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Hearing impairment may be inherited, caused by maternal rubella or complications at birth, certain infectious diseases such as meningitis, use of ototoxic drugs, exposure to excessive noise and ageing. Around half of all deafness and hearing impairment can be prevented if common causes were dealt with at primary health care level. Personal Injury firm Mercury Legal Solicitors are supporting the event, which runs from 6th-12th May and are focusing specifically on noise-induced hearing loss, offering specialist legal advice to those suffering hearing loss caused by inadequate hearing protection in their past or present work environment.
The firm have launched a specialist website designed to provide targeted information on noise-induced hearing loss and give details of the legal options available. Figures show that tinnitus is a common condition, with 1 in 10 people having some awareness of it and 1 in 200 people severely affected by it. Gavin Moat, Senior Partner at Mercury Legal said of the website launch: “We wanted to create a website dedicated to sufferers of noise-induced hearing loss to provide the most targeted service we can to those affected by the condition. Reach out to the author: contact and available social following information is listed in the top-right of all news releases. We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Mutation of the GJB2 gene, which encodes the connexin 26 (Cx26) gap junction (GJ) protein, is the most common cause of hereditary, sensorineural hearing loss. It has been over 15 years since the GJB2 gene encoding the Cx26 gap junction (GJ) protein was identified as a susceptibility gene for sensorineural deafness (Kelsell et al., 1997).
To date, mutations at 18 positions in Cx26 have been identified in association with syndromic deafness (Figure 1). Cx channels are unique in that they can adopt two very different structural configurations, as intercellular GJ channels formed by the docking of two hemichannels (HCs), one contributed by each of two apposed cells, and as undocked HCs operating in the plasma membrane (Figures 1A,B). Of the three fluid filled compartments in the cochlea, the scala media consisting of endolymph plays a special role in the transduction of electrical signals by sensory hair cells.
Although Cx30 is co-localized with Cx26 and deletion of Cx30 produces deafness in mice, it is now apparent that the loss of Cx30 itself is not the cause of deafness. ATP and IP3 release from cochlear support cells was attributed to Cx HCs after ruling out other pathways such as P2X receptors, pannexin channels and anion channels through the use of blockers, although blocker specificity is lacking. The Cx subunits that constitute a HC have four transmembrane domains (TM1–TM4), with N-terminal (NT) and carboxy-terminal (CT) domains located on the cytoplasmic side (Figure 1C).
Cx HCs have large aqueous pores, which not only permits inorganic cations and anions to pass, but also larger molecules such as metabolites, second messengers and other active biomolecules. Undocked Cx HCs are closed at negative potentials by the loop-gating mechanism and opening is promoted by membrane depolarization. A potentially significant impact of the G45E mutation was uncovered by Sánchez et al. MSHA has developed a series of presentations that can be used by the mining community as a training resource in the area of noise and hearing loss prevention.
They have also produced an infographic with all the facts and figures on tinnitus along with advice on what to do if you think you may have a claim against your current or previous employer. The condition is most often caused by damage that occurs inside the inner ear and, although other causes do exist, in the majority of cases tinnitus can be traced back to a time spent working in a noisy work environment, with little or no ear protection. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Cx26 is not expressed in hair cells, but is widely expressed throughout the non-sensory epithelial cells of the cochlea. In the original study, Cx26 mutations were shown to result in premature stop codons in several autosomal recessive non-syndromic deafness pedigrees.
These two channel configurations perform very different functions, with GJs providing direct signaling between cells and HCs providing signaling across the plasma membrane. Illustrations depicting the cellular organization of the mammalian cochlea and the putative roles of Cx channels. Dye uptake studies using multiple fluorescent probes reported increased uptake only in cochlear support cells that was ascribed to functional HCs (Zhao, 2005). In fact, exchange of the NT halves (NT through CL) of Cx46 and Cx50 was shown to result in HCs in which the gating and unitary conductance properties remarkably correspond to the WT Cx constituting the N-terminal half of the protein (Kronengold et al., 2012).
In addition to ATP, signaling molecules reported to permeate through HCs include glutamate, IP3 and Ca2+ (reviewed by Evans et al., 2006). However, the degree to which inhibition by Ca2+ is impaired does not correlate with the severity of the disease phenotype. Most GJB2 mutations produce non-syndromic deafness, but a subset produces syndromic deafness in which profound hearing loss is accompanied by a diverse array of infectious and neoplastic cutaneous disorders that can be fatal.

Given that loss of GJ function does not lead to skin disorders and that some syndromic deafness mutants function as GJs whereas others do not, the disease mechanisms in non-syndromic and syndromic cases likely differ.
