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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most significant finding of the past year in gap junction research has been the association of connexin defects with human diseases. Connexin32 mutations cause X-linked Charcot-Marie-Tooth disease, a demyelinating peripheral neuropathy. Mutations in connexin43 may underlie cardiac malformations in visceroatrial heterotaxia syndromes. Genetic approaches and gene targeting have provided new insights, but also raise new questions concerning connexin function, the significance of connexin diversity and the regulation of intercellular communication.
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PMID:New functions for gap junctions. 857 41

Gap junctional intercellular communication mediates the transfer of small molecules from the cytoplasm of one cell to that of neighbouring cells. Connexins are the proteins that form the channels responsible for this type of communication. Aberrant expression and function of connexins are often found in cells exposed to tumor-promoting agents and during carcinogenesis, both in cell culture systems and in tissues freshly removed directly from patients and exposed animals. Transfection of connexin genes into tumorigenic cells often exerts negative growth control, suggesting that connexins act as a family of tumor-suppressor genes. Connexin gene mutations appear to be the cause of two human diseases, i.e. X-linked Charcot-Marie-Tooth syndrome and visceroatrial heterotaxia. Connexin genes are therefore important for the maintenance of homeostasis and thus their dysfunction could lead to various forms of disease.
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PMID:Role of blocked gap junctional intercellular communication in non-genotoxic carcinogenesis. 859 29

We have characterized the function of connexin (Cx) 32 gene mutations found in X-linked dominant Charcot-Marie-Tooth disease with respect to their ability to form functional gap junctions among themselves and to inactivate wild-type Cx32 by a dominant negative mechanism. We prepared four types of Cx32 mutant cDNAs and transfected them into HeLa cells, which do not show detectable levels of gap junctional intercellular communication (GJIC), nor expression of any connexins examined. Cells transfected with the wild-type Cx32 gene, but not those transfected with three different base substitution mutations (i.e. Cys 60 to Phe, Val 139 to Met, and Arg 215 to Trp), restored GJIC. Unexpectedly, in cells transfected with a nonsense mutant at codon 220, there was also restored GJIC. When we double-transfected these mutant constructs into the HeLa cells that had already been transfected with the wild-type Cx32 gene and thus were GJIC proficient, three base substitution mutants inhibited GJIC, suggesting that these three mutants can eliminate the function of wild-type Cx32 in a dominant negative manner. The nonsense mutation at codon 220 did not show such a dominant negative effect. Since both mutant and wild-type Cx32 mRNAs were detected, but only poor Cx32 protein expression at cell-cell contact areas was observed in the double transfectants, it is suggested that certain mutants form nonfunctional chimeric connexons with wild-type connexins, which are not properly inserted into the cytoplasmic membrane.
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PMID:Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects. 881 97

Connexins form a multigene family of polytopic membrane proteins that, in vertebrates, are the constitutive subunits of intercellular channels and provide the structural basis for electrical coupling. The appearance of electrical coupling in the nervous system is developmentally regulated and restricted to distinct cell types. Electrical coupling between neurons persists after the establishment of chemical transmission, thus suggesting that this form of cell-cell signalling may be functionally interrelated with, rather than alternative to chemical transmission. Furthermore, evidence for the possible role of gap junctions in human neurological diseases is also mounting, following the discovery that the X-linked form of Charcot-Marie-Tooth syndrome, a demyelinating neuropathy of the peripheral nervous system, is associated with mutations in a connexin gene. These findings raise new questions on the significance of connexin diversity and on their functional role in the nervous system.
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PMID:Connexins, gap junctions and cell-cell signalling in the nervous system. 904 62

Gap junction channels in mammalian organs can be built up of at least 13 different connexin proteins, most of which are expressed in only few cell types, although many cells express more than one connexin protein. Recently, the consequences of missing or defective connexin proteins were studied in human patients with defects in connexin32 (Cx32; beta 1; X-linked Charcot-Marie-Tooth disease) or in Cx26 (beta 2; non-syndromic sensorineural deafness), and in mice with targeted deletions in the Cx26, Cx32, Cx37 (alpha 4), Cx43 (alpha 1), Cx46 (alpha 3) or Cx50 (alpha 8) genes. Some effects of dominant negative mutations in connexin genes have been characterized in Xenopus oocytes and transfected mammalian cells in culture. Here we review results of these different experimental approaches and report new findings regarding the characterization of Cx40 (alpha 5)- and Cx31 (beta 3)-deficient mice. The phenotypic alterations, caused by different defective connexin genes in mice or humans, are divergent, although in most known cases the viability is not affected. When more than one connexin gene, coexpressed in the same cell, is inactivated, development or maturation can be more severely affected at an earlier stage. Some connexin proteins, if present in the same cell, can partially replace each other in certain functions. Thus, the diversity of connexin proteins in mammalian cells may provide functional overlap and complementation.
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PMID:Biological functions of connexin genes revealed by human genetic defects, dominant negative approaches and targeted deletions in the mouse. 1020 99

