Alternative titles; symbols
HGNC Approved Gene Symbol: GJB3
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38) : 1:34,781,214-34,786,364 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.3 | Deafness, autosomal dominant 2B, with or without peripheral neuropathy | 612644 | Autosomal dominant | 3 |
| Deafness, digenic, GJB2/GJB3 | 220290 | Autosomal recessive; Digenic dominant | 3 | |
| Erythrokeratodermia variabilis et progressiva 1 | 133200 | Autosomal dominant; Autosomal recessive | 3 |
Gap junctions are conduits that allow the direct cell-to-cell passage of small cytoplasmic molecules, including ions, metabolic intermediates, and second messengers, and thereby mediate intercellular metabolic and electrical communication. Gap junction channels consist of connexin protein subunits, which are encoded by a multigene family that includes GJB3 (summary by Richard et al., 1998; Wenzel et al., 1998).
Richard et al. (1998) identified 2 expressed sequence tags (ESTs) from the human EST database by their similarity to mouse Gjb3 and Gjb5. By radiation hybrid mapping, they placed them in proximity with a sequenced tag site (STS) that is linked to GJA4 (121012). Comparison of genomic and cDNA sequence of GJB3 showed an exon-intron organization common to that of genes encoding connexins. The complete coding sequence was contained in a single, uninterrupted open reading frame (ORF) of 813 nucleotides preceded by a putative splice junction located 25 nucleotides upstream of the ATG initiation site and followed by the 3-prime untranslated region with a polyadenylation signal at position 1,583. The protein Cx31, of predicted molecular mass 30.8 kD, consists of 270 amino acids and differs from its rodent homologs at 40 residues that are confined mainly to the cytoplasmic loop. Protein structure analysis confirmed a structural organization typical for beta-connexins, including a conserved arrangement of 3 cysteine residues in each extracellular loop.
By screening a human genomic library with a mouse Cx31 cDNA, Wenzel et al. (1998) isolated the CX31 gene. Southern blot analysis of human DNA showed that CX31 is a single-copy gene. Northern blot analysis of human keratinocyte cell lines detected approximately 2.2- and 1.8-kb CX31 transcripts. The deduced CX31 protein contains 4 putative transmembrane domains and 3 potential phosphorylation sites. Human CX31 is 83% identical to the mouse and rat Cx31 proteins.
Xia et al. (1998) cloned the gene (GJB3) encoding human gap junction protein beta-3 using homologous EST searching and nested PCR.
Lopez-Bigas et al. (2001) demonstrated expression of mouse Gjb3 in the cochlea and in the auditory and sciatic nerves in a pattern similar to that of Gjb1 (304040).
By analysis of somatic cell hybrids, Wenzel et al. (1998) mapped the GJB3 gene to chromosome 1p36-p34. Xia et al. (1998) mapped the GJB3 gene to 1p35-p33 by fluorescence in situ hybridization.
Plantard et al. (2003) showed that expression of wildtype CX30.3 (GJB4; 605425) in HeLa cells resulted only in minor amounts of protein addressed to the plasma membrane. Mutant CX30.3 (605425.0001) was hardly detectable and disturbed intercellular coupling. In contrast, coexpression of both wildtype CX30.3 and CX31 proteins led to a large increase of stabilized heteromeric gap junctions. Coexpressed wildtype CX30.3 and CX31 coprecipitated, demonstrating a physical interaction. Inhibitor experiments revealed that this interaction began in the endoplasmic reticulum.
Using transfected mouse neuroblastoma and HeLa cell lines, Abrams et al. (2006) found that CX31 channels, like other connexin channels, were gated by voltage and closed at low pH when exposed to long-chain alkanols. CX31 channels were relatively nonselective, allowing passage of both negatively and positively charged dyes. In contrast to mouse Cx31, human CX31 appeared to form functional heterotypic channels with all 4 connexins tested: CX26 (GJB2; 121011), CX30 (GJB6; 604418), CX32 (GJB1; 304040), and CX45 (GJA7; 608655).
Liu et al. (2009) found that Cx31 and Cx26 were coexpressed in the mouse cochlea and coassembled into gap junctions when expressed in HEK293 cells.
