Indian Journal of Occupational and Environmental Medicine   Official publication of Indian Association of  0ccupational  Health  
 Print this page Email this page   Small font sizeDefault font sizeIncrease font size
 Users Online:859

  IAOH | Subscription | e-Alerts | Feedback | Login 

Home About us Current Issue Archives Search Instructions
  Search
 
  
 
    Similar in PUBMED
     Search Pubmed for
     Search in Google Scholar for
   Related articles
    Article in PDF (1,217 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


   Abstract
  Introduction
  Source of Data
   Proteins Associa...
   Hair Cells and S...
  Stereocilin
  Prestin
  Whirlin
  Myosin
  Harmonin
  Cadherin 23
  Connexons 26
   Tip Links and Me...
  Espins
   Ezrin–radi...
  Wolframin
  Claudin 14
  Tricellulin
  Cochlin
  Collagen Ix
  Otoferlin
  Protocadherin-15
  Actin-Gamma 1
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed603    
    Printed66    
    Emailed0    
    PDF Downloaded40    
    Comments [Add]    

Recommend this journal

 


 
  Table of Contents 
TECHNICAL AND REVIEW ARTICLE
Year : 2018  |  Volume : 22  |  Issue : 2  |  Page : 60-73
 

Cochlear proteins associated with noise-induced hearing loss: An update


1 Department of Biochemistry, National Institute of Miners' Health JNARDDC Campus, Wadi, Nagpur, Maharashtra, India
2 National Centre for Microbial Resources, National Centre for Cell Science, University of Pune Campus, Pune, Maharashtra, India
3 B. K. Birla College of Science, Arts & Commerce (Autonomous), Kalyan, Maharashtra, India

Date of Web Publication1-Oct-2018

Correspondence Address:
Dr. Shubhangi K Pingle
Department of Biochemistry, National Institute of Miners' Health (NIMH), JNARDDC Campus, Wadi, Nagpur - 440 023, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijoem.IJOEM_43_18

Rights and Permissions

 

  Abstract 


Noise-induced hearing loss (NIHL) is one of the major occupational disease that has influence on the quality of life of mining workers. Several reports suggest NIHL is attributed to noise exposure at workplace and approximately 16% of hearing loss is due to it. NIHL occurs as a result of exposure to high-level noise (>85 dB) in the workplace. Noise disrupts proteins present in the micromachinery of the ear that is required for mechano-electric transduction of sound waves. High-level noise exposure can lead to hearing impairment owing to mechanical and metabolic exhaustion in cochlea, the major organ responsible for resilience of sound. Several key proteins of cochlea include tectorial membrane, inner hair cells, outer hair cells, and stereocilia are damaged due to high-level noise exposure. Numerous studies conducted in animals have shown cochlear proteins involvement in NIHL, but the pertinent literature remains limited in humans. Detection of proteins and pathways perturbed within the micromachinery of the ear after excessive sound induction leads toward the early identification of hearing loss. The situation insisted to present this review as an update on cochlear proteins associated with NIHL after an extensive literature search using several electronic databases which help to understand the pathophysiology of NIHL.


Keywords: Cochlear proteins, inner hair cells, noise-induced hearing loss, outer hair cells, stereocilia, tectorial membrane


How to cite this article:
Jain RK, Pingle SK, Tumane RG, Thakkar LR, Jawade AA, Barapatre A, Trivedi M. Cochlear proteins associated with noise-induced hearing loss: An update. Indian J Occup Environ Med 2018;22:60-73

How to cite this URL:
Jain RK, Pingle SK, Tumane RG, Thakkar LR, Jawade AA, Barapatre A, Trivedi M. Cochlear proteins associated with noise-induced hearing loss: An update. Indian J Occup Environ Med [serial online] 2018 [cited 2018 Dec 15];22:60-73. Available from: http://www.ijoem.com/text.asp?2018/22/2/60/242541





  Introduction Top


Occupational noise exposure is considered as the major risk factor of workplace that causes hearing loss in workers. It is defined as an impairment of hearing, resulting from exposure to excessive noise that manifests over a number of years and results in bilateral and symmetrical impairment of hearing. The cumulative permanent loss of hearing is always of the sensorineural type, which develops over months or years of hazardous noise exposure.[1]

Noise-induced hearing loss (NIHL) is one of the most leading occupational disease that contributes toward social isolation and leads to degraded quality of life.[2] It is caused by the workplace noise exposure, mainly reported in developing countries.[3] According to the World Health Organization (WHO), 16% of hearing loss in workers is due to occupational noise, ranging from 7 to 21% in various subregions [Figure 1]. Globally, 1,628,000 (in million) NIHL cases have been reported every year and the incidence rate is around two new cases out of 1000 older workers.[4] Even though NIHL is preventable, it is one of the most important problems of the industry and considered as one of the 10 major occupational diseases.[2] Asia is the world's largest and populated continent in the world that faces many challenges related to the occupational health and safety. NIHL in Asia shows complex scenario where rapid industrialization and economic growth occur in many developing countries.[4]
Figure 1: Attributable fraction (in %) for occupational hearing loss in various subregions reported by WHO

