Gap Junctions and Connexins: The Molecular Genetics of Deafness


Mutations in the gene GJB2 encoding the gap‐junction protein connexin 26 (Cx26), in particular, and in GJB6 coding for connexin 30 (Cx30) are the most common cause of autosomal recessive sensorineural hearing loss in many world populations. Variants of GJB2 are also associated with dominant forms of both nonsyndromic and syndromic deafness. A complex picture of the roles of gap junctions in cochlear physiology has emerged. Rather than being mere conduits for the circulation of potassium ions in the inner ear, gap junctions have been implicated in the maintenance of metabolic homeostasis and in intercellular signalling among nonsensory cells. Studies of mutant channels and mouse models for connexin‐related deafness have provided valuable insights into the heterogeneous mechanisms by which connexin mutations may cause cochlear dysfunction. Despite recent advances it is still not fully understood what roles gap junctions play in the inner ear and how connexin mutations cause deafness.

Key Concepts:

  • GJB2 and GJB6 have been mapped to the DFNB1 locus, which accounts for up to 50% of all cases of autosomal recessive nonsyndromic hearing loss.

  • Molecular genetic tests for DFNB1 should include DNA sequencing of the GJB2 exons and mutation analysis for GJB6 deletions.

  • The identification of factors underlying the phenotypic variability of connexin‐related hearing loss may improve clinical diagnosis and genetic counselling.

  • A better understanding of the role of gap‐junctional communication in the inner ear and the structure–function relationships of connexin proteins is required for the development of mechanism‐based treatments of connexin‐associated hearing loss.

Keywords: gap junction; connexin; inner ear; cochlea; hearing loss; deafness

Figure 1.

Gap junctions, connexons and connexins. (a) Transmission electron micrograph of a gap junction in the mammalian cochlea. Gap junctions are identified as regions of close membrane apposition between neighbouring cells, separated by a ‘gap’ of approximately 2–4 nm. Scale bar=100 nm. (b) A freeze‐fracture replica of an inner‐ear gap junction showing the array of connexon particles within the plaque. Scale bar=50 nm. (c) Structure of a Cx26 hemichannel. Top and side views of the channel are shown. Cx26 subunits are individually coloured and the (IC), (TM) and (EC) regions are indicated. For a clear view of the channel pore, two connexin subunits in the foreground are omitted in the side view.

Figure 2.

Gap junction networks in the mammalian cochlea. The epithelial gap junction network (green) comprises interdental cells of the spiral limbus, supporting cells in the organ of Corti and root cells. The connective tissue network (red) is composed of various types of fibrocytes in the spiral limbus and spiral ligament, and basal cells and intermediate cells of the stria vascularis. Sensory hair cells and strial marginal cells are excluded from the gap junction networks. The scala media is filled with endolymph. The scala vestibuli, the scala tympani (fluid space below the organ of Corti) and the extracellular spaces within the organ of Corti and spiral ligament contain perilymph. The ionic composition of the endolymph and the endocochlear potential are generated and maintained by the stria vascularis.

Figure 3.

Deafness‐related GJB2 mutations. (a) Heterogeneous mechanisms of channel dysfunction caused by recessive GJB2 missense mutations. The location of amino acid substitutions within a Cx26‐hemichannel that result in nonfunctional or partially functional channels (green: M34, W44 and R75), impaired transfer of IP3 (red: V84, A88 and V95), ‘leaky’ hemichannels (orange: A40, G45 and D50) and impaired trafficking (blue: T55, D66 and W77) are shown. (b) Location of dominant GJB2 missense mutations associated with nonsyndromic (red) and syndromic (green) deafness. Intracellular (IC), transmembrane (TM) and extracellular (EC) regions are indicated. For a clear view of the pore, two subunits in the foreground are omitted.

Figure 4.

Genotype–phenotype variations of DFNB1 deafness. Audiograms of hearing impaired patients with different genotypes, whose hearing loss was significantly different from that of the reference group of 35delG homozygotes (shaded). The audiograms show the difference (in dB) between the patient's hearing threshold and normal hearing at each frequency. Median thresholds (solid line), and tenth and ninetieth percentiles (dashed lines) are displayed (n>10). Modified from Snoeckx et al. . Reproduced by permission of Elsevier.

