Alternative titles; symbols
HGNC Approved Gene Symbol: GJB1
SNOMEDCT: 111499002, 763455008; ICD10CM: G60.0;
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:71,215,239-71,225,516 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Charcot-Marie-Tooth neuropathy, X-linked dominant, 1 | 302800 | X-linked dominant | 3 |
Connexins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells (Bergoffen et al., 1993).
Kumar and Gilula (1986) isolated the human CX32 gene from a human liver cDNA library. By Northern blot analysis, Bergoffen et al. (1993) showed CX32 expression in liver and peripheral nerve.
Sohl et al. (2003) stated that mouse and human CX32 share 99% amino acid identity and differ at only 4 residues. They also share significant similarity in the 5-prime UTR and promoter region. Northern blot analysis detected a 1.6-kb CX32 transcript in both mouse and human. In both species, expression was highest in liver and moderate in pancreas, kidney, and brain. No expression was detected in skeletal muscle, lung, and heart.
Willecke et al. (1990) used a rat cDNA probe in Southern analysis of a panel of human-mouse somatic cell hybrids to map CX32 to Xp11-q13. Through analysis of somatic cell hybrids by PCR and hybridization, Fishman et al. (1991) assigned the GJA1 gene (121014) to chromosome 6 and the GJB1 gene to Xp11-q22. Structural comparisons of these genes indicated that they probably arose from a common progenitor gene. Because of a critical function, the connexins may have evolved early and have remained relatively conserved despite their disparate locations.
Using a series of somatic cell hybrid mapping panels and a rat GJB1 probe, Corcos et al. (1992) mapped the CX32 gene to proximal Xq13.1, in interval 8, as described by Lafreniere et al. (1991). By somatic cell hybrids, Hsieh et al. (1991) mapped GJB1 to Xcen-q22 and mapped the corresponding gene to the X chromosome in the mouse. Raimondi et al. (1992) refined the assignment to Xq13 by in situ hybridization.
Bergoffen et al. (1993) found CX32 expression in myelinated peripheral nerve at the nodes of Ranvier and Schmidt-Lanterman incisures. CX32 may form intracellular gap junctions that connect to the folds of Schwann cell cytoplasm, allowing the transfer of nutrients, ions, and molecules to the innermost myelin layers.
Scherer et al. (1995) demonstrated that CX32 is normally found in the paranodal myelin loops and Schmidt-Lanterman incisures of myelinating Schwann cells in the peripheral nervous system, as well as in oligodendrocytes and their processes, but not in compact myelin of the central nervous system.
Kumar and Gilula (1996) gave a general review of the gap junction communication channel. Beta-1 connexin is widely expressed in many tissues, including liver.
Bondurand et al. (2001) showed that the transcription modulator SOX10 (602229), in synergy with EGR2 (129010), strongly activates CX32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects failed to transactivate the CX32 promoter.
By direct sequencing, Bergoffen et al. (1993) identified 7 different mutations in the CX32 gene (see, e.g., 304040.0001-304040.0003) in affected persons from 8 families with X-linked dominant Charcot-Marie-Tooth disease (CMTX1; 302800).
Bone et al. (1995) described sequence analysis from 19 unrelated patients with X-linked Charcot-Marie-Tooth disease, detecting 6 novel mutations and 3 previously reported mutations (see, e.g., 304040.0003-304040.0011). Analysis of the distribution of these mutations as well as those previously reported suggested to the authors that virtually all regions of connexin 32 are important in its function.
Ionasescu et al. (1996) studied 27 families with X-linked Charcot-Marie-Tooth neuropathy. Mutations in the coding region of the CX32 gene were found in 22 families. These mutations included 4 nonsense mutations, 8 missense mutations, 2 medium-sized deletions, and 1 insertion. Most missense mutations showed a mild clinical phenotype (5 of 8), whereas all nonsense mutations, the larger of the 2 deletions, and the insertion that produced frameshifts showed severe phenotypes. No point mutations in the CX32 gene coding region were found in 5 CMTX1 families with mild clinical phenotype. In 3 of these families, positive genetic linkage with the markers of the Xq13.1 region were found; the genetic linkage of the remaining 2 families could not be evaluated because of their small size.