Click here to view


Noise management is an intricate task in various occupations. Several reports have shown the incidence rate of NIHL in different occupations. The workers in different industries such as mining, construction, printing, crushers, drop forging, iron, and steel companies are at high risk for severe hearing loss [Figure 2].[5] Almost all highest 60% of incidence rate of hearing loss was reported in mining and construction industry as compared to other occupations. Almost 15–20% of workers in mining industry are exposed to high level of noise at workplace, which ultimately leads to NIHL. In the mining industries, two out of three workers will have to suffer from hearing loss by the age of 50 years.[6] In developing countries exposure to occupational and environmental noise is more as compared to developed countries because of lack of often effective legislation programs to prevent NIHL.[7]
Figure 2: Incidence rate (%) of hearing loss by occupation via AUIDICUS database 2011

Click here to view


NIHL that usually occurs initially at high and then spreads to the low frequencies is a well-established clinical sign. NIHL is generally used to denote the cumulative, permanent loss of hearing that develops gradually after months or years of exposure to high levels of noise, resulting in irreversible damage to the delicate hearing mechanisms of the inner ear.[8] Noise exposure destroys the tympanic membrane, middle ear, and inner ear that directly affect the normal hearing mechanism [Figure 3].[9] Micromachinery of the inner ear is involved in sound processing inside the cochlea.[10] Hair cells (HCs) act as mechanosensors for sound perception, acceleration, and fluid motion. Mechanotransduction channels in HC are gated by tip link that connect the stereocilia of HC in the direction of their mechanical sensitivity. Several studies have shown that the excessive auditory stimulation damages fragile inner ear sensory HCs that lack regenerative potential.[11] The tectorial membrane (TM) is an extracellular matrix of the inner ear that connects with stereocilia bundles of specialized sensory HCs. Sound-induced movement to HCs affect the TM, deflects the stereocilia that leads to fluctuations in HC membrane, transducing electrical signals recognized by the afferent nerve endings and pass signals to the brain.[12],[13]
Figure 3: Mechanism of hearing: the schematic drawing of the human hearing system. (a) Three parts are shown: the outer, middle, and inner ear. The transverse section of the cochlea (b) divided into three parts: scala media, vestibuli, and tympani. The organ of corti (c) with its complex structure consists of tectorine membrane, OHCs and IHCs shown in detail

Click here to view


Numerous studies have demonstrated links of acoustic trauma and metabolic exhaustion in the inner ear owing to continuous and impulsive noise stimulation. Prolonged noise exposure produce pathological effects in the cochlea with substantial damage to HCs of the inner ear.[14] Scientists reported characteristics V-shaped notch typically noted as a “threshold dip”/“hearing notch&” at 4 and 6 kHz frequency on pure-tone audiometry testing as an indicator of NIHL. Majority of the literature considered 4 kHz as a standard notch to detect NIHL.[15]

Proteins present in the inner ear are disturbed by loud sound through multiple mechanisms such as loss of protein–protein interactions, aberrant accumulation, targeted degradation, mechanical damage, excitotoxicity, ischemia, metabolic exhaustion, ionic imbalance, etc.[10],[14] Specific proteins are identified with hearing loss-related dysfunction due to noise stimulations in the cochlea.[16]

Despite these findings, function of the cochlear proteins and its expression in NIHL is still not fully understood. Although animal studies have provided much of our understanding of cochlear protein expression but not extensively addressed in humans, the electronic database online literature searches related to NIHL in animal models as well as in human [Table 1] and [Table 2].[12],[14],[16],[24],[45] There has been very little research reported on cochlear proteins which may be used as biomarkers for early detection of NIHL. Hence, this situation prompted to present this succinct review using the available literature on cochlear protein expression in NIHL.
Table 1: Electronic database online literature searches related to NIHL in animal models

Click here to view
Table 2: Electronic database online literature searches related to NIHL in human