The cells of the stria vascularis, via a series of transporters and K+ channels, produce movement of K+ back into the endolymph and the generation of the EP (Adachi et al., 2013), which is an important driving force for the influx of K+ that depolarizes hair cells during mechano-transduction. When Cx26 expression was increased in Cx30 null mice by introducing a bacterial artificial chromosome containing additional copies of the Cx26 gene, hearing was rescued (Ahmad et al., 2007). The presence of HC activity in support cells of the cochlea has been inferred from dye uptake, but has not been confirmed electrophysiologically.
An interesting feature that emerges from the mapping of the syndromic deafness mutations onto topology of a Cx subunit is that they largely cluster in the NT and E1 domains (Figure 1C). The co-segregation of biophysical properties with the NT half extends to Ca2+- and K+-dependent regulatory mechanisms in Cx46 and Cx50 HCs (Srinivas et al., 2006). Thus, as we discuss in the following sections, other aberrant HC properties, other than simply increased activity due to impaired inhibition by Ca2+, are emerging as potential contributors to disease pathogenesis.
Furthermore, cysteine substitutions at these positions and subsequent application of thiol-modifying, methane-thiosulfonate reagents from either side of the membrane confirmed that G45 and D50, but not A40, are exposed to the aqueous pore in the open state of the Cx26 HC. Although GJ channels, which are assembled by the docking of two, so-called hemichannels (HCs), have been the main focus of deafness-associated disease models, it is now evident that the HCs themselves can function in the absence of docking and contribute to signaling across the cell membrane as a novel class of ion channel.
GJ channels cluster into plaques and provide a direct intercellular communication pathway between cells. A property in common among syndromic deafness mutants is functional HCs that show aberrant properties, suggesting that aberrant signaling across the plasma membrane mediated by mutant HCs may be the principal cause of cellular dysfunction.
Figure 3 shows images of cultured cochlea explants from mice immunostained for Cx26 and Cx30. The reciprocal experiment of increasing Cx30 expression in Cx26 null mice did not restore hearing (Qu et al., 2012). There is Cx expression both in basolateral and apical regions of support cells, suggesting that signaling molecules could be released both into perilymphatic and endolymphatic compartments.
In contrast, the ~100 non-syndromic Cx26 deafness mutations (not shown) are scattered throughout the Cx protein (see Lee and White, 2009). The polarity of Vj gating is Cx-dependent and can be of either sign (Verselis et al., 1994). Thus, syndromic deafness mutants map onto the domains that constitute the core elements that determine gating, permeability and regulatory characteristics of Cx HCs and GJ channels. Extracellular Ca2+ shifts HC activation positive along the voltage axis (Ebihara and Steiner, 1993) and has been shown to act selectively on loop gating (Verselis and Srinivas, 2008). Modification of G45C to a positively charged side chain with MTSET irreversibly reduced unitary conductance, whereas modification to a negatively charged side chain with MTSES had the opposite effect, increasing unitary conductance, much like the G45E KID mutation. For D50N HCs, however, outward currents in 2 mM extracellular Ca2+ were large due to loss of the inhibitory effect of Ca2+. A notable feature of syndromic deafness mutants is that the HCs exhibit aberrant behaviors providing a plausible basis for disease that is associated with excessive or altered contributions of Cx26 HCs that, in turn, lead to compromised cell integrity. However, a subset of these mutations has been shown to cause sensorineural deafness that is accompanied by severe skin disorders. For mutants that function as GJ channels and HCs, both channel configurations can contribute to disease mechanisms.
Regions of cell-cell contact show strong staining indicative of large clusters or plaques of GJ channels. Furthermore, deletion of Cx30 using a strategy in which Cx26 expression was preserved did not result in hearing loss (Boulay et al., 2013). The second voltage gating mechanism closes channels fully, with gating transitions comprised a series of transient subconductance states, which gives them the appearance of being slow when recorded at typical filtering frequencies. Thus, Ca2+ can act in conjunction with loop gating to effectively close Cx HCs over a wide range of voltages. Modification of D50C with oppositely charged reagents had the same qualitative effect, with MTSES essentially restoring WT conductance and rectification.
However, if at the end of the activation step, the membrane was stepped to a large negative potential, the peak tail current for G45E was followed by activation of a large inward current. Here we discuss some of the aberrant Cx26 HC properties that have been described for mutants associated with keratitis-ichthyosis-deafness (KID) syndrome, a particularly severe Cx26-associated syndrome, which shed light on genotype-phenotype relationships and causes underlying cochlear dysfunction. In contrast to non-syndromic deafness, syndromic deafness is characteristically cause by missense mutations that result in single amino acid substitutions and behave in an autosomal dominant manner.
They are hexamers of six Cx subunits and are strongly regulated by pH, voltage and divalent cations, principally Ca2+.
In the latter study, the R75W mutant gene was introduced using Cre-loxP recombination under a CAG promoter, which has widespread activity and resulted in deafness associated with deformity of the supporting cells, loss of the tunnel of Corti and degeneration of sensory hair cells.