Figure 5.

Gene map showing the location of GJB6 deletions in relation to GJB2, GJB6, CRYL1 on chromosome 13q11–12. Del(GJB6‐D13S1830), del(GJB6‐D13S1854) and del(ch13:19,837,344–19,968,698) directly affect GJB6 and CRYL1, and share a common 94.5 kb interval, which may harbour a regulatory element influencing the transcription of GJB2. The transcriptional start sites are indicated by right‐angled arrows, exons are indicated by vertical lines. Adapted from Wilch et al. .



Abrams CK, Freidin MM, Verselis VK et al. (2006) Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness. Proceedings of the National Academy of Sciences of the USA 103: 5213–5218.

Ahmad S, Shnaping C, Sun J et al. (2003) Connexins 26 and 30 are co‐assembled to form gap junctions in the cochlea of mice. Biochemical and Biophysical Research Communications 307: 362–368.

Ahmad S, Tang W, Chang Q et al. (2007) Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30‐linked deafness. Proceedings of the National Academy of Sciences of the USA 104: 1337–1341.

Anselmi F, Hernandez VH, Crispino G et al. (2008) ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. Proceedings of the National Academy of Sciences of the USA 105: 18770–18775.

Bakirtzis G, Choudhry R, Trond A et al. (2003) Targeted epidermal expression of mutant connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. Human Molecular Genetics 12: 1737–1744.

Beltramello M, Piazza V, Bukauskas F et al. (2005) Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nature Cell Biology 7: 63–69.

Bruzzone R, Veronesi V, Gomes D et al. (2003) Loss‐of‐function and residual channel activity of connexin26 mutations associated with non‐syndromic deafness. FEBS Letters 533: 79–88.

del Castillo FJ, Rodríguez‐Ballesteros M, Alvarez A et al. (2005) A novel deletion involving the connexin‐30 gene, del(GJB6‐d13s1854), found in trans with mutations in the GJB2 gene (connexin‐26) in subjects with DFNB1 non‐syndromic hearing impairment. Journal of Medical Genetics 42: 588–594.

del Castillo I, Villamar M, Moreno‐Pelayo MA et al. (2002) A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. New England Journal of Medicine 346: 243–249.

Chang Q, Tang W, Ahmad S et al. (2008) Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice. PLoS ONE 3: e4088.

Chen Y, Deng Y, Bao X et al. (2005) Mechanism of the defect in gap‐junctional communication by expression of a connexin 26 mutant associated with dominant deafness. FASEB Journal 19: 1516–1518.

Cohen‐Salmon M, Maxeiner S, Krüger O et al. (2004) Expression of the connexin43‐ and connexin45‐encoding genes in the developing and mature mouse inner ear. Cell and Tissue Research 316: 15–22.

Cohen‐Salmon M, Ott T, Michel V et al. (2002) Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Current Biology 12: 1106–1111.

Cohen‐Salmon M, Regnault B, Cayet N et al. (2007) Connexin30 deficiency causes instrastrial fluid‐blood barrier disruption within the cochlear stria vascularis. Proceedings of the National Academy of Sciences of the USA 104: 6229–6234.

Common JE, Becker D, Di W et al. (2002) Functional studies of human skin disease‐ and deafness‐associated connexin 30 mutations. Biochemical and Biophysical Research Communications 298: 651–656.

Common JE, Di W, Davies D et al. (2004) Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival. Journal of Medical Genetics 41: 573–575.

Cottrell G T and Burt J M (2005) Functional consequences of heterogeneous gap junction channel formation and its influence in health and disease. Biochimica et Biophysica Acta 1711: 126–141.

Cruciani V and Mikalsen SO (2006) The vertebrate connexin family. Cellular and Molecular Life Sciences 63: 1125–1140.

Denoyelle F, Lina‐Granade G, Plauchu H et al. (1998) Connexin 26 gene linked to a dominant deafness. Nature 393: 319–320.