Omori et al. (1996) studied 4 known mutations in the connexin-32 gene: lys60 to phe, a mutation in a highly conserved cysteine residue; val139 to met (304040.0003), located in the transmembrane region; arg215 to trp, located in the cytoplasmic tail; and ala220 to ter (304040.0005), also located in the cytoplasmic tail. Since HeLa cells do not show detectable levels of gap junction intercellular communication (GJIC) or expression of any connexins, they tested the functional effects of transfecting mutant genes in HeLa cultures. The first 3 mutations were unable to restore GJIC in transfected HeLa cells (although their gene products were detectable), in contrast to normal GJIC detected with the last mutation. In addition, the dominant-negative effect was tested in doubly transfected HeLa cells and the investigators found that low expression of the mutant CX32 gene had a relatively significant effect on diminishing GJIC. Omori et al. (1996) therefore concluded that certain mutants form nonfunctional chimeric connexins with wildtype connexins.
Nelis et al. (1997) described 5 new mutations in the CX32 gene. Janssen et al. (1997) performed SSCP analysis of the CX32 gene in 121 patients selected from the larger group of 443 patients on the basis of linkage to Xq13.1, absence of the 17p12 duplication or deletion, and absence of point mutations in PMP22 and P0. They found 5 new mutations and 3 mutations previously described in other unrelated families.
In 35 unrelated CMTX patients without the 17p11.2 duplication but with median nerve conduction between 30 and 40 m/s, Rouger et al. (1997) screened for a CX32 mutation. A total of 14 mutations were found, 5 of which had not previously been reported. All but 1 of the mutations were detected by SSCP. Mutations causing CMTX have been found mostly in exon 2 of the gene.
Latour et al. (1997) identified a total of 19 separate mutations in the CX32 gene as the cause of CMTX in 21 French families.
Ainsworth et al. (1998) reported a family in which affected members with CMTX had complete deletion of the GJB1 gene with complete absence of the Cx32 gene product. The clinical phenotype in the affected individuals in this kindred did not appear to differ greatly from the phenotype observed in other individuals with missense, nonsense, or frameshift mutations in the gene. This would appear to make a dominant-negative effect of the mutation unlikely.
Ikegami et al. (1998) stated that more than 130 different mutations of the GJB1 gene, including coding and noncoding regions, had been reported in patients with X-linked CMT. In studies of 49 Japanese families with CMT1 they found 5 mutations of the GJB1 gene; 4 of which had not previously been reported.
Nelis et al. (1999) identified 163 distinct mutations in the coding region of the CX32 gene in 268 unrelated patients with hereditary peripheral neuropathy. Of these mutations, 125 were missense mutations, 1 a double missense mutation, 1 a missense mutation combined with a 1-amino acid deletion, 12 nonsense mutations, 17 frameshift mutations, and 6 in-frame deletions and insertions. Further, in 1 case a complex rearrangement in the coding region of CX32 was found. Most missense mutations showed a mild clinical phenotype, whereas all nonsense mutations and frameshift deletion/insertions showed severe phenotypes. Forty-four percent of the codons were mutated in more than 1 patient. At codon 22, 4 distinct mutations were identified in 20 unrelated patients. In 2 X-linked families not showing mutations in the coding region of CX32, mutations in the noncoding region were identified by Ionasescu et al. (1996). In addition to the 163 mutations tabulated for the CX32 gene in patients with hereditary peripheral neuropathy, Nelis et al. (1999) identified 58 mutations in the MPZ gene (159440) and 27 mutations in the PMP22 gene (601097).
GJB1 is expressed in both the peripheral and the central nervous system. In consequence, it is not surprising that patients with CMTX1 and specific GJB1 mutations have both peripheral neuropathy and a mild or transient brain disorder (Paulson et al., 2002; Hanemann et al., 2003; Takashima et al., 2003).
