Alternative titles; symbolsCONNEXIN 30.2; CX30.2CONNEXIN 31.3; CX31.3CONNEXIN 29; CX29GAP JUNCTION PROTEIN, EPSILON-1, FORMERLY; GJE1, FORMERLYHGNC Approved Gene...
Alternative titles; symbols
HGNC Approved Gene Symbol: GJC3
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38): 7:99,923,265-99,929,619 (from NCBI)
Connexins, such as GJC3, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003).
▼ Cloning and Expression
Altevogt et al. (2002) cloned the mouse ortholog of GJC3, Cx29, and identified human GJC3, which they called CX31.3, by database analysis. The deduced mouse and human proteins contain 258 and 279 amino acids, respectively. They share 61% amino acid identity, and the human protein has a C-terminal extension relative to mouse Cx29. Northern blot analysis detected highest expression of Cx29 in mouse sciatic nerve, with lower levels in brain and spinal cord. Expression of Cx29 mRNA in the developing central nervous system paralleled that of other myelin-related mRNAs, including Cx32 (GJB1; 304040). Immunohistochemical analysis revealed Cx29 expression in internodal and juxtaparanodal regions of small myelin sheaths, whereas Cx32 was restricted to large myelinated fibers. In the peripheral nervous system, Cx29 expression preceded that of Cx32 and declined to levels below that of Cx32 in adulthood. In adult sciatic nerve, Cx29 primarily localized to the innermost aspects of the myelin sheath, the paranode, the juxtaparanode, and the inner mesaxon. Cx29 colocalized with Kv1.2 (KCNA2; 176262) in axonal membranes. Both Cx29 and Cx32 were detected in incisures.
By database analysis and PCR of human genomic DNA, Sohl et al. (2003) cloned GJC3, which they called CX30.2. Northern blot analysis detected a major 1.9-kb transcript that was expressed predominantly in skeletal muscle, liver, and heart and more weakly in kidney. A 1.6-kb transcript was weakly expressed in pancreas. No CX30.2 expression was detected in brain.
By RT-PCR and immunohistochemical analysis of mouse and rat tissues, Yang et al. (2005) found that Cx29 was expressed in cochlea neurons, spiral limbus, spiral ligament, organ of Corti, stria vascularis, and lateral wall. Higher Cx29 mRNA was detected in spiral ligament and spiral limbus than in whole cochlea or other parts of cochlea.
Using Western blot and immunohistochemical analyses, Tang et al. (2006) found that Cx29 was strongly and exclusively expressed in Schwann cells myelinating the auditory nerve in mouse cochlea.
By RT-PCR, Hong et al. (2010) cloned GJC3 from human glioma cells. The deduced 279-amino acid protein has 4 transmembrane domains, 1 cytoplasmic loop, 2 extracellular loops, and cytoplasmic N and C termini. Transfected HeLa cells expressed epitope-tagged GJC3 at the plasma membrane as small plaques at points of contact between adjacent cells.
▼ Gene Structure
Yang et al. (2005) stated that the GJC3 gene contains 2 exons.
Yang et al. (2005) stated that the GJC3 gene maps to chromosome 7q22.1.
▼ Gene Function
Altevogt et al. (2002) found that mouse Cx29 did not induce intercellular conductances when expressed alone in mouse neuroblastoma cells, but that it participated in formation of active channels when coexpressed with Cx32.
▼ Animal Model
Tang et al. (2006) stated that hearing sensitivity in mice is fully developed to the adult level by 3 weeks after birth. They found that Cx29 -/- mice were delayed in developing hearing sensitivity and that the phenotype showed about 50% penetrance. Ultrastructurally, Cx29 -/- mice exhibited elevated sensitivity to noise damage, with demyelination and vacuolization at the soma of spiral ganglion neurons. Cx29 -/- auditory nerve fibers appeared normal. Tang et al. (2006) concluded that CX29 has a unique role in myelination of spiral ganglion cell bodies.
Although GJC3 was formerly designated GJE1 and has been referred to as GJE1 in the literature (e.g., Yang et al., 2005), GJE1 now refers to a distinct gene that should not be confused with GJC3. The GJC3 gene is located on human chromosome 7q22.1 and is associated with the aliases CX31.3, CX30.2, and CX29. Sonntag et al. (2009) showed that GJE1, which is associated with the alias CX23, has been inactivated in all primate genomes and is therefore a pseudogene. Gje1 appears to be functional in mouse and zebrafish. In human, the GJE1 pseudogene is located on chromosome 6q24.1 and overlaps with the VTA1 gene (610902) (Scott, 2014).
▼ ALLELIC VARIANTS ( 1 Selected Example):
.0001 VARIANT OF UNKNOWN SIGNIFICANCE
This variant is classified as a variant of unknown significance because its contribution to nonsyndromic hearing loss has not been confirmed.
In 2 of 260 unrelated Taiwanese patients with nonsyndromic hearing loss, Yang et al. (2007) identified a heterozygous 807A-T transversion in the GJC3 gene, resulting in a glu269-to-asp (E269D) substitution in the C-terminal domain. The variant was not found in 120 controls. Yang et al. (2007) postulated that the variant may have contributed to hearing loss in these patients, but noted that it could represent a rare or uncommon polymorphism. The authors stated that the GJC3 variant per se may not result in hearing loss, but may interact with other genes to cause the phenotype.
Hong et al. (2010) noted that the E269D substitution occurs in a moderately conserved residue in the C-terminal cytoplasmic domain. In HeLa cells, the wildtype protein localized to the plasma membrane, whereas the variant E269D protein was retained in the endoplasmic reticulum, indicating a trafficking defect. The mutant E269D protein showed a dominant-negative effect when coexpressed with the wildtype protein, causing impaired gap junction formation. However, the accumulation of the E269D protein in the ER did not trigger apoptosis.