Eiberger J, Kibschull M, Strenzke N et al. (2006) Expression pattern and functional characterization of connexin29 in transgenic mice. Glia 53: 601–611.

Forge A, Becker D, Casalotti S et al. (2003) Gap junctions in the inner ear: comparison of distribution patterns in different vertebrates and assessement of connexin composition in mammals. Journal of Comparative Neurology 467: 207–231.

Gale JE, Piazza V, Ciubotaru C et al. (2004) A mechanism for sensing noise damage in the inner ear. Current Biology 14: 526–529.

Goodenough DA and Paul DL (2003) Beyond the gap: functions of unpaired connexon channels. Nature Reviews. Molecular Cell Biology 4: 285–294.

Goodenough DA and Paul DL (2009) Gap junctions. Cold Spring Harbor Perspectives in Biology 1: a002576.

Grifa A, Wagner C, D'ambrosio L et al. (1999) Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nature Genetics 23: 16–18.

Harris AL (2007) Connexin channel permeability to cytoplasmic molecules. Progress in Biophysics and Molecular Biology 94: 120–143.

Hernandez VH, Bortolozzi M, Pertegato V et al. (2007) Unitary permeability of gap junction channels to second messengers measured by FRET microscopy. Nature Methods 4: 353–358.

Hibino H and Kurachi Y (2006) Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology (Bethesda) 21: 336–345.

Hilgert N, Huentelman MJ, Thorburn AQ et al. (2009) Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene. European Journal of Human Genetics 17: 517–524.

Inoshita A, Iizuka T, Okamura H et al. (2008) Postnatal development of the organ of Corti in dominant‐negative Gjb2 transgenic mice. Neuroscience 156: 1039–1047.

Jagger DJ and Forge A (2006) Compartmentalized and signal‐selective gap junctional coupling in the hearing cochlea. Journal of Neuroscience 26: 1260–1268.

Kelsell DP, Dunlop J, Stevens HP et al. (1997) Connexin 26 mutations in hereditary non‐syndromic sensorineural deafness. Nature 387: 80–83.

Kenneson A, Van Naarden Braun K and Boyle C (2002) GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genetics in Medicine 4: 258–274.

Kikuchi T, Adams JC, Miyabe Y et al. (2000) Potassium ion recycling pathway via gap junction systems in the mammalian cochlea and its interruption in hereditary nonsyndromic deafness. Medical Electron Microscopy 33: 51–56.

Kikuchi T, Kimura RS, Paul DL et al. (1995) Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anatomy and Embryology 191: 101–118.

Kudo T, Kure S, Ikeda K et al. (2003) Transgenic expression of a dominant‐negative connexin26 causes degeneration of the organ of Corti and non‐syndromic deafness. Human Molecular Genetics 12: 995–1004.

Laird DW (2006) Life cycle of connexins in health and disease. Biochemical Journal 394: 527–543.

Laird DW (2010) The gap junction proteome and its relationship to disease. Trends in Cell Biology 20: 92–101.

Lampe PD and Lau AF (2004) The effects of connexin phosphorylation on gap junctional communication. International Journal of Biochemistry & Cell Biology 36: 1171–1186.

Lee JR, Derosa AM and White TW (2009) Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes. Journal of Investigative Dermatology 129: 870–878.

Liu XZ, Xia XJ, Adams J et al. (2001) Mutations in GJA1 (connexin 43) are associated with non‐syndromic autosomal recessive deafness. Human Molecular Genetics 10: 2945–2951.

Liu XZ, Xia XJ, Xu LR et al. (2000) Mutations in connexin31 underlie recessive as well as dominant non‐syndromic hearing loss. Human Molecular Genetics 9: 63–67.

Liu XZ, Yuan Y, Yan D et al. (2009) Digenic inheritance of non‐syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. Human Genetics 125: 53–62.

Lopez‐Bigas N, Olive M, Rabionet R et al. (2001) Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Human Molecular Genetics 10: 947–952.

Maeda S, Nakagawa S, Suga M et al. (2009) Structure of the connexin 26 gap junction channel at 3.5 A resolution. Nature 458: 597–602.

