Alternative titles; symbols
HGNC Approved Gene Symbol: GJB6
SNOMEDCT: 54209007;
Cytogenetic location: 13q12.11 Genomic coordinates (GRCh38): 13:20,221,962-20,232,319 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.11 | Deafness, autosomal dominant 3B | 612643 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 1B | 612645 | Autosomal recessive | 3 | |
| Deafness, digenic GJB2/GJB6 | 220290 | Autosomal recessive; Digenic dominant | 3 | |
| Ectodermal dysplasia 2, Clouston type | 129500 | Autosomal dominant | 3 |
The connexin gene family codes for the protein subunits of gap junction channels that mediate direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Connexins span the plasma membrane 4 times, with amino- and carboxy-terminal regions facing the cytoplasm. Connexin genes are expressed in a cell type-specific manner with overlapping specificity. The gap junction channels have unique properties depending on the type of connexins constituting the channel. Connexin-30 (GJB6) is a gap junction subunit expressed abundantly in brain and cochlea (summary by Dahl et al., 1996; Lautermann et al., 1998).
Dahl et al. (1996) cloned a cDNA of a novel mouse connexin, gap junction protein beta-6 (Gjb6), which they called connexin-30 (Cx30). The Gjb6 gene, which is uninterrupted by introns, encodes a 261-amino acid protein that has 77% identity with mouse connexin-26 (GJB2; 121011). In 4-week-old mice, Northern blot analysis revealed the expression of GJB6 most abundantly in brain and skin.
Grifa et al. (1999) cloned a cDNA fragment of human connexin-30 that encoded a 261-amino acid protein. The GJB6 protein shares 93% homology with mouse connexin-30 and 76% identity with human GJB2 (Cx26). Northern blot, RT-PCR, and in situ hybridization analyses revealed mouse Gjb6 expression in trachea, thyroid, brain, and cochlea. Using immunocytochemistry, Lautermann et al. (1999) detected Cx26 and Cx30 in the lateral wall of the cochlea of a 22-week-old human embryo.
Dahl et al. (1996) assigned the Gjb6 gene to mouse chromosome 14 by somatic cell hybrid analysis. Grifa et al. (1999) noted that the mouse Gjb6 gene had been mapped to a region with syntenic homology to human chromosome 13q12 and that some deaf families linked to 13q12 are negative for mutations in GJB2, suggesting the presence of other deafness genes in the region. By FISH, Kelley et al. (1999) mapped the GJB6 gene to human chromosome 13q12.
Deafness, Autosomal Dominant/Autosomal Recessive
By SSCP mutation analysis in 198 deaf patients, including 38 families linked to 13q12, Grifa et al. (1999) identified a thr5-to-met (T5M) mutation (604418.0001) in GJB6 in a family with autosomal dominant, bilateral, middle to high frequency hearing loss (DFNA3B; 612643). The threonine at position 5 is conserved both evolutionarily and in human connexin-26. Electrophysiologic studies on Xenopus laevis oocytes determined that wildtype but not T5M mutant GJB6 produced gap junctional currents. When coexpressed, T5M mutant GJB6 suppressed wildtype transjunctional conductance in a dominant-negative manner.
Kelley et al. (1999) detected no significant mutations in the GJB6 gene in a screening of 23 dominant families and 64 American and 30 Japanese recessive families with nonsyndromic hearing loss.
Up to 50% of all patients with autosomal recessive nonsyndromic prelingual deafness in different populations have mutations in the GJB2 gene, which encodes connexin-26 and is situated at the locus arbitrarily designated DFNB1 (220290) on 13q12. However, a large fraction (10 to 42%) of patients with GJB2 mutations have only 1 mutant allele at that locus, with the accompanying mutation unidentified. DFNB1-linked familial cases with no mutation in GJB2 had also been reported. In a study of 33 unrelated probands with nonsyndromic prelingual deafness and only 1 mutant GJB2 allele, 9 subjects had evidence of linkage to DFNB1. Del Castillo et al. (2002) identified a 342-kb deletion in the GJB6 gene (604418.0004), which encodes a protein, connexin-30, that is reported to be expressed with connexin-26 in the inner ear. The deletion extended distally to GJB2, which remained intact. The breakpoint junction of the deletion was isolated and sequenced, and a specific diagnostic test was developed for this common mutation. They found that 22 of the 33 subjects were heterozygous for both GJB6 and GJB2 mutations, including all 9 with evidence of linkage to the DFNB1 locus. Two subjects were homozygous for the GJB6 mutation. In the Spanish population, the 342-kb deletion in GJB6 was the second most frequent mutation causing prelingual deafness. The authors concluded that mutations in the complex DFNB1 locus, which contains 2 genes (GJB2 and GJB6), can result in a monogenic or in a digenic pattern of inheritance of prelingual deafness. Del Castillo et al. (2005) noted that the deletion size was 309 kb, according to more recent sequencing data.
