Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0031117 (peripheral neuropathy)
10,577 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

Peripheral neuropathies can result from a failure to form or maintain the myelin internode or from autoimmune-mediated demyelination. Several gene defects responsible for the most common inherited human peripheral neuropathies referred to as Charcot-Marie-Tooth disease have been reported. These studies identified PMP-22 and connexin-32 as proteins that are essentiel for normal myelination. Point mutations in Po protein, PMP-22, and connexin-32 have been identified as causes of inherited peripheral neuropathies. In addition, studies indicated for the first time that alterations in PMP-22 gene dosage (trisomy and monosomy) can induce inherited peripheral neuropathies. Little is known, however, about how these gene defects cause myelin pathology. This report describes the distributions of proteins within the peripheral myelin internode and discusses how these molecules contribute to the pathogenesis of inherited and autoimmune peripheral neuropathy. A better understanding of the molecular composition of the myelin internode is essential for diagnosis and treatment of human peripheral neuropathies.
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PMID:Molecular pathogenesis of peripheral neuropathy. 888 22

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

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

Many lines of evidence suggest that connexin-32 gap junction is involved in the exchange of information and metabolites in the peripheral nervous system. It has been shown that connexin-32 protein and mRNA are expressed in Schwann cells that function as myelinating cells of the peripheral nervous system. The physiological importance of connexin-32 gap junctions in regulating the normal function of myelinating Schwann cell is indicated by recent findings that X-linked dominant Charcot-Marie-Tooth disease, a hereditary peripheral neuropathy, is associated with the mutations of connexin-32 gene. Recently, we encountered a Taiwanese family affected with X-linked dominant Charcot-Marie-Tooth neuropathy. Therefore, we investigated the possible mutation in the coding and noncoding regions of the connexin-32 gene of affected members of this family. Our results suggest that a G-to-A transition at the position -215 (in relation to the transcription initiation site) of the nerve-specific P2 promoter region is associated with the pathogenesis of X-linked dominant Charcot-Marie-Tooth disease. Further experiments using the promoter assay indicate that G-to-A mutation at the position -215 greatly impairs the transcriptional activity of connexin-32 P2 promoter. These findings propose that a reduced expression of connexin-32 mRNA and protein in the myelin sheath could be responsible for the development of X-linked dominant Charcot-Marie-Tooth neuropathy.
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PMID:Point mutation associated with X-linked dominant Charcot-Marie-Tooth disease impairs the P2 promoter activity of human connexin-32 gene. 1089 94

Deafness is a complex disorder that involves a high number of genes and environmental factors. There has been enormous progress in non-syndromic deafness research during the last five years, with the identification of over 50 loci and 15 genes. Among these, three genes, GJB2, GJB3, and GJB6, encode for connexin proteins (Connexin26, Connexin31, and Connexin30, respectively). Another connexin (Connexin32, encoded by GJB1) is involved in X-linked peripheral neuropathy and hearing impairment. Mutations in these genes cause autosomal recessive (GJB2 and GJB3), autosomal dominant (GJB2, GJB3, and GJB6) or X-linked (GJB1) hearing impairment, both syndromic (GJB2, keratoderma; GJB3 erythrokeratodermia variabilis; and GJB1, peripheral neuropathy), and non-syndromic (GJB2, GJB3, and GJB6). Among these genes, mutations in GJB2 account for about 50% of all congenital cases of hearing impairment. Three mutations in GJB2 (35delG, 167delT, and 235delC) are particularly common in specific populations (Caucasoid, Jewish Ashkenazi, and Oriental, respectively), leading to carrier frequencies between one in 30 and one in 75. Over 50 mutations have been identified in the GJB2 gene, of which some missense changes (M34T, W44C, G59A, D66H, and R75W) have a negative dominant action in hearing impairment, with partial to full penetrance. Functional studies for some missense mutations in connexins 26, 30, and 32 have indicated abnormal gap junction conductivity. Expression patterns in mouse and rat cochlea indicate that Connexin26 and Connexin30 are expressed in the supportive cells of the cochlea, suggesting a potential role in endolymph potassium recycling. The high prevalence of mutations in GJB2 in some populations provides the tools for molecular diagnosis, carrier detection, and prenatal diagnosis of congenital hearing impairment.
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PMID:Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins. 1098 May 26