Man YK, Trolove C, Tattersall D et al. (2007) A deafness‐associated mutant human connexin 26 improves the epithelial barrier in vitro. Journal of Membrane Biology 218: 29–37.

Manthey D, Banach K, Desplantez T et al. (2001) Intracellular domains of mouse connexin26 and ‐30 affect diffusional and electrical properties of gap junction channels. Journal of Membrane Biology 181: 137–148.

Marziano NK, Casalotti SO, Portelli AE et al. (2003) Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Human Molecular Genetics 12: 805–812.

Matos TD, Caria H, Simões‐Teixeira H et al. (2007) A novel hearing‐loss‐related mutation occurring in the GJB2 basal promoter. Journal of Medical Genetics 44: 721–725.

Mese G, Londin E, Mui R et al. (2004) Altered gating properties of functional Cx26 mutants associated with recessive non‐syndromic hearing loss. Human Genetics 115: 191–199.

Ortolano S, Di Pasquale G, Crispino G et al. (2008) Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear. Proceedings of the National Academy of Sciences of the USA 105: 18776–18781.

Oyamada M, Oyamada Y and Takamatsu T (2005) Regulation of connexin expression. Biochimica et Biophysica Acta 1719: 6–23.

Palmada M, Schmalisch K, Böhmer C et al. (2006) Loss of function mutations of the GJB2 gene detected in patients with DFNB1‐associated hearing impairment. Neurobiology of Disease 22: 112–118.

Peracchia C (2004) Chemical gating of gap junction channels; roles of calcium, pH and calmodulin. Biochimica et Biophysica Acta 1662: 61–80.

Plum A, Winterhager E, Pesch J et al. (2001) Connexin31‐deficiency in mice causes transient placental dysmorphogenesis but does not impair hearing and skin differentiation. Developmental Biology 231: 334–347.

Primignani P, Castorina P, Sironi F et al. (2003) A novel dominant missense mutation – D179N – in the GJB2 gene (connexin 26) associated with non‐syndromic hearing loss. Clinical Genetics 63: 516–521.

Rodriguez‐Paris J and Schrijver I (2009) The digenic hypothesis unraveled: the GJB6 del(GJB6‐D13S1830) mutation causes allele‐specific loss of GJB2 expression in cis. Biochemical and Biophysical Research Communications 389: 354–359.

Rouan F, White TW, Brown N et al. (2001) Trans‐dominant inhibition of connexin‐43 by mutant connexin‐26: implications for dominant connexin disorders affecting epidermal differentiation. Journal of Cell Science 114: 2105–2113.

Shahin H, Walsh T, Sobe T et al. (2002) Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Human Genetics 110: 284–289.

Snoeckx RL, Huygen PLM, Feldmann D et al. (2005) GJB2 mutations and degree of hearing loss: a multicenter study. American Journal of Human Genetics 77: 945–957.

Stong BC, Chang Q, Ahmad S et al. (2006) A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels. Laryngoscope 116: 2205–2210.

Sun J, Ahmad S, Chen S et al. (2005) Cochlear gap junctions coassembled from Cx26 and 30 show faster intercellular Ca2+ signaling than homomeric counterparts. American Journal of Physiology. Cell Physiology 288: C613–C623.

Sun Y, Tang W, Chang Q et al. (2009) Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea. Journal of Comparative Neurology 516: 569–579.

Tang W, Zhang Y, Chang Q et al. (2006) Connexin29 is highly expressed in cochlear Schwann cells, and it is required for the normal development and function of the auditory nerve of mice. Journal of Neuroscience 26: 1991–1999.

Teubner B, Michel V, Pesch J et al. (2003) Connexin30 (Gjb6)‐deficiency causes severe hearing impairment and lack of endocochlear potential. Human Molecular Genetics 12: 13–21.

Thomas T, Telford D and Laird DW (2004) Functional domain mapping and selective trans‐dominant effects exhibited by Cx26 disease‐causing mutations. Journal of Biological Chemistry 279: 19157–19168.

Unsworth HC, Aasen T, McElwaine S et al. (2007) Tissue‐specific effects of wild‐type and mutant connexin 31: a role in neurite outgrowth. Human Molecular Genetics 16: 165–172.