In a sporadic case of congenital profound deafness with no mutation in the GJB2 gene, Pallares-Ruiz et al. (2002) found a homozygous deletion including the 5-prime end of the GJB6 gene, covering at least 150 kb. This finding confirmed that homozygous absence of this gene is responsible for severe hearing impairment at the DFNB1 locus. Furthermore, Pallares-Ruiz et al. (2002) found the GJB6 deletion in trans in 4 of 6 deafness patients heterozygous for a GJB2 mutation, thereby suggesting a digenic mode of inheritance.
In 255 French patients with a phenotype compatible with DFNB1, Feldmann et al. (2004) found that 32% had biallelic GJB2 mutations, and 6% were heterozygous for a GJB2 mutation and the GJB6 342-kb deletion. Profoundly deaf children were more likely to have the biallelic GJB2 or heterozygous GJB2/GJB6 mutations.
Mutations in the GJB2 gene have been linked to sensorineural hearing loss either alone or as part of a syndrome. Marziano et al. (2003) compared the properties of 4 CX26 mutants derived from point mutations associated with dominantly inherited hearing loss, either nonsyndromic (W44S, 121011.0031; R75W, 121011.0011) or with various skin disorders (G59A, 121011.0015; D66H, 121011.0012). Since CX26 and CX30 colocalize to the inner ear, the effect of the dominant CX26 mutations on both of these wildtype proteins was determined. Communication-deficient HeLa cells were transiently transfected with the various cDNA constructs, and dye transfer studies demonstrated disruption of intercellular coupling for all 4 CX26 mutant proteins. Immunostaining of the transfected cells revealed that G59A and D66H mutants had impaired intracellular trafficking and targeting to the plasma membrane. Impaired trafficking was rescued by oligomerization with both CX26 and CX30, suggesting that CX26 and CX30 can form heteromeric connexons. Significantly reduced dye transfer rates were observed between cells coexpressing either CX26 or CX30 together with W44S or R75W compared with wildtype proteins alone. The dominant actions of the G59A and D66H mutants were only on CX30 and CX26, respectively. Marziano et al. (2003) suggested that in the inner ear CX26 and CX30 may form heteromeric connexons with particular properties essential for hearing and that disruption of these heteromeric channels underlies the nonsyndromic nature of certain deafness-causing GJB2 mutations.
Clouston Syndrome
Lamartine et al. (2000) presented evidence that missense mutations in the GJB6 gene cause hidrotic ectodermal dysplasia (ECTD2; 129500), also known as Clouston syndrome. This disease is an autosomal dominant skin disorder characterized by palmoplantar hyperkeratosis, hair defects (from partial to total alopecia), nail hypoplasia, and nail deformities. Clouston syndrome had been mapped to the pericentromeric region of 13q, where the GJB2 and GJB6 genes are located. Involvement of GJB2 in Clouston syndrome was excluded by Kelsell et al. (1997). GJB6 seemed to be a good candidate for the disorder because hearing impairment had been reported in a few cases of Clouston syndrome. In addition, expression of GJB6 had been observed in mouse epidermis (Dahl et al., 1996), and Lamartine et al. (2000) detected a GJB6 transcript in human epidermal cells. They detected 2 missense mutations in the GJB6 gene: gly11 to arg (G11R; 604418.0002) and ala88 to val (A88V; 604418.0003). Affected individuals were heterozygous.
Common et al. (2002) transfected a keratinocyte cell line and HeLa cells with wildtype CX30 and CX30 mutants harboring disease-associated mutations. Mutations that result in skin disease, such as G11R (604418.0002) and A88V (604418.0003), impaired trafficking of the protein to the plasma membrane, thus preventing the formation of functional CX30 gap junctions. The deafness-associated mutation, T5M, resulted in correct trafficking of the protein to the membrane, but channel activity was impaired.