Kleopa et al. (2006) reported 2 novel mutations in the GJB1 gene that segregated with CMTX1 in 2 unrelated families. In vitro expression studies and immunohistochemistry showed that the mutant proteins were retained within the Golgi apparatus and failed to reach the cell membrane where gap junctions are normally formed.
Casasnovas et al. (2006) identified 34 GJB1 mutations, including 6 novel mutations, in 59 patients from 34 CMT families of Spanish or Portuguese descent. The extracellular loop domains were affected in 64.6% of mutations.
In 28 (5.3%) of 527 unrelated Korean families with CMT, Kim et al. (2012) identified 23 different mutations in the GJB1 gene (see, e.g., 304040.0005 and 304040.0011). Nine of the mutations were novel. Mutations affected the extracellular 2 (EC2) domain of the protein in 44% of families.
In affected members of a large Australian family with an unusual form of X-linked CMT, originally reported by Spira et al. (1979), Caramins et al. (2013) identified a missense mutation in the GJB1 gene (304040.0022).
The chemokine monocyte chemoattractant protein-1 (MCP1; 158105) had been shown to be a mediator of macrophage-related neural damage in models of 2 distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A (118220) and 1B (118200). In mice deficient in connexin-32 (Cx32def), Groh et al. (2010) investigated the role of the chemokine in macrophage immigration and neural damage by crossbreeding the Cx32def mice with MCP1 knockout mutants. In Cx32def mutants typically expressing increased levels of MCP1, macrophage numbers were strongly elevated, caused by an MCP1-mediated influx of hematogenous macrophages. In contrast, heterozygous deletion of MCP1 led to reduced numbers of phagocytosing macrophages and an alleviation of demyelination. Whereas alleviated demyelination was transient, axonal damage was persistently improved and even robust axonal sprouting was detectable at 12 months. Other axon-related features were alleviated electrophysiologic parameters, reduced muscle denervation and atrophy, and increased muscle strength. Similar to models for CMT1A and CMT1B, MEK-ERK (see 176872; see 601795) signaling mediated MCP1 expression in Cx32-deficient Schwann cells. Blocking this pathway by the inhibitor CI-1040 caused reduced MCP1 expression, attenuation of macrophage increase, and amelioration of myelin- and axon-related alterations. Groh et al. (2010) concluded that attenuation of MCP1 upregulation by inhibiting ERK phosphorylation could be a promising approach to treat CMT1X and other inherited peripheral neuropathies.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bergoffen et al. (1993) found a C-to-T transition in codon 142 of the CX32 gene, resulting in substitution of tryptophan for arginine.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bergoffen et al. (1993) found a G-to-A transition in codon 172 of the CX32 gene, resulting in substitution of serine for proline.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bergoffen et al. (1993) found a G-to-A transition in codon 139 of the CX32 gene, resulting in a substitution of valine for methionine. The identical mutation was found in an unrelated patient by Bone et al. (1995).
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a T-to-C transition in codon 133 of the CX32 gene, resulting in a substitution of arginine for tryptophan.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Fairweather et al. (1994) found a C-to-T transition in codon 220 of the CX32 gene, resulting in a stop signal in place of an arginine (R220X). The same mutation was found in an unrelated Virginia family by Bone et al. (1995).
In a Korean patient with CMTX1, Kim et al. (2012) identified a c.658C-T transition in the GJB1 gene, resulting in an R220X substitution in the C-terminal domain. The patient had a demyelinating neuropathy.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a T-to-A transversion in codon 30 of the CX32 gene, resulting in the substitution of asparagine for isoleucine.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a T-to-G transversion in codon 156 of the CX32 gene, resulting in the substitution of arginine for leucine.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found an A-to-G transition in codon 65 of the CX32 gene, resulting in a substitution of cysteine for tyrosine.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a G-to-T transversion in codon 13 of the CX32 gene, resulting in a substitution of leucine for valine.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a deletion of thymidine residue in codon 137 of CX32, resulting in a frameshift mutation which predicted a truncated 194-amino acid protein with the last 58 amino acids starting at codon 137 altered from wildtype.
