Gap Junctions and Connexins: The Molecular Genetics of Deafness

Abstract

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 intercellular (IC), transmembrane (TM) and extracellular (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..

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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 http://www.genetests.org

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 http://www.genetests.org

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. http://www.els.net [doi: 10.1002/9780470015902.a0021441]