Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
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.
Abrams CK, Freidin MM, Verselis VK, Bennett MV, Bargiello TA.
???displayArticle.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.
Abel,
Studies in transgenic mice indicate a loss of connexin32 function in X-linked Charcot-Marie-Tooth disease.
1999, Pubmed
Abel,
Studies in transgenic mice indicate a loss of connexin32 function in X-linked Charcot-Marie-Tooth disease.
1999,
Pubmed Ainsworth,
Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene.
1998,
Pubmed Barrio,
Species-specific voltage-gating properties of connexin-45 junctions expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase Bergoffen,
Connexin mutations in X-linked Charcot-Marie-Tooth disease.
1993,
Pubmed Bevans,
Isoform composition of connexin channels determines selectivity among second messengers and uncharged molecules.
1998,
Pubmed Bone,
New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.
1995,
Pubmed Bruzzone,
Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease.
1994,
Pubmed
,
Xenbase Bukauskas,
Heterotypic gap junction channels (connexin26-connexin32) violate the paradigm of unitary conductance.
1995,
Pubmed Bukauskas,
Biophysical properties of gap junction channels formed by mouse connexin40 in induced pairs of transfected human HeLa cells.
1995,
Pubmed Bukauskas,
Cytoplasmic bridges and gap junctions in an insect cell line (Aedes albopictus).
1992,
Pubmed Bukauskas,
Two distinct gating mechanisms in gap junction channels: CO2-sensitive and voltage-sensitive.
1997,
Pubmed Bukauskas,
Clustering of connexin 43-enhanced green fluorescent protein gap junction channels and functional coupling in living cells.
2000,
Pubmed Bukauskas,
Multiple conductance states of newly formed single gap junction channels between insect cells.
1993,
Pubmed Deschênes,
Altered trafficking of mutant connexin32.
1997,
Pubmed Fairweather,
Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).
1994,
Pubmed Fischbeck,
X-linked Charcot-Marie-Tooth disease and connexin32.
1999,
Pubmed Fischbeck,
X-linked neuropathy: gene localization with DNA probes.
1986,
Pubmed Fryns,
Sex-linked recessive inheritance in Charcot-Marie-tooth disease with partial clinical manifestations in female carriers.
1980,
Pubmed Gutierrez,
Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease.
2000,
Pubmed Hahn,
Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.
1999,
Pubmed Harris,
Kinetic properties of a voltage-dependent junctional conductance.
1981,
Pubmed Heimler,
Naevoid basal cell carcinoma syndrome and Charcot-Marie-Tooth disease: two autosomal dominant disorders segregating in a family.
1978,
Pubmed Ionasescu,
Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy.
1994,
Pubmed Ionasescu,
Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy.
1996,
Pubmed Janssen,
Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).
1997,
Pubmed Mambetisaeva,
Multiple connexin expression in peripheral nerve, Schwann cells, and Schwannoma cells.
1999,
Pubmed Martin,
Analysis of gap junction assembly using mutated connexins detected in Charcot-Marie-Tooth X-linked disease.
2000,
Pubmed Nelis,
Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.
1999,
Pubmed Niessen,
Strongly decreased gap junctional permeability to inositol 1,4, 5-trisphosphate in connexin32 deficient hepatocytes.
2000,
Pubmed Obaid,
Cell-to-cell channels with two independently regulated gates in series: analysis of junctional conductance modulation by membrane potential, calcium, and pH.
1983,
Pubmed Oh,
Molecular determinants of electrical rectification of single channel conductance in gap junctions formed by connexins 26 and 32.
1999,
Pubmed Oh,
Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease.
1997,
Pubmed
,
Xenbase Omori,
Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.
1996,
Pubmed Peracchia,
Chemical gating of gap junction channels.
2000,
Pubmed
,
Xenbase Ri,
The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions.
1999,
Pubmed
,
Xenbase Rubin,
Molecular analysis of voltage dependence of heterotypic gap junctions formed by connexins 26 and 32.
1992,
Pubmed
,
Xenbase Rubin,
A domain substitution procedure and its use to analyze voltage dependence of homotypic gap junctions formed by connexins 26 and 32.
1992,
Pubmed
,
Xenbase Scherer,
Connexin32 is a myelin-related protein in the PNS and CNS.
1995,
Pubmed Senderek,
X-linked dominant Charcot-Marie-Tooth disease: nerve biopsies allow morphological evaluation and detection of connexin32 mutations (Arg15Trp, Arg22Gln).
1998,
Pubmed Senderek,
X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).
1999,
Pubmed Török,
Connexin 32 of gap junctions contains two cytoplasmic calmodulin-binding domains.
1997,
Pubmed Trexler,
Voltage gating and permeation in a gap junction hemichannel.
1996,
Pubmed
,
Xenbase Trexler,
Rapid and direct effects of pH on connexins revealed by the connexin46 hemichannel preparation.
1999,
Pubmed
,
Xenbase VanSlyke,
Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins.
2000,
Pubmed Verselis,
Opposite voltage gating polarities of two closely related connexins.
1994,
Pubmed
,
Xenbase Verselis,
A voltage-dependent gap junction in Drosophila melanogaster.
1991,
Pubmed Wang,
Connexin 32/38 chimeras suggest a role for the second half of inner loop in gap junction gating by low pH.
1996,
Pubmed
,
Xenbase Wang,
Chimeric evidence for a role of the connexin cytoplasmic loop in gap junction channel gating.
1996,
Pubmed
,
Xenbase Wang,
Molecular dissection of a basic COOH-terminal domain of Cx32 that inhibits gap junction gating sensitivity.
1998,
Pubmed
,
Xenbase Wicklein,
Missense mutation (R15W) of the connexin32 gene in a family with X chromosomal Charcot-Marie-Tooth neuropathy with only female family members affected.
1997,
Pubmed Wilders,
Limitations of the dual voltage clamp method in assaying conductance and kinetics of gap junction channels.
1992,
Pubmed Yoshimura,
Connexin43 is another gap junction protein in the peripheral nervous system.
1996,
Pubmed
