Disease relevance of GJB1

• X-linked Charcot-Marie-Tooth disease: phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene [1].
• Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity [2].
• CONCLUSION: These findings suggest that some gain of function mutations of GJB1 may be related to CNS symptoms because the patients with GJB1 deletion only had peripheral neuropathy, although other unknown associated factors may contribute to their clinical phenotypes [3].
• Two siblings with deletion of the entire GJB1 gene had mild to moderate lower extremity muscle weakness and sensory disturbance without CNS involvement [3].
• If one further specifies the clinical type (demyelinating vs. axonal), the yield of detecting a molecular defect increases to 75% to 80% in the demyelinating or CMT1 group with a screening test that evaluates for CMT1A duplication/hereditary neuropathy with liability to pressure palsies deletion and GJB1 point mutations [4].

High impact information on GJB1

• 1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX [5].
• X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination [5].
• We propose that CMTX mutations impair the transduction of signals arising from normal glial-neuronal interactions and thereby cause demyelination and axonal degeneration [6].
• In contrast to hepatocytes, hepatic stellate cells do not express connexin 32 [7].
• Connexin 32 also was observed in the epithelial cells of atrophic mucosa in a pattern similar to that observed in normal controls [8].

Chemical compound and disease context of GJB1

• Cx43, but not Cx32, suppressed C6 glioma cell growth [9].
• We show here that in androgen-responsive human prostate cancer cells, androgens control the expression level of Cx32-and hence the extent of gap junction formation-post-translationally [10].

Biological context of GJB1

• Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy [11].
• Seven of these had genetically proven CMT disease type 1A (CMT1A) due to chromosome 17p11.2-12 duplication, and one had X-linked disease (CMTX) due to a mutation in the GJB1 gene [12].
• Novel missense mutation of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy [13].
• We screened the GJB1 gene for mutations by SSCP analysis and sequencing of candidate regions, in five unrelated CMT affected individuals, members of families presenting a mode of transmission and clinical findings compatible with CMTX [14].
• Clinical, electrophysiological and molecular genetic studies in a family with X-linked dominant Charcot-Marie-Tooth neuropathy presenting a novel mutation in GJB1 Promoter and a rare polymorphism in LITAF/SIMPLE [15].

Anatomical context of GJB1

• Charcot-Marie-Tooth (CMT) disease type CMTX has been linked with mutations in GJB1, a gene on chromosome X coding for a gap junction protein, Connexin 32 [14].
• By using a series of somatic cell hybrid mapping panels and a rat connexin32 cDNA probe, we have localized the human GJB1 locus to a much smaller region in proximal Xq13.1, in interval 8, as described by Lafrenière et al [16].
• Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease [3].
• To clarify the pathomechanism in three patients with X-linked Charcot-Marie-Tooth disease (CMTX) and unique clinical features, we studied three connexin (Cx) 32 (GJB1) mutants with respect to cellular localization in cultured cells [17].
• In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelin defects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10 [18].

Associations of GJB1 with chemical compounds

• A novel isoleucine at position 127 with serine (Ile127Ser) mutation in the gap junction protein beta 1 (GJB1) gene was detected [1].
• Six out of nine nucleotide substitutions in the Cx32 gene involved two codons encoding arginine at positions 164 and 183, suggesting that these two codons may constitute two Cx32 regions prone to mutate in the Spanish population [19].
• Cx 43 and Cx 32 never colocalized to the same cell indicating that gap junction intercellular communication differs between basal and luminal prostatic cells [20].
• While epithelial connexin expression was not initially altered in the developing prostates following estrogen exposure, adult prostates of neonatally estrogenized rats exhibited a marked decrease in Cx 32 staining and an increased proportion of Cx 43 expressing cells [20].
• The transfer of Lucifer yellow across gap junctions between cells expressing wild-type Cx32, Cx43, and the corresponding Cx32-Aeq and Cx43-Aeq chimeras was reduced by nocodazole treatment and abolished by brefeldin A treatment [21].

Physical interactions of GJB1

• The D355V mutation decreases EGR2 binding to an element within the Cx32 promoter [22].

Regulatory relationships of GJB1

• Overall, these data indicate that Cx32 is downregulated by the ILK pathway activation in rat hepatocytes and that this is mediated via the activation and nuclear translocation of Akt [23].

Other interactions of GJB1

• Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter [18].
• In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22 [24].
• Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations [25].
• Two members of this gene family, connexin43 (Cx43) and connexin32 (Cx32), are abundantly expressed in the heart and liver, respectively [26].
• Some mutations of MPZ and Cx32 were also associated with the clinical CMT2 phenotype [27].

Analytical, diagnostic and therapeutic context of GJB1

• The study of phenotype-genotype correlations in transgenic animal models for PMP22, MPZ and Cx32 mutations will help elucidate the underlying disease mechanisms and will provide a basis for gene therapy and/or other therapeutic approaches such as treatment with neurotrophic growth factors [28].
• Molecular dissection of transjunctional voltage dependence in the connexin-32 and connexin-43 junctions [29].
• Using GAP11, a rabbit polyclonal antibody against the Cx32 extracellular loop 2 (151-187), a sequence that is highly homologous in Cx43, the Cx43(dim) and Cx43(bright) cells were selected from primary limbal epithelial cultures by fluorescence-activated cell sorting and were evaluated for stem cell properties [30].
• CMT1A and CMTX xenografts examined at 16 weeks show that the nude mouse axons within the proximal part of grafts demonstrate a significant increase in axonal area with an increase in the neurofilament and membranous organelle density compared to distal graft and distal host segments [31].
• Immunostaining for cultured dental pulp fibroblasts (DPFs) showed that Cx32 and 43 were expressed in human DPFs, and proteins corresponding to 27 (Cx32) and 43kDa (Cx43) were identified by Western blot analysis [32].

References