Myelinating Schwann cells express the gap junction protein, connexin (Cx)32, which is present at the nodes of Ranvier and Schmidt-Lantermann incisures (Bergoffen et al. [1993] Science (Wash. ) 262:2039-2042). Following peripheral nerve injury, other members of the connexin gene family are also expressed (Chandross et al. [1996a] Mol. Cell. Neurosci. 7:501-518). This study surveys the connexin(s) expressed by rat sciatic nerve, cultured Schwann cells, and a mouse Schwannoma (TR6 Bc1) cell line. Reverse transcriptase-polymerase chain reaction (RT-PCR) amplification revealed a constitutive expression of mRNA encoding Cx32 and 43 but not Cx26, 37, 40, 45, and 46 in sciatic nerve. Mitogenic stimulation of cultured Schwann cells expressing Cx32 also resulted in the appearance of Cx43 mRNA. Schwannoma cells expressed exclusively Cx43 mRNA. These results were confirmed by Northern blot analysis. Functional gap junctions in cultured Schwann and Schwannoma cells were shown by analysis of the intercellular transfer of Lucifer yellow, although the coupling between primary Schwann cells was weak or undetectable. Treatment of primary Schwann cells with mitogens resulted in extensive dye coupling. An immunohistochemical study of adult sciatic nerve sections demonstrated Cx32 immunoreactivity at the nodes of Ranvier and in Schwann cell bodies. Lower intensity staining of Cx43 along the myelin sheath and Schwann cell bodies was also observed. Indirect immunofluorescent studies of Schwann cells treated with mitogens showed characteristic punctate cell surface staining of Cx43; Cx32 staining was detected mainly intracellularly. These results lead to the conclusion that in addition to the expression of Cx32 by normal adult sciatic nerve, low amounts of Cx43 protein are also present. The implications of the expression of two connexins by Schwann cells in Charcot-Marie-Tooth X-linked disease, a demyelinating peripheral neuropathy, are discussed.
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PMID:Multiple connexin expression in peripheral nerve, Schwann cells, and Schwannoma cells. 1039 94

X-linked Charcot-Marie-Tooth disease (CMT-X) is caused by mutations of connexin-32 (Cx-32), which encodes a gap-junction protein. Whether the neuropathy is primarily demyelinative or axonal remains to be established. We report findings of prominent demyelination in a 71-year-old woman with late-onset disease. Electrophysiological studies revealed a nonuniform slowing of motor conduction velocities and dispersion of compound action potentials indicative of a demyelinating process which was confirmed by nerve biopsy. Such electrophysiological features are unusual in hereditary neuropathies and are more commonly found with acquired chronic demyelinating neuropathies. A systematic search confirmed the molecular genomic diagnosis of CMT-X, illustrating the value of such tests in sporadic cases. Severity of clinical symptoms and signs may vary with age and sex of the patient. The pathology of CMT-X in other reported cases has been variably interpreted as axonal, demyelinating, or showing both features. Our observations emphasize the demyelinative nature.
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PMID:Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings. 1048 13

Two patients with a mild to moderate phenotype of Charcot-Marie-Tooth disease were identified to carry the mutations of the connexin (Cx) 32 gene. One of the patient had a novel nonsense mutation of tryptophan at amino acid 132 and the other had a deletion of the Cx 32 gene. Our study indicated that a loss of Cx 32 function contributes to a major pathogenesis of X-linked Charcot-Marie-Tooth disease.
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PMID:Deletion and nonsense mutations of the connexin 32 gene associated with Charcot-Marie-Tooth disease. 1058 15

The assembly of gap junction intercellular communication channels was studied by analysis of the molecular basis of the dysfunction of connexin 32 mutations associated with the X-linked form of Charcot-Marie-Tooth disease in which peripheral nervous transmission is impaired. A cell-free translation system showed that six recombinant connexin 32 mutated proteins-four point mutations at the cytoplasmic amino terminus, one at the membrane aspect of the cytoplasmic carboxyl terminus, and a deletion in the intracellular loop-were inserted into microsomal membranes and oligomerised into connexon hemichannels with varying efficiencies. The functionality of the connexons was determined by the ability of HeLa cells expressing the respective connexin cDNAs to transfer Lucifer yellow. The intracellular trafficking properties of the mutated connexins were determined by immunocytochemistry. The results show a relationship between intracellular interruption of connexin trafficking, the efficiency of intercellular communication, and the severity of the disease phenotype. Intracellular retention was explained either by deficiencies in the ability of connexins to oligomerise or by mutational changes at two targeting motifs. The results point to dominance of two specific targeting motifs: one at the amino terminus and one at the membrane aspect of the cytoplasmically located carboxyl tail. An intracellular loop deletion of six amino acids, associated with a mild phenotype, showed partial oligomerisation and low intercellular dye transfer compared with wild-type connexin 32. The results show that modifications in trafficking and assembly of gap junction channels emerge as a major feature of Charcot-Marie-Tooth X-linked disease.
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PMID:Analysis of gap junction assembly using mutated connexins detected in Charcot-Marie-Tooth X-linked disease. 1064 23

More than 130 different mutations in the gap junction integral plasma membrane protein connexin32 (Cx32) have been linked to the human peripheral neuropathy X-linked Charcot-Marie-Tooth disease (CMTX). How these various mutants are processed by the cell and the mechanism(s) by which they cause CMTX are unknown. To address these issues, we have studied the intracellular transport, assembly, and degradation of three CMTX-linked Cx32 mutants stably expressed in PC12 cells. Each mutant had a distinct fate: E208K Cx32 appeared to be retained in the endoplasmic reticulum (ER), whereas both the E186K and R142W mutants were transported to perinuclear compartments from which they trafficked either to lysosomes (R142W Cx32) or back to the ER (E186K Cx32). Despite these differences, each mutant was soluble in nonionic detergent but unable to assemble into homomeric connexons. Degradation of both mutant and wild-type connexins was rapid (t(1/2) < 3 h) and took place at least in part in the ER by a process sensitive to proteasome inhibitors. The mutants studied are therefore unlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared from the cell by quality control processes that prevent abnormal connexin molecules from traversing the secretory pathway.
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PMID:Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. 1084 20


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