Erythrokeratodermia Variabilis et Progressiva 1
Erythrokeratodermia variabilis et progressiva (EKVP1; 133200) is a disorder of keratinization characterized by fixed erythrokeratotic plaques, associated with migratory erythematous lesions ('variabilis;' EKV) in some patients. In 4 of 12 families with EKV, Richard et al. (1998) detected heterozygous missense mutations in the GJB3 gene leading to substitution of a conserved glycine by charged residues (G12R, 603324.0001; G12D, 603324.0002), or change of a cysteine (C86S; 603324.0003). These mutations were predicted to interfere with normal Cx31 structure and function, possibly due to a dominant-negative effect. Thus, the results provided evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors. Richard et al. (1998) stated that this report was the first to link mutations in a gene encoding a connexin to a human skin disorder, and noted that further functional in vitro and in vivo studies were needed to understand how mutant Cx31 alters differentiation of the epidermis (hyperkeratosis) and affects the cutaneous microcapillary system (transient erythema).
Wilgoss et al. (1999) identified heterozygosity for a missense mutation in the GJB3 gene (R42P; 603324.0008) in affected members of a family with EKV.
Richard et al. (2000) analyzed the GJB3 gene in 2 families and 3 sporadic patients with EKV and in 2 families and 4 sporadic patients with the progressive, symmetric form (PSEK) of erythrokeratodermia, including a family previously described by Macfarlane et al. (1991) in which 1 sister had features of EKV and the other of PSEK. Richard et al. (2000) identified 3 heterozygous mutations in GJB3 in EKV patients: in a sporadic case, they detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexins. In another EKV family, all 3 affected individuals carried 2 distinct mutations on the same GJB3 allele; however, only the R42P mutation (603324.0008) cosegregated with the disease, whereas a 12-bp deletion predicted to eliminate 4 amino acid residues in the variable carboxy-terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. No mutations were detected in the 6 probands with PSEK. Richard et al. (2000) stated that overall, they had identified GJB3 mutations in 6 of 17 families with EKV; all of the mutations presumably affect the cytoplasmic amino-terminal and transmembrane domains of Cx31. In contrast, 2 mutations linked to progressive high-tone hearing impairment (DFNA2B; 612644) were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues.
In a brother and sister from an Israeli family segregating autosomal recessive EKV, Gottfried et al. (2002) identified homozygosity for a missense mutation in the GJB3 gene (L34P; 603342.0010). The unaffected parents were heterozygous for the mutation, which was not found in 208 control chromosomes. Gottfried et al. (2002) suggested that the missense mutation might not be able to exert a dominant-negative effect in heterozygous form, thus manifesting itself clinically only in the homozygote.
In a 4-year-old Dutch boy with the migratory form of EKVP, van Geel et al. (2002) identified a heterozygous R32W mutation in the GJB3 gene as well as a homozygous 4-bp deletion (154delGTCT) in the GJB4 gene. Analysis of unaffected family members revealed that both parents and the maternal grandfather were heterozygous for the GJB4 deletion, whereas the mother and maternal grandfather were heterozygous for the GJB3 variant; in addition, the patient's unaffected sister carried the identical GJB3/GJB4 genotype as the patient, thus excluding either DNA variation as causative for the disease. Van Geel et al. (2002) subsequently examined 84 unrelated controls and found 5 heterozygotes for the GJB4 deletion (allele frequency, 0.03) and 3 for the GJB3 variant (0.02), suggesting that both variations represent normal polymorphisms in the Dutch population. Van Geel et al. (2002) noted that the GJB3 variant had previously been detected in a family with palmoplantar keratoderma and hearing defects (see GJB2, 121011) by Kelsell et al. (2000), who suggested that it might be a polymorphism; analysis of R32W in Spanish patients and controls by Lopez-Bigas et al. (2001) confirmed that the variant is a common polymorphism in the Spanish population (allele frequency, 7.5%).
Di et al. (2002) observed that immunostaining of a skin biopsy taken from an EKV patient harboring the R42P mutation (603324.0008) revealed sparse epidermal staining of Cx31 with aberrant perinuclear localization. Transfection and microinjection studies in keratinocytes and fibroblast cell lines demonstrated that R42P and 4 other EKV-associated mutant Cx31 proteins displayed defective trafficking to the plasma membrane. The deafness/neuropathy-only 66delD (603324.0009) mutant protein had primarily a cytoplasmic localization, but some protein was visualized at the plasma membrane in a few transfected cells. Both 66delD- and R32W-Cx31/EGFP proteins had significantly impaired dye transfer rates compared to wildtype Cx31/EGFP protein. A high incidence of cell death was observed with the dominant skin disease Cx31 mutations, but not with wildtype, R32W, or 66delD Cx31 proteins.