These results indicate that deafness in original reports of Cx30 KO mice were likely due to reduced expression of Cx26. In Cx26 HCs, Vj gating operates only at larger inside positive voltages and is unlikely to play much of a role in gating Cx26 HCs.
In WT Cx26, increasing Ca2+ shifted activation in the depolarizing direction and suppressed current magnitude. Thus, charges at these positions strongly influence ion flux through the HC pore, explaining the effects of the KID mutations on HC conductance and rectification.
Using ion substitutions, blockers and intracellular chelation of Ca2+, this current was established to be a Ca2+-activated Cl current endogenous to Xenopus oocytes. EP does decline with Cx26 deficiency as postnatal development proceeds, likely due to loss of integrity of the epithelium. Thus, although the specific roles of GJs in the cochlea have yet to be defined, it is apparent that expression of Cx26, but not Cx30, is crucial for auditory function.
In mouse cochlea, ATP release through HCs was suggested to mediate Ca2+ wave propagation within the support cell network (Anselmi et al., 2008).
Interestingly, replacement of Cx26 with Cx32 under the Cx26 promoter resulted in mice with normal hearing (Degen et al., 2011) suggesting Cx32 and Cx26 are interchangeable, at least in terms of Cx26 loss-of-function models for deafness. Thus, normal plasma levels of Ca2+, 1–2 mM, would tend to keep Cx26 HCs closed at resting potentials with opening requiring a large depolarizing stimulus. Examination of the relationship between the Cl current and HC activation showed that substantially fewer G45E HCs were needed to activate Cl currents than WT Cx26 HC (Figure 5B).
Merged image of Cx26 and Cx30 immunostaining shows extensive co-localization of both connexins. It is also possible that IP3 signaling modulates other components, such as K+ channels and co-transporters in the non-sensory epithelial cells and, through propagation, to the intermediate cells (IC) of the stria vascularis that regulates K+ flux into the intrastrial space and ultimately into marginal cells (MC) and the endolymphatic compartment. At lower extracellular Ca2+ concentrations, less depolarization becomes necessary to elicit Cx26 HC opening, which can lead to substantial opening even at resting membrane potentials. There are four helical transmembrane domains (TM1–TM4) and two extracellular loop domains, E1 and E2. Since the organ of Corti is avascular, it was suggested that GJs between the support cells may help deliver glucose from the highly-vascularized stria vascularis (Chang et al., 2008). Developmentally, spontaneous release of ATP through HCs in support cells in the developing rat cochlea was suggested as a mechanism by which hair cells depolarize and synchronize their outputs to promote firing of the auditory nerve, which could help refine the development of central auditory pathways prior to the onset of hearing (Tritsch et al., 2007). Loss or weakened regulation by Ca2+ caused by KID mutations could increase Cx26 HC opening without a need for a reduction in extracellular Ca2+ levels. These data demonstrate that the G45E KID mutation substantially increases permeability of Cx26 HCs to Ca2+. The short helical segments in NT and E1 identified in the crystal structure are also shown (Maeda et al., 2009).
In this representation, the relative sizes of the different structures are altered to emphasize the organ of Corti, which contains inner hair cells (IHC), outer hair cells (OHC), different types of support cells and structures including afferent (AN) and efferent (EN) nerve fibers, blood vessel (BV), Boettcher cells (BoC), Claudius cells (CC), Deiter’s cells (DC), Hensen cells (HC), Inner border cells (IBC), Inner pilar cells (IPC), Inner phalangeal cells (IPhC), Inner Sulcus cells (ISC), Outer pilar cells (OPC), space of Nuel (SN) and tunnel of Corti (TC). GJs also were reported to mediate the spread of Ca2+ waves in support cells of the organ of Corti through the intercellular diffusion of IP3 and subsequent Ca2+ release (Beltramello et al., 2005).
Since Cx26 HCs are not selective for Na+ and K+, increased opening of the mutant HCs would tend to collapse the resting membrane potential leading to cell dysfunction. Locations of the 18 residues that have been associated with mutations causing syndromic deafness are indicated; those associated with KID syndrome are indicated in red. Inset (C) Structure of the Stria vascularis containing endothelial cells (EC), fibrocytes (FC), basal cells (BC), intermediate cells (IC) and marginal cells (MC).
Ca2+ acting on the Ca2+-dependent Cl–K co-transport systems may function to maintain the ionic balance of cochlear fluids. Oocytes expressing A40V, in particular, as well as G45E exhibit widespread disorganization of pigmentation and blebbing of the membrane. Cx HCs and GJ channels in support cells have been proposed to mediate the flux of K+, ATP, IP3 and Ca2+ across the membrane and between cells, respectively. After 4 days, the mutants tended to accelerate rundown of the membrane potential and to lead to cell death, although the extent to which this occurred differed among the mutants (Figure 4C).

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