Disease relevance of GJB2

• Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss [1].
• Our data reveal striking genotype-phenotype correlations and demonstrate that dominant GJB2 mutations can disturb the gap junction system of one or several ectodermal epithelia, thereby producing multiple phenotypes: nonsyndromic SNHL, syndromic SNHL with palmoplantar keratoderma, and KID [2].
• Cx26 was up-regulated in the carcinoma cells of 15 of the 27 invasive NST carcinomas, although the staining was usually cytoplasmic and heterogeneous [3].
• Similarly, a lobular carcinoma did not express Cx26 or Cx43, but there was punctate Cx43 in the epithelial cells of a mucoid carcinoma [3].
• We have now determined the GJB2[connexin 26 (Cx26)] mutation spectrum in 60 index patients from mostly large Turkish families with autosomal-recessive inherited non-syndromic sensorineural hearing loss (NSSHL) [4].
• Survey of metastatic lesions revealed that lung metastasis, but not liver and lymph nodes metastases, expressed higher Cx26 than the CRC series or corresponding primary CRCs (P < 0.0001 and P = 0.0001, respectively) [5].

Psychiatry related information on GJB2

• GJB2 mutations will be of particular interest in combination with universal infant hearing screening programs, because it has been shown that early identification of hearing loss and early intervention are crucial for language development [6].
• The purpose of the study was to compare the speech perception performance of cochlear implant patients with GJB2-related deafness to patients without GJB2-related deafness [7].
• The GJB2 negative and those children not receiving GJB2 testing had motor delays, language delay, autism, specific learning disability, and attention deficit disorder [8].
• The disabilities in the GJB2 positive group included specific learning disability, apraxia, epileptiform aphasia, attention deficit disorder, global developmental delay, and gross motor delay [8].
• METHODS: Eight children with cochlear implants were subjected to genetic testing for GJB2 and underwent the Raven colored progressive matrices test, Rey's auditory verbal learning test, Rey's complex figure test, the standardized language test for aphasia, the picture vocabulary test, and the standardized comprehension test for abstract words [9].

High impact information on GJB2

• Mutations in the gene encoding connexin 26 (GJB2) cause both autosomal recessive and dominant forms of hearing impairment [10].
• RESULTS: Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness [11].
• The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions [11].
• Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa [12].
• So far, ten DFNB genes have been mapped to human chromosomes, one of which has been isolated [13].

Chemical compound and disease context of GJB2

• Here, we report a family from Southern Italy affected by non-syndromic autosomal dominant post-lingual hearing loss, due to a novel missense mutation in the GJB2 gene, a threonine to asparagine amino acid substitution at codon 55 (T55N) [14].
• STUDY DESIGN: We completed retrospective mutation screening of GJB2 and SLC26A4 and screened for three mtDNA mutations in patients with a history of childhood cancer who developed severe hearing loss at cumulative cisplatin doses of less than 400 mg/M2 [15].
• To explore the mechanism responsible for the downregulation of Cx26, we treated 2 lung cancer cell lines H2170 and H226 with the demethylation agent 5-aza-2'-deoxycytidine and found the reexpression of Cx26 mRNA [16].
• Connexin 26 induces growth suppression, apoptosis and increased efficacy of doxorubicin in prostate cancer cells [17].
• We hypothesized that Cx26, Cx32, or Cx43 would display differential growth suppression of C6 glioma cells and uniquely modulate the bystander effect following transduction of C6 cells with HSVtk followed by suicide gene therapy [18].

Biological context of GJB2

• Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2 [2].
• Of their 38 chromosomes, 71% resulted with mutations in the GJB2 gene and 11% in GJB6 [19].
• Specific genetic counseling for GJB2-linked hearing impairment in heterozygotes will depend on future research [20].
• CONCLUSION: Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness [21].
• We report on the prevalence of GJB2 and GJB6 mutations in a large North American Repository of DNA from deaf probands and document the profound effects of familial ethnicity and parental mating types on the frequency of these mutations in the population [22].

Anatomical context of GJB2

• In order to search for the origin of this inner ear malformation, mutations in genes GJB2 (connexin-26 gene), PDS (Pendred's syndrome gene) and mitochondrial 12sRNA were studied, without positive results [23].
• These results suggest that Cx26 expression, but not the mediated intercellular communication, may regulate tight junction barrier and fence functions in human airway epithelial cell line Calu-3 [24].
• Interestingly, transfection with Cx26 prevented disruption of both functions of tight junctions by treatment with ouabain without changes in the tight junction proteins [24].
• Human connexin 26 and connexin 30 are expressed in the same cells of the cochlea [25].
• The objective of this study was to analyze the expression and possible roles of Cx43 and Cx26 in human cholesteatoma compared to normal epithelium [26].

Associations of GJB2 with chemical compounds

• Pretreatment with the GJIC blockers 18beta-glycyrrhetinic acid and oleamide did not affect the changes induced by Cx26 transfection [24].
• Connexin-32, but not connexin-26, is phosphorylated by both protein kinase A and protein kinase C in serine residues and the sites of phosphorylation by both kinases remain in the major 26-kDa fragment resulting from calpain proteolysis [27].
• They indicate that expression of Cx26 and Cx32 is correlated with cell differentiation and with the glandular function of the endometrial epithelium and suggest that expression of Cxs is controlled by serum progesterone [28].
• An increase in the amount of connexin 43 in stromal cells and of connexin 26 in glandular and luminal epithelial cells was seen from days 11-15 of the cycle [29].
• Strong expression of Cx43 was correlated with a high serum value of 17 beta-oestradiol, whereas a strong expression of Cx26 was found with high values of progesterone mainly in patients after progestin treatment [30].

Physical interactions of GJB2

• Significantly, immobilized OCP1 binds (35)S-labeled connexin 26 (Cx26) produced by in vitro transcription-translation [31].

Regulatory relationships of GJB2

• CTGF mRNA and protein levels were found to be down-regulated by both Cx26 and GFP-Cx26 [32].

Other interactions of GJB2

• Qualitative polymerase chain reaction-based allele-specific expression assays showed that expression of both GJB2 and GJB6 from the novel allele is dramatically reduced [33].
• trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation [34].
• In addition to the previously described sequence variant M34T in GJB2, two other sequence variants were identified: D66H also in GJB2 and R32W in GJB3 [35].
• Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family [36].
• Hearing impairment was caused in one family by a novel mutation in the recently identified OTOF (the DFNB9 gene), by a novel Pendred syndrome mutation (Thr193Ile) in another family, and by a GJB2 mutation (35delG also known as 30delG) in the third family [37].

Analytical, diagnostic and therapeutic context of GJB2

• DNA studies were performed for the GJB2 and GJB6 loci by sequencing and PCR methods [22].
• OBJECTIVE: To compare performance after cochlear implantation in children with mutations in connexin (Cx) 26 (GJB2) or Cx30 (GJB6) and children with deafness of unknown etiology [38].
• 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 [39].
• In parallel, we have performed a molecular epidemiology study on more than 3000 dried blood spots and established the frequency of the GJB2 variants in our population [40].
• Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study [41].

References