Tattersall et al. (2009) reported that in vitro expression of connexin-31 mutants R42P (603324.0008), C86S (603324.0003), and G12D (603324.0002), but not wildtype or 66delD (603324.0009), cause elevated levels of cell type-specific cell death. Their observations did not support the hypothesis that Cx-associated cell death is related to abnormal 'leaky' calcium hemichannels. Tattersall et al. (2009) observed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not wildtype or 66delD. The authors concluded that the endoplasmic reticulum (ER) stress leading to the UPR may be the main mechanism of mutant Cx31-associated cell death, and that ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin.
Deafness, Autosomal Dominant 2B
In affected members of 2 Chinese families with autosomal dominant hearing loss (DFNA2B; 612644), Xia et al. (1998) identified heterozygous mutations in the GJB3 gene (603324.0004; 603324.0005). Gjb3 expression was identified in rat inner ear tissue by RT-PCR. It is well known that age-related hearing impairment is more prevalent in males than in females. It was noteworthy that, in the 2 families studied by Xia et al. (1998), female carriers were either subclinically affected or had undetectable hearing impairment. Noise exposure for male mutation carriers was not significantly different from their female sibs (as recalled by the family members).
In affected members of a 4-generation Spanish family with mild hearing impairment and peripheral neuropathy, Lopez-Bigas et al. (2001) identified a heterozygous 3-bp deletion in the GJB3 gene (603324.0009). In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory and sciatic nerves, similar to the expression pattern of Gjb1 (304040).
Associations Pending Confirmation
Following the demonstration that mutations in the GJB3 gene can cause autosomal dominant nonsyndromic sensorineural deafness, Liu et al. (2000) screened 25 Chinese families with recessive deafness to determine whether mutations at this locus can also cause recessive nonsyndromic deafness. Among the 25 families, 2 contained individuals who were compound heterozygous for GJB3 mutations. The 3 affected individuals in the 2 families were born to nonconsanguineous parents and had an early-onset bilateral sensorineural hearing loss. In both families, differing SSCP patterns were observed in affected and unaffected individuals. Sequence analysis in both families demonstrated an in-frame 3-bp deletion (423_425delATT; 603324.0006) on one allele, which led to the loss of an isoleucine residue at codon 141, and a 423A-G transition on the other allele, which created an ile141-to-val missense mutation (I142V; 603324.0007). Neither of these mutations was detected in DNA from 100 unrelated control subjects. Both the deletion of isoleucine-141 and its substitution by valine could alter the structure of the third conserved alpha-helical transmembrane domain (M3) and impair the function of the gap junction.
Schnichels et al. (2007) generated a conditional mouse model of EKV using the human F137L mutation in the Cx31 gene. Although homozygosity for the mutation was embryonic lethal, heterozygous mice were fertile and showed no obvious abnormalities. In vitro cellular functional expression studies showed that the heterozygous mutant channel had approximately 30% decreased neurobiotin transfer activity, probably due to a dominant-negative effect. Heterozygous mutant mice showed a decreased healing time of tail incision wounds by 1 day, similar to mice with decreased expression of Cx43 (121014) in the epidermis. These findings suggested again that the Cx31 and Cx43 proteins functionally interact. No erythema was detected in young mice before 2 weeks of age, and only about 5% of the skin area of mutant mice showed hyperproliferation of the stratum germinativum. In addition, heterozygous Cx31 mutant mice showed normal epidermal expression patterns and levels of other connexin proteins.
In a Swiss patient with erythrokeratodermia variabilis et progressiva (EKVP1; 133200) who had localized hyperkeratosis, Richard et al. (1998) detected a heterozygous 34G-C transversion in the GJB3 gene that resulted in a nonconservative change (G12R) from glycine (GGT) to a positively-charged arginine (CGT) in the site.
In a parent-offspring pair with a generalized, migratory form of erythrokeratodermia variabilis et progressiva (EKVP1; 133200), Richard et al. (1998) identified a 35G-A transition in the GJB3 gene, changing glycine-12 to aspartic acid (G12D).
In a 3-generation family with erythrokeratodermia variabilis et progressiva (EKVP1; 133200) who had localized hyperkeratosis and also in a sporadic case with generalized hyperkeratosis, Richard et al. (1998) identified a heterozygous 256T-A transversion in the GJB3 gene, which resulted in replacement of cysteine-86 with serine (C86S).
