
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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
VL - 21
SP - 607
EP - 617
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 3
ER -