In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a G-to-A transition in codon 95 of the CX32 gene, resulting in the substitution of methionine for valine (V95M).
Montenegro et al. (2011) reported the use of exome sequencing to identify the V95M mutation in affected members of a large family with Charcot-Marie-Tooth disease and a questionable inheritance pattern. Affected individuals had classic features of the disease, with onset between ages 14 and 40 years of distal sensory impairment and muscle weakness and atrophy affecting the upper and lower limbs. Nerve conduction velocities were in the intermediate range.
In a Korean family with CMTX1, Kim et al. (2012) identified a c.283G-A transition in the GJB1 gene, resulting in a V95M substitution at a highly conserved residue in the TM2 domain. The patients had a demyelinating neuropathy.
Since CX32 is expressed not only in Schwann cells in the peripheral nervous system but also in oligodendrocytes in the central nervous system, Bahr et al. (1999) examined a CMTX1 (302800) family for evidence of CNS involvement. The family had an asn205-to-ser mutation involving the fourth transmembrane domain of CX32. The patients showed typical clinical and electrophysiologic abnormalities in the peripheral nervous system, but, in addition, visual, acoustic, and motor pathways of the CNS were affected subclinically. This was indicated by pathologic changes in visual evoked potentials, brainstem auditory evoked potentials, and central motor evoked potentials. They suggested that abnormal electrophysiologic findings in CNS pathway examinations should raise the suspicion of CMTX and a search for mutations in the GJB1 gene.
In a 71-year-old woman with X-linked Charcot-Marie-Tooth disease (302800), Tabaraud et al. (1999) identified a truncating mutation, GAG to TAG at nucleotide 367, in the GJB1 gene. The mutation led to termination by a glutamic acid in codon position 102 instead of codon 283 for the normal protein.
Janssen et al. (1997) identified a C-to-G transversion in the GJB1 gene, resulting in a ser85-to-cys (S85C) substitution, associated with X-linked Charcot-Marie-Tooth disease (302800).
Abrams et al. (2002) showed that expression of the S85C mutation resulted in large, relatively nonselective, voltage-dependent currents not seen in oocytes expressing wildtype Cx32. The findings suggested that the S85C mutant has a much greater propensity to form conducting hemichannels than does wildtype Cx32. The authors suggested that the resulting increase in membrane permeability may prevent normal functioning of the Schwann cells and peripheral nerves of patients harboring this mutation.
Ionasescu et al. (1996) described a family with X-linked CMT (302800) that harbored a T-to-G transversion at position -528 with respect to the ATG start codon. Bondurand et al. (2001) used gelshift experiments to show that the mutation impaired the binding of SOX10 (602229) to the CX32 promoter region.
In 2 sibs with X-linked Charcot-Marie-Tooth disease (302800), Panas et al. (2001) identified a C-to-T transition at position 164 in exon 2 of the GJB1 gene, resulting in a thr55-to-ile (T55I) substitution. In addition to extremity weakness and atrophy and polyneuropathy, the patients had episodes of severe weakness lasting from hours to days, dysarthria, dysphagia, and bilateral hyperintensities of the periventricular white matter on MRI. Panas et al. (2001) noted that connexin-32 is expressed in Schwann cells, oligodendrocytes, and some neuronal populations, which may explain the CNS involvement.
In a patient with X-linked Charcot-Marie-Tooth disease (302800), Kawakami et al. (2002) identified a 21-bp duplication from residues 55 to 61 in exon 2 of the GJB1 gene, resulting in a 7-amino acid insertion in the first extracellular loop of the protein. The patient showed clinical cerebellar abnormalities with a normal MRI and prolonged central somatosensory conduction times. His clinically asymptomatic mother carried the mutation. The authors referred to the report by Panas et al. (2001) (see 304040.0016), and suggested that mutation in this area of the GJB1 gene, specifically residue 55, may lead to CNS manifestations.