In a family (NDF006) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; 612644) from the Zhejiang province of China, Xia et al. (1998) found a heterozygous G-to-A transition at position 547 of the GJB3 gene, resulting in a glutamic acid-to-lysine change at codon 183. (The paper by Xia et al. (1998) identified the substitution as gln183 to lys, but a correction to the paper noted that the mutation was actually glu183 to lys.) The mutation was found in 4 individuals in 3 generations of the family. Two males were diagnosed with bilateral sensorineural deafness. Both had had progressive hearing difficulties and tinnitus since approximately 40 years of age. A female with the mutation, aged 27, had normal hearing with tinnitus and an audiogram showing a 20- to 25-dB decrease at frequencies of 2,000 to 8,000 Hz. Another female carrier, aged 3 years, had a normal acoustic impedance test and auditory evoked brainstem response.
In a family (NDF005) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; 612644) from the Hunan province of China, Xia et al. (1998) found that 4 individuals carried a heterozygous C-to-T mutation at nucleotide 538 of GJB3, resulting in a stop codon at amino acid 180. Two male carriers, aged 51 and 23, had hearing difficulties with clinical symptoms and audiograms showing high frequency hearing loss beginning after 30 and 20 years of age, respectively. One female carrier, aged 46, had an audiogram similar to that of the 27-year-old carrier in family NDF0006 (see 603324.0004). The other female carrier, aged 43, had normal hearing.
This variant, formerly designated DEAFNESS, AUTOSOMAL RECESSIVE, has been reclassified because its pathogenicity has not been confirmed.
In 2 Chinese families, Liu et al. (2000) found that individuals with autosomal recessive nonsyndromic hearing loss were compound heterozygous for 2 mutations in the GJB3 gene: a 3-bp deletion (423_425delATT) leading to an in-frame deletion of codon 141 (ile141del) on one allele, and a 423A-G transition leading to an ile141-to-val substitution (I141V; 603324.0007) on the other allele.
This variant, formerly designated DEAFNESS, AUTOSOMAL RECESSIVE, has been reclassified because its pathogenicity has not been confirmed.
For discussion of the ile141-to-val (I141V) mutation in the GJB3 gene that was found in compound heterozygous state in 2 families with autosomal recessive nonsyndromic hearing loss by Liu et al. (2000), see 603324.0006.
In a family with the migratory form of autosomal dominant erythrokeratodermia variabilis et progressiva (EKVP1; 133200), Wilgoss et al. (1999) found that affected members had an arg42-to-pro (R42P) mutation in the GJB3 gene.
Richard et al. (2000) found the same heterozygous mutation as the cause of EKV in another family.
In affected members of a 4-generation Spanish family with autosomal deafness with peripheral neuropathy (DFNA2B; 612644), Lopez-Bigas et al. (2001) reported a 3-bp deletion in the GJB3 gene, resulting in an asp deletion at codon 66. Nerve conduction studies revealed a markedly decreased amplitude with normal velocity, and sural nerve biopsy of 1 affected family member revealed a demyelination/remyelination appearance. In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory nerve, and in the sciatic nerve similar to the expression pattern of Gjb1 (connexin-32; 304040).
Gottfried et al. (2002) identified 3 Israeli sibs with an autosomal recessive migratory form of erythrokeratodermia variabilis et progressiva (EKVP1; 133200) who were homozygous for a 101T-C transition in GJB3. The mutation was predicted to result in a leu34-to-pro (L34P) substitution in the first transmembrane helix. In transfected keratinocytes, the mutant protein demonstrated a cytoplasmic distribution, suggesting that the mutant protein could not localize to gap junctions between adjacent cells.
In a Chinese patient with autosomal recessive profound hearing impairment (see 220290), Liu et al. (2009) found compound heterozygosity for a 497A-G transition in the GJB3 gene, resulting in an asn166-to-ser (N166S) substitution in the second extracellular loop, and a 1-bp deletion in the GJB2 gene (121011.0014). The findings were consistent with digenic inheritance. Each unaffected parent was heterozygous for 1 of the mutant alleles.
In a Chinese patient with autosomal recessive profound hearing impairment (see 220290), Liu et al. (2009) found compound heterozygosity for a 580G-A transition in the GJB3 gene, resulting in an ala194-to-thr (A194T) substitution in the fourth transmembrane domain, and a 1-bp deletion in the GJB2 gene (121011.0014). Another unrelated Chinese individual with hearing loss was compound heterozygous for A194T and another pathogenic mutation in the GJB2 gene. The findings were consistent with digenic inheritance. Each unaffected parent was heterozygous for one of the mutant alleles.
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