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

X-linked dominant Charcot-Marie-Tooth (CMTX) neuropathy has been mapped to the Xq13 region. Subsequently, several mutations that could account for CMTX have been detected in the coding part of the connexin32 (Cx32) gene, which is located within this region. In order to develop more specific diagnostic tools, we have begun a systematic screening of families with dominant CMTX for mutations in the coding region of the Cx32 gene. This report describes a study of ten families and different mutations segregating with the disease were detected in five of them. In addition to the previously reported Arg22stop and Arg215Trp substitutions, three novel mutations are described, including two different missense mutations at codon Arg22 (Arg22Pro and Arg22Gly), and a nonsense mutation at codon Trp133. The identification of new CMTX-causing mutations is a critical step for carrier detection and presymptomatic diagnosis, and should provide essential information on the structure-function relationship of Cx32 in vitro as well as in vivo.
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PMID:X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene. 869 35

We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size.
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PMID:Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy. 873 58

The connexin32 (cx32) gene codes for the gap junction protein found in liver, pancreas and nervous tissue. Recently mutations in the coding region of this gene have been associated with the dominant X-linked form of Charcot-Marie-Tooth (CMTX1) neuropathy. Since some CMTX1 patients show no mutations in their cx32 gene coding region, it was speculated that these patients carry mutations in the promoter region of the gene. This paper describes the organization of the human cx32 gene and its tissue-specific transcription. The gene consists of three exons that are alternatively spliced to produce mRNAs with different 5'-untranslated regions (UTRs). Transcription is initiated from two tissue-specific promoters. In liver and pancreas, promoter P1, located more than 8 kb upstream of the translation start codon, is used, and the transcript is processed to remove a large intron. In contrast, in nerve cells, transcription is initiated from promoter P2, located 497 bp upstream from the translation start codon, and the transcript is processed to remove a small 355-pb intron. The downstream exon, which includes the entire coding sequence, is shared by both mRNAs. CMTX1 patients with a normal cx32 coding region are expected to have mutations in this newly described promoter P2 rather than the known promoter P1.
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PMID:The human connexin32 gene is transcribed from two tissue-specific promoters. 884 74

In recent years, there have been remarkable advances in the understanding of the molecular genetic basis of the hereditary polyneuropathies. Linkage of the genes for Charcot-Marie-Tooth disease to chromosomes 1 and then 17 was followed by the discovery that the commonest form of Charcot-Marie-Tooth disease (CMT1A) was due to a duplication of DNA at 17p11.2-12. This duplication was shown to contain the gene for peripheral myelin protein PMP22. The finding that mutations of the myelin protein PMP22 gene were present in some Charcot-Marie-Tooth disease cases lacking the duplication confirmed the myelin protein PMP22 gene as the site of the defect in Charcot-Marie-Tooth disease. Similarly, defects of the myelin protein P0 gene on chromosome 1 have been demonstrated in a rarer form of Charcot-Marie-Tooth disease (CMT1B). A deletion of DNA at 17p11.2-12 results in the disorder hereditary neuropathy with liability to pressure palsies. Other mutations of the myelin protein PMP22 and myelin protein P0 genes have been associated with the clinical syndrome known as Dejerine-Sottas disease. An X-linked form of Charcot-Marie-Tooth disease (CMTX) has been characterized and shown to be due to mutations of the gap junction protein, connexin 32. Transgenic murine models with inactivated myelin protein PMP22 and myelin protein P0 genes have shown pathologic changes strinkingly similar to those seen in human patients with disturbances of those genes. In this paper, the clinical and histopathologic characteristics of these conditions are discussed in relation to the genotypic basis. It will be argued that there is still an important place for the clinician and nerve pathologist in a medical world immersed in the wonders of molecular genetics.
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PMID:Correlation between the histopathologic, genotypic, and phenotypic features of hereditary peripheral neuropathies in childhood. 888 91

This report describes two families with type 1 Charcot-Marie-Tooth disease (CMTX), or hereditary motor sensory neuropathy type 1. Pedigree analysis is consistent with X-linked recessive inheritance in one family and X-linked dominant inheritance in the second. In the first family, a mutation in the connexin32 gene has been demonstrated and analyzed in family members. In the second family, linkage analysis is consistent with a mutation at the same locus. This report demonstrates the interfamilial variability in X-linked CMT and underscores the observation that regardless of the pattern of inheritance, X-linked CMT constitutes a single, variable disorder.
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PMID:X-linked Charcot-Marie-Tooth disease: molecular analysis of interfamilial variability. 895 25