Essenfelder et al. (2004) analyzed the consequences of the G11R and A88V mutations on the functional properties of connexons. The distribution of CX30 was similar in affected palmoplantar skin and in normal epidermis. The presence of the wildtype protein improved trafficking of mutated CX30 to the plasma membrane where both G11R and A88V CX30 colocalized with wildtype CX30 and formed functional intercellular channels. Electrophysiologic properties of channels made of mutant CX30 differed slightly from those of wildtype CX30 but allowed for dye transfer between transfected HeLa cells. A gain of function was observed for G11R and A88V CX30, which formed functional hemichannels at the cell surface and, when expressed in HeLa cells, generated a leakage of ATP into the extracellular medium. Essenfelder et al. (2004) suggested that such increased ATP levels might act as a paracrine messenger that, by altering the epidermal factors that control proliferation and differentiation of keratinocytes, could play a role in the pathophysiologic processes leading to the Clouston syndrome phenotype.
Teubner et al. (2003) generated Gjb6-deficient mice by deletion of the Gjb6 coding region. Homozygous null mutants were born at the expected Mendelian frequency, developed normally, and were fertile; however, they exhibited a severe constitutive hearing impairment. From the age of hearing onset, these mice lacked the electrical potential difference between the endolymphatic and perilymphatic compartments of the cochlea (i.e., the endocochlear potential), which plays a key role in the high sensitivity of the mammalian auditory organ. In addition, after postnatal day 18, the cochlear sensory epithelium started to degenerate by cell apoptosis. Teubner et al. (2003) concluded that the Gjb6 null phenotype revealed a critical role of GJB6 both in generating the endocochlear potential and for survival of the auditory hair cells after the onset of hearing.
Using homologous recombination, Schutz et al. (2010) created a line of mice expressing human CX30 with the T5M substitution (604418.0001). Homozygous CX30-T5M mice were born at the expected mendelian ratio and were viable and fertile. In contrast to patients with a heterozygous T5M substitution, homozygous CX30-T5M mice showed only mild hearing impairment, with significantly increased hearing thresholds of about 15 decibels at all frequencies. In adult homozygous mice, CX30-T5M expression was reduced by approximately one-third compared with wildtype Cx30 levels, concomitant with downregulation of Cx26. CX30-T5M was expressed at cell membranes and formed gap junctions, and homozygous CX30-T5M mice showed normal endocochlear potentials.
In affected members of an Italian family with sensorineural hearing loss and linkage to chromosome 13q12 (DFNA3B; 612643), Grifa et al. (1999) identified a heterozygous C-to-T transition in the GJB6 gene, resulting in a thr5-to-met (T5M) substitution. In vitro functional expression studies in Xenopus oocytes showed that the mutant protein did not induce membrane potential coupling and suppressed the wildtype protein, consistent with a dominant-negative effect. The authors postulated that the negative inhibitory effect was due to direct interaction of intact and defective connexins at the plasma membrane level.
Using homologous recombination, Schutz et al. (2010) created a line of mice expressing human CX30 with the T5M substitution. Homozygous CX30-T5M mice were born at the expected mendelian ratio and were viable and fertile. In contrast to patients with a heterozygous T5M substitution, the homozygous CX30-T5M mice showed only mild hearing impairment, with significantly increased hearing thresholds of about 15 decibels at all frequencies. In adult homozygous mice, CX30-T5M expression was reduced by approximately one-third compared with wildtype Cx30 levels, concomitant with downregulation of Cx26. CX30-T5M was expressed at cell membranes and formed gap junctions, and homozygous CX30-T5M mice showed normal endocochlear potentials.
In 2 unrelated French families segregating a typical form of hidrotic ectodermal dysplasia (129500), Lamartine et al. (2000) found, in the GJB6 gene, a 31G-A transition leading to a gly11-to-arg (G11R) missense mutation. They analyzed 10 additional unrelated affected individuals of various geographic origins and found the same mutation in 1 African, 1 Spanish, 3 French-Canadian, 1 Scottish-Irish, and 1 additional French case. Three other patients had another missense mutation, ala88 to val (604418.0003).
In 3 patients with hidrotic ectodermal dysplasia (129500) originating from India, Malaysia, and Wales, Lamartine et al. (2000) found a 263C-T transition in the GJB6 gene leading to an ala88-to-val (A88V) missense mutation.
