Disease relevance of GJB6

• Human connexin 30 (GJB6), a candidate gene for nonsyndromic hearing loss: molecular cloning, tissue-specific expression, and assignment to chromosome 13q12 [1].
• Missense mutations in the closely related Cx30 gene GJB6 underlie Clouston syndrome (autosomal dominant hidrotic ectodermal dysplasia) [2].
• These data indicate that skin disease associated Cx26 or Cx30 mutations are likely to disrupt a number of different channel types important in distinct aspects of keratinocyte biology [3].
• We analyzed the staining patterns of the GJ proteins Cx26, Cx30, and Cx43 in human cutaneous wound healing and compared ex vivo spontaneous wound healing to non-healing wounds (chronic leg ulcers) and to ex vivo accelerated wound healing after transplantation of cultured keratinocytes [4].
• The GJB2 mutation R75Q can cause nonsyndromic hearing loss DFNA3 or hereditary palmoplantar keratoderma with deafness [5].

High impact information on GJB6

• Mutations in GJB6 cause hidrotic ectodermal dysplasia [6].
• Cx26 and Cx30 are the two major Cx isoforms found in the cochlea, and they coassemble to form hybrid (heteromeric and heterotypic) gap junctions (GJs) [7].
• We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30(-/-) background [7].
• In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30(-/-) mice [7].
• Expression of GJB2 and GJB6 is reduced in a novel DFNB1 allele [8].

Chemical compound and disease context of GJB6

• In order to examine the potential role of connexin-30 in tumour cell proliferation, we transfected the connexin-30 cDNA into two rat glioma cell lines (9L and C6) which have lost its expression [9].
• Osteoclast number in callus surface was decreased in both ED-71 and alendronate treatment groups at 6 weeks and in EDH, ALL and ALH at 16 weeks, indicating that ED-71 inhibits osteoclastic bone resorption, but its effect is less prominent than alendronate [10].

Biological context of GJB6

• Another gap junction gene, connexin 30 (HGMW-approved symbol GJB6), is found to lie on the same PAC clone that hybridizes to chromosome 13q12 [1].
• Heterozygotes at the GJB2 locus should be screened for the GJB6 deletion as a cause of deafness [11].
• 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 [11].
• In this study, we performed bidirectional sequencing of the GJB2 gene and polymerase chain reaction (PCR) screening for the common GJB6 deletion, as well as PCR/RFLP analysis for three mutations in mtDNA (A1555G, A3243G, A7445G), in 109 predominantly simplex AA and CH individuals [12].
• Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia [2].

Anatomical context of GJB6

• RESULTS: We identified a 342-kb deletion in the gene encoding connexin 30 (GJB6), a protein that is reported to be expressed with connexin 26 in the inner ear [13].
• Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm [14].
• Inhibition of protein synthesis with cyclohexamide (CHX) revealed that S. aureus directly modulates, in part, Cx43 and Cx30 expression, whereas Cx26 levels appear to be regulated by a factor(s) that requires de novo protein production; however, CHX did not alter the inhibitory effects of S. aureus on astrocyte GJC [15].
• When coexpressed with Cx30, a connexin partially colocalized with Cx26 in the cochlea, all mutants had a dominant behavior [16].
• Towards understanding these disease mechanisms, transfection studies were performed in a keratinocyte cell line and in HeLa cells using EGFP tagged wildtype Cx30 and mutant Cx30 constructs harbouring dominant disease-associated GJB6 mutations [17].

Associations of GJB6 with chemical compounds

• MATERIALS AND METHODS: Female SD rats (n=201) allocated into 6 groups were treated with MCT-vehicle and ED-71 at 0.025 and 0.05 mug/kg/day (EDL and EDH groups), and with saline-vehicle and alendronate at 5 and 10 mug/kg/day (ALL and ALH groups) [10].
• Biochemical parameters of endometrial secretion [oestradiol dehydrogenase (EDH), isocitrate dehydrogenase (ICDH)] measured in endometrial tissue and placental protein (PP14) measured in serum were all low in the groups receiving the continuous combination and placebo [18].
• The diphosphonate disodium etidronate (EDHP) was given to all patients in an attempt to suppress calcification of new lesions; in five of them ectopic bone was removed during the treatment [19].
• In addition, gadolinium injection reduced the number of Kupffer cells reactive with monoclonal antibodies directed against macrophages ED2 and Ki-M2R [20].
• We have recently identified the ED2 antigen as the rat CD163 glycoprotein [21].

Other interactions of GJB6

• In our sample, the overall incidence of GJB2/GJB6 deafness was 2.57% [11].
• Gap junctions may include GJB2, GJB3 and GJB6 [22].
• Two additional genes, connexin 30 and retinoic acid receptor gamma were induced by Xwnt-3a alone [23].

Analytical, diagnostic and therapeutic context of GJB6

• DNA studies were performed for the GJB2 and GJB6 loci by sequencing and PCR methods [11].
• OBJECTIVE: To determine the relationship between ethnicity and mutations in the GJB2 and GJB6 genes in multi-cultural patients enrolled in a Canadian paediatric Cochlear Implant Program. METHODS: Blood was analyzed from 65 paediatric cochlear implant users by direct sequencing of the coding region and intron/exon boundaries of the GBJ2 gene [24].
• We show a subsequent induction of Cx26 and Cx30 near the wound margins in spontaneous wound healing and-even earlier-after the transplantation of keratinocytes [4].
• 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 [25].
• RESULTS: The immunofluorescence staining of the normal human vocal fold's epithelium showed the expression of Cx26 and Cx30 in the parabasal and intermediate layers, whereas Cx43 was localized in the basal, parabasal and lower intermediate layers [26].

References