Mutations affecting the connexin 32 (Cx32) gene are associated with the X-linked form of the hereditary peripheral neuropathy Charcot-Marie-Tooth disease (CMTX). We show that Cx32-deficient mice develop a late-onset progressive peripheral neuropathy with abnormalities comparable to those associated with CMTX, thus providing proof of the critical role of Cx32 in the maintenance of peripheral nerve myelin and an animal model for CMTX. Frequently observed features include abnormally thin myelin sheaths, cellular onion bulb formation reflecting myelin degeneration-induced Schwann cell proliferation, and enlarged periaxonal collars while nerve conductance properties are altered only slightly. These observations are consistent with earlier hypotheses suggesting a function of Cx32 as a channel-forming protein that facilitates the communication between the abaxonal and adaxonal aspects of Schwann cell cytoplasm.
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PMID:Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32. 916 15

The X-linked dominant form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in a gene coding for the gap-junction protein connexin 32 (Cx32). We screened 32 CMT families with a pedigree pattern suggestive of X-linked inheritance for the presence of mutations in the coding region of Cx32 by direct sequencing. Five of the families had a CMT1 diagnosis, 24 had a CMT2 diagnosis and 3 patients had an unspecified CMT. Eight families with a Cx32 point mutation were detected. Five different mutations (four of them published previously) were found in six CMT2 families and one mutation was found in a sporadic CMT1 male patient. One of the mutations, Met194Val, is among the first described in the fourth transmembrane domain of Cx32. Two CMT2 families and the sporadic CMT1 patient had the same mutation, Arg22Gln. An additional, previously unpublished mutation, Arg75Trp, was found in a male patient with unspecified CMT, who subsequently was verified to have a variant Klinefelter syndrome with 48,XXYY karyotype. Our findings show the difficulty in distinguishing CMTX patients from CMT1 and CMT2 patients, and they emphasize the need for Cx32 mutation screening in families previously diagnosed with CMT2.
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PMID:Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance. 927 61

We examined the cellular localization of nine different connexin32 (Cx32) mutants associated with X-linked Charcot-Marie-Tooth disease (CMTX) in communication-incompetent mammalian cells. Cx32 mRNA was made, but little or no protein was detected in one class of mutants. In another class of mutants, Cx32 protein was detectable in the cytoplasm and at the cell surface, where it appeared as plaques and punctate staining. Cx32 immunoreactivity in a third class of mutants was restricted to the cytoplasm, where it often colocalized with the Golgi apparatus. Our studies suggest that CMTX mutations have a predominant effect on the trafficking of Cx32 protein, resulting in a potentially toxic cytoplasmic accumulation of Cx32 in these cells. These results and evidence of cytoplasmic accumulation of other mutated myelin proteins suggest that diseases affecting myelinating cells may share a common pathophysiology.
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PMID:Altered trafficking of mutant connexin32. 936 54

Charcot-Marie-Tooth disease can be inherited either autosomal dominantly or recessively or linked to the X chromosome. X-linked dominant Charcot-Marie-Tooth disease (CMTX) is a sensorimotor peripheral neuropathy in which males have usually more severe clinical symptoms and decreased nerve conduction velocities than do females. CMTX is usually associated with mutations in exon 2 of the connexin 32 (Cx32) gene. DNA from 35 unrelated CMT patients, without the 17p11.2 duplication, but with median nerve conduction between 30 and 40 m/s, were tested for the presence of Cx32 mutations. The entire coding sequence of the Cx32 gene was explored using a rapid nonradioactive technique to detect single-strand conformation polymorphisms (SSCP) on large PCR fragments. Thirteen abnormal SSCP profiles were detected and characterized by sequencing. In addition, systematic sequencing of the entire Cx32 coding region in the remaining index cases revealed another mutation that was not detected by SSCP. A total of 14 mutations were found, five of which were not previously reported. These results demonstrate the high frequency (40%) of mutations in the coding region of the Cx32 gene in CMT patients with intermediate MNCV, without 17p11.2 duplications. Most of these mutations (93%) can be detected by SSCP.
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PMID:Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families. 940 Oct 7

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expressed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by testing their ability to form intercellular channels in the paired oocyte expression system. Although seven mutations were functionally incompetent, four others were able to generate intercellular currents of the same order of magnitude as those induced by wild-type Cx32 (Cx32wt). In homotypic oocyte pairs, CMTX mutations retaining functional activity induced the development of junctional currents that exhibited changes in the sensitivity and kinetics of voltage dependence with respect to that of Cx32wt. The four mutations were also capable of interacting in heterotypic configuration with the wild-type protein, and in one case the result was a marked rectification of junctional currents in response to voltage steps of opposite polarity. In addition, the functional CMTX mutations displayed the same selective pattern of compatibility as Cx32wt, interacting with Cx26, Cx46, and Cx50 but failing to do so with Cx40. Although the functional mutations exhibited sensitivity to cytoplasmic acidification, which induced a >/=80% decrease in junctional currents, both the rate and extent of channel closure were enhanced markedly for two of them. Together, these results indicate that the functional consequences of CMTX mutations of Cx32 are of two drastically distinct kinds. The presence of a functional group of mutations suggests that a selective deficit of Cx32 channels may be sufficient to impair the homeostasis of Schwann cells and lead to the development of CMTX.
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PMID:Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. 959 87


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