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is an inherited peripheral neuropathy that arises in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32), which is expressed by Schwann cells. We recently showed that Cx32 containing the CMTX-associated mutation, Ser-85-Cys (S85C), forms functional cell-cell channels in paired Xenopus oocytes. Here, we describe that this mutant connexin also shows increased opening of hemichannels in nonjunctional surface membrane. Open hemichannels may damage the cells through loss of ionic gradients and small metabolites and increased influx of Ca(2+), and provide a mechanism by which this and other mutant forms of Cx32 may damage cells in which they are expressed. Evidence for open hemichannels includes: (i) oocytes expressing the Cx32(S85C) mutant show greatly increased conductance at inside positive potentials, significantly larger than in oocytes expressing wild-type Cx32 (Cx32WT); and (ii) the induced currents are similar to those previously described for several other connexin hemichannels, and exhibit slowly developing increases with increasing levels of positivity and reversible reduction when intracellular pH is decreased or extracellular Ca(2+) concentration is increased. Although increased currents are seen, oocytes expressing Cx32(S85C) have lower levels of the protein in the surface and in total homogenates than do oocytes expressing Cx32WT; thus, under the conditions examined here, hemichannels in the surface membrane formed of the Cx32(S85C) mutant have a higher open probability than hemichannels formed of Cx32WT. This increase in functional hemichannels may damage Schwann cells and ultimately lead to loss of function in peripheral nerves of patients harboring this mutation.
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PMID:Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease. 1189 46

Gap junctional intercellular communication plays an important role in the maintenance of cellular homeostasis. The flow of chemical messengers through gap junctions, gap junctional intercellular communication, is essential in processes such as electrical coupling, embryonic development and adaptive tissue response. Gap junctions are formed by connexin proteins. Mutational alterations in the connexin genes are associated with the occurrence of multiple diseases, such as peripheral neuropathy, cardiovascular disease, dermatological disease, hereditary deafness and cataract. Consequently, modulation of gap junctional intercellular communication is a potential pharmacological target. Future research, based, for example, on the recent developments in genetics, may clarify gap junction physiology. This will in turn provide promising perspectives for the development of targeted drugs.
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PMID:[The role of intercellular communication via "gap junctions" in disease]. 1470 10

To investigate the pathogenic role of connexin-32 (Cx32) mutation in X-linked dominant Charcot-Marie-Tooth disease (CMTX), dual whole-cell voltage-clamp recordings and tracer coupling were performed to investigate functional properties of wild-type and 22 CMTX mutant Cx32 proteins expressed in N2A cells. Ten mutant Cx32 proteins either formed defective junctional channels (Y65C, V95M, R107W, L156R, R164W and G199R) or failed to form gap junctions (G12S, S182T, E208K and Y211stop). Except (G12S) and (E208K) mutants, other mutant Cx32 proteins were localized in the cell membrane despite their impaired ability to form functional gap junctions. Twelve CMTX mutations (V13L, R15Q, R22Q, I30N, V35M, V63I, R75Q, Q80R, W133R, P158A, P172S and N205S) did not affect the ability of Cx32 to form homotypic gap junctions in N2A cells. Our results indicate that 10 of 22 CMTX Cx32 mutations studied in the present investigation could lead to the assembly of defective Cx32 gap junctions, which in turn may result in peripheral neuropathy. However, further studies are required to elucidate the exact mechanism by which CMTX mutant Cx32 proteins, which retain the ability to form homotypic junctional channels, damage Schwann cells and cause demyelinating neuropathy.
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PMID:Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. 1500 6

Gap junctions contain hydrophilic membrane channels that allow direct communication between neighboring cells through the diffusion of ions, metabolites, and small cell signaling molecules. They are made up of a hexameric array of polypeptides encoded by the connexin multi-gene family. Cell-cell communication mediated by connexins is crucial to various cellular functions, including the regulation of cell growth, differentiation, and development. Mutations in connexin genes have been linked to a variety of human diseases, including cardiovascular anomalies, peripheral neuropathy, deafness, skin disorders, and cataracts. In addition to their coupling function, recent studies suggest that connexin proteins may also mediate signaling. This could involve interactions with other protein partners that may play a role not only in connexin assembly, trafficking, gating and turnover, but also in the coordinate regulation of cell-cell communication with cell adhesion and cell motility. The integration of these cell functions is likely to be important in the role of gap junctions in development and disease.
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PMID:Connexins and cell signaling in development and disease. 1547 61


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