In 2 Spanish sibs with autosomal recessive deafness-1B (DFNB1B; 612645), del Castillo et al. (2002) identified homozygosity for a 342-kb deletion (342-KB DEL) in the GJB6 gene. The parents, who were deaf, were both found to be compound heterozygous for the GJB6 deletion and a common mutation in the GJB2 gene (35delG; 121011.0005), consistent with digenic inheritance (see 220290). A heterozygous GJB6 deletion was also identified in 22 of 33 additional Spanish patients with only 1 mutant GJB2 allele, again consistent with digenic inheritance due to compound heterozygous mutations in 2 different genes. Del Castillo et al. (2005) noted that the deletion size was 309 kb, according to more recent sequencing data. This deletion truncating the GJB6 gene was shown to be the accompanying mutation in approximately 50% of deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain.
In a multicenter study in 9 countries, del Castillo et al. (2003) showed that the GJB6 deletion was present in most of the screening populations, with higher frequencies in France, Spain, and Israel where the percentages of unexplained GJB2 heterozygotes fell to 16 to 20.9% after screening for the GJB6 deletion mutation. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in western Europe (the deletion mutation was referred to as del(GJB6-D13S1830) by del Castillo et al. (2003)).
Seeman et al. (2005) identified the 342-kb deletion in the GJB6 gene in 1 of 13 Czech patients with prelingual nonsyndromic sensorineural deafness who also carried 1 pathogenic mutation in the GJB2 gene. The deletion was not detected in 600 control chromosomes from Czech individuals with normal hearing. Seeman et al. (2005) concluded that the 342-kb deletion is very rare in central Europe compared to reports from Spain, France, and Israel.
In 324 probands with hearing loss and 280 controls, including 135 probands and 280 controls previously reported by Tang et al. (2006), Tang et al. (2008) screened for DNA sequence variations in GJB2 and for deletions in GJB6. The 232-kb GJB6 deletion (604418.0006) was not found, and the 309-kb GJB6 deletion was found only once, in a patient of unknown ethnicity who was also heterozygous for a truncating mutation in the GJB2 gene. Tang et al. (2008) suggested that the 232- and 309-kb deletions in the GJB6 gene may not be common in all populations.
Smith et al. (2002) reported a novel mutation, val37 to glu (V37E), within the first transmembrane domain of connexin-30 in a spontaneous case of Clouston syndrome (ECTD2; 129500). The amino acid substitution arose from a heterozygous 110T-to-A transversion in the GJB6 gene.
In 4 unrelated Spanish patients with autosomal recessive nonsyndromic hearing impairment who were heterozygous for 1 GJB2 (121011) mutant allele and did not carry the 309-kb GJB6 deletion (604418.0004), del Castillo et al. (2005) identified a 232-kb deletion, which they referred to as del(GJB6-D13S1854). The findings were consistent with digenic inheritance (see 220290). The 232-kb deletion was identified in trans in 12 of 47 unrelated affected Spanish individuals who were unresolved GJB2 heterozygotes. The deletion was not found in 100 control subjects with normal hearing. The 232-kb deletion was found to account for 22.2% of affected GJB2 heterozygotes who were unresolved after screening for the 309-kb deletion in the United Kingdom, for 6.3% in Brazil, and for 1.9% in northern Italy. By haplotype analysis, del Castillo et al. (2005) showed a common founder for the 232-kb deletion in Spain, the United Kingdom, and Italy.
In 324 probands with hearing loss and 280 controls, including 135 probands and 280 controls previously reported by Tang et al. (2006), Tang et al. (2008) screened for DNA sequence variations in GJB2 and for deletions in GJB6. The 232-kb GJB6 deletion was not found, and the 309-kb GJB6 deletion was found only once, in a patient of unknown ethnicity who was also heterozygous for a Q57X mutation in GJB2. Tang et al. (2008) suggested that the 232- and 309-kb deletions in the GJB6 gene may not be common in all populations.
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Teubner, B., Michel, V., Pesch, J., Lautermann, J., Cohen-Salmon, M., Sohl, G., Jahnke, K., Winterhager, E., Herberhold, C., Hardelin, J.-P., Petit, C., Willecke, K. Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential. Hum. Molec. Genet. 12: 13-21, 2003. [PubMed: 12490528] [Full Text: https://doi.org/10.1093/hmg/ddg001]