Uyguner O, Emiroglu M, Uzumcu A et al. (2003) Frequencies of gap‐ and tight‐junction mutations in Turkish families with autosomal‐recessive non‐syndromic hearing loss. Clinical Genetics 64: 65–69.

Van Laer L, Coucke P, Mueller RF et al. (2001) A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment. Journal of Medical Genetics 38: 515–518.

Wang Y, Chang Q, Tang W et al. (2009) Targeted connexin26 ablation arrests postnatal development of the organ of Corti. Biochemical and Biophysical Research Communications 385: 33–37.

Wilch E, Azaiez H, Fisher RA et al. (2010) A novel DFNB1 deletion allele supports the existence of a distant cis‐regulatory region that controls GJB2 and GJB6 expression. Clinical Genetics (DOI: 10.1111/j.1399‐0004.2010.01387.x).

Xia AP, Ikeda K, Katori Y et al. (2000) Expression of connexin 31 in the developing mouse cochlea. Neuroreport 11: 2449–2453.

Xia AP, Kikuchi T, Minowa O et al. (2002) Late‐onset hearing loss in a mouse model of DFN3 non‐syndromic deafness: morphologic and immunohistochemical analyses. Hearing Research 166: 150–158.

Xia JH, Liu CY, Tang BS et al. (1998) Mutations in the gene encoding gap junction protein beta‐3 associated with autosomal dominant hearing impairment. Nature Genetics 20: 370–373.

Yang JJ, Huang SH, Chou KH et al. (2007) Identification of mutations in members of the connexin gene family as a cause of nonsyndromic deafness in Taiwan. Audiology & Neuro‐Otology 12: 198–208.

Yum SW, Zhang J and Scherer SS (2010) Human connexin26 and connexin30 form functional heteromeric and heterotypic channels. American Journal of Physiology. Cell Physiology 293: C1032–1048.

Yum SW, Zhang J, Valiunas V et al. (2007) Dominant connexin26 mutants associated with human hearing loss have trans‐dominant effects on connexin30. Neurobiology of Disease 38: 226–236.

Zhang Y, Tang W, Ahmad S et al. (2005) Gap junction‐mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions. Proceedings of the National Academy of Sciences of the USA 102: 15201–15206.

Zhao HB and Santos‐Sacchi J (2000) Voltage gating of gap junctions in cochlear supporting cells: evidence for nonhomotypic channels. Journal of Membrane Biology 175: 17–24.

Zhao HB, Yu N and Fleming C (2005) Gap junctional hemichannel‐mediated ATP release and hearing controls in the inner ear. Proceedings of the National Academy of Sciences of the USA 102: 18724–18729.

Zoidl G and Dermietzel R (2010) Gap junctions in inherited human disease. Pflugers Archiv 460: 451–466.

Further Reading

Hoang Dinh E, Ahmad S, Chang Q et al. (2009) Diverse deafness mechanisms of connexin mutations revealed by studies using in vitro approaches and mouse models. Brain Research 1277: 52–69.

Martínez AD, Acuña R, Figueroa V et al. (2009) Gap‐junction channels dysfunction in deafness and hearing loss. Antioxidants & Redox Signaling 11: 309–322.

Nickel R, Forge A and Jagger D (2008) Connexins in the inner ear. In: Harris LA and Locke D (eds) Connexins – A Guide, pp. 419–434. New York: Humana Press.

Smith RJH and Van Camp G (Updated July 2008). Nonsyndromic hearing loss and deafness, DFNB1. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Seattle: Copyright, University of Washington. 1997–2010. Available at

Smith RJH, Sheffield AM and Van Camp G (Updated April 2009). Nonsyndromic hearing loss and deafness, DFNA3. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Seattle: Copyright, University of Washington. 1997–2010. Available at

Wangemann P (2006) Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential. Journal of Physiology 576: 11–21.

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Nickel, Regina, and Forge, Andrew(Oct 2010) Gap Junctions and Connexins: The Molecular Genetics of Deafness. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021441]