Hanemann et al. (2003) reported a family in which 3 members were affected with X-linked Charcot-Marie-Tooth disease (302800). Direct sequencing of the GJB1 gene in 2 living patients identified a 3-bp deletion (304delGAG), resulting in deletion of a glutamic acid at codon 102 (glu102). In addition to classic CMT clinical findings, all 3 patients had transient CNS symptoms correlating with transient and reversible white matter lesions on MRI. CNS symptoms included paraparesis, monoparesis, tetraparesis, dysarthria, aphasia, and cranial nerve palsies.
In affected members of a large family with X-linked CMT (302800), Houlden et al. (2004) identified a -526G-C transversion in a highly conserved region of the nerve-specific P2 promoter of the GJB1 gene. The mutation occurs within a SOX10 (602229) S2 binding site, similar to the -528T-G mutation (304040.0015). Functional expression studies showed that the -526G-C mutation impaired SOX10 binding, resulting in a 65% decrease in transcriptional activation.
In a girl with a severe early-onset form of X-linked CMT (302800), Liang et al. (2005) identified a 766T-G transversion in the GJB1 gene, resulting in a phe235-to-cys (F235C) substitution in the carboxy tail domain of the protein. The mutation was not identified in 50 control chromosomes. The patient's asymptomatic mother also carried the mutation, but Southern blot analysis showed preferential inactivation of the mutant X-chromosome by a ratio of approximately 9 to 1. Functional expression studies demonstrated that cells with the F235C mutant protein had normal plasma membrane expression of the channel protein, but showed a reduction of the resting membrane potential of more than 40 mV, with a decrease in the threshold of activation. Cells expressing the mutant protein also showed decreased viability compared to wildtype. Liang et al. (2005) concluded that the propensity of the F235C hemichannels to be open at resting membrane potential ('leaky channel') adversely affected cell viability, thus resulting in a severe phenotype. Similar in vitro findings had been reported for another GJB1 mutation (S85C; 304040.0014).
In Korean patients with X-linked CMT (302800), Choi et al. (2004) identified a 407T-C transition in the GJB1 gene, resulting in a val136-to-ala (V136A) substitution. (In the original publication, Choi et al. (2004) erroneously designated the nucleotide change as 408T-C.)
In a Korean girl with Dejerine-Sottas syndrome (145900), Chung et al. (2005) identified 2 mutations in 2 different genes: the V136A substitution in the GJB1 gene and an R359W mutation in the EGR2 gene (129010.0004). She inherited the EGR2 mutation from her father, who had Charcot-Marie-Tooth disease-1D (607678). The GJB1 gene was de novo. The father had pes cavus and developed difficulty walking at age 8 years, but had a milder phenotype than the daughter, who had experienced gait difficulties since infancy and facial weakness. She also had bilateral hand muscle weakness and atrophy and had sensory impairment of both upper and lower extremities. Chung et al. (2005) concluded that the more severe phenotype in the daughter was caused by an additive effect of the 2 mutations.
In affected members of a large Australian family with an unusual form of X-linked CMT (302800), originally reported by Spira et al. (1979), Caramins et al. (2013) identified a c.172C-T transition in exon 2 of the GJB1 gene, resulting in a pro58-to-ser (P58S) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP or Exome Variant Server databases or in a local exome database, and was filtered for less than 1% in the 1000 Genomes Project database. In vitro functional expression studies in HeLa cells showed that the mutant P58S protein was localized broadly in the cytoplasm with only occasional gap junction plaque localization. The mutation reduced the number and size of gap junction plaques compared to wildtype, although conductance of the gap junctions was basically unaffected. The P58S mutant hemichannel tended to close more than wildtype at negative voltages. The phenotype of this pedigree was unique in that affected individuals had spinocerebellar ataxia and spasticity in addition to peripheral nervous system abnormalities.
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