Click here to view



  Source of Data Top


Extensive literature search was conducted in the following electronic databases, viz., PubMed, Cochrane Library, KoreaMed, Virtual Health Library, Audicus, IndMed, PakMediNet, Google, etc., using the MeSH terms such as noise, hearing loss, noise-induced hearing loss, cochlear proteins, expression of proteins during NIHL, biomarkers for NIHL, proteomics in NIHL, hearing impairment, sensorineural hearing loss, tinnitus (n = 101) with initial searches limited to materials available with complete abstracts (to govern the suitability for full-text retrieval) and those available in the English language were included. Systematic reviews, review and research articles, case reports related to NIHL (n = 71) extracted from the searched literatures was included. Opinions, news, letters to the editor, and articles merely describing about the techniques were excluded (n = 68) [Figure 4]. These reviews included the above electronic database online literature searches related to NIHL in animal models and human [Table 1] and [Table 2].[16],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44] The information regarding numbers of publication on NIHL from Asian countries was obtained from ISI Web of Science [Figure 5]. According to the database, only five publications on NIHL were reported from India.[46] Information on cochlear proteins, biomarkers identified, subject population, technique used, different animal model used as well as sample collection and processing were also included in this review. On the basis of literature search, it was found that very limited information regarding cochlear proteins associated to NIHL. To the best of knowledge, in this review attempt was made to incorporate all those citations that may provide future insights to study the importance of cochlear proteins in NIHL.
Figure 4: A flowchart showing search results from each database, including inclusion and exclusion criteria

Click here to view
Figure 5: Number of research publications on NIHL from Asian countries that included the ISI Web of Science database

Click here to view



  Proteins Associated With Noise-Induced Hearing Loss Top


A significant first step toward the early identification of hearing loss after excessive sound induction is the detection of proteins and pathways perturbed within the micromachinery of the ear. Several proteins present in TM, inner HCs (IHCs), outer HCs (OHCs), and stereocilia in the cochlea are responsible for hearing and loss of proteins cause NIHL. Cochlea and its structural integrity is maintained by myosins, transmembrane inner ear protein, otoferin, cadherin 23 (CDH 23), stereocilin, harmonin, protocadherin-15, radixin, whirlin, espin, prestin, worfferin wolframin, connexin 26 and 30, claudin 14, tricellulin, cochlin, collagen xi, alpha-tectorine [as mentioned in [Table 3].[47],[48] Cochlear proteins overexpressed during occurrence of NIHL were included in the current review. The specific protein related to NIHL is described one by one as follows: TM proteins: alpha (α) tectorine and beta (β) tectorine.
Table 3: Expression of inner ear cochlear protein associated with the NIHL

Click here to view


The TM is an extracellular matrix of the inner ear that covers the neuroepithelium of the cochlea and contacts the stereocilia bundles of specialized sensory HCs. Sound induces movement of these HCs relative to the TM, deflects the stereocilia, and leads to fluctuations in HC membrane potential, transducing sound into electrical signals.[47] The presence of a hydrophobic C-terminus preceded by a potential cleavage site strongly suggests that tectorins are synthesized as glycosylphosphatidylinositol-linked, membrane-bound precursors. Tectorins are targeted to the apical surface of the inner ear epithelia by the lipid and proteolytically released into the extracellular compartment.[48]

Alpha and beta tectorins are important noncollagenous component of the TM. The alpha tectorine (TECTA) protein can form homomeric or heteromeric filaments after self-association or association with beta-tectorine (TECTB), respectively.[49] Many different types of cells synthesize alpha-tectorine protein during development of the inner ear. Due to sequence of DNA in TECTA gene, it is assumed that tectorine protein is synthesized from a precursor adjacent to plasma membrane, via glycosylphosphatidylinositol, released from the membrane by proteolytic cleavage of precursor. Gene TECTA (23 exons), located in chromosome 11, codifies alpha-tectorine protein (2155 amino acids) and it is one of the components of TM. Mutations in gene cause two forms of autosomal dominant hearing loss (DFNA8 and DFNA12 – 11q22-24, both prelingual and they may be progressive and nonprogressive) and an autosomal recessive form (DFNB21 – 11q, prelingual, severe to profound). Mutation in TECTA gene is not fully understood, which produce an abnormally small protein by premature stop signal by instructions to alpha-tectorine protein. Small concentration of alpha-tectorine protein disturbs integrity of tectorine membrane required for conversion of sound to nerve impulses.[49]

The association between tectorine membrane proteins and NIHL has been well established. Alpha-tectorine, beta-tectorine, and otogelin are glycoproteins. These unique molecules from the inner ear have been associated with a moderate to severe deafness, which contacts the steriocilia bundles of specialized sensory HCs with extracellular matrix of the TM associated with pathophysiology of NIHL. Alpha-tectorine plays a vital role in the mechanism of hearing, changes in their expression due to prolonged noise exposure, and leads to hearing loss. Damage in the alpha- and beta-tectorine proteins can cause nonsyndromic, sensorineural, and moderate-to-severe degree of hearing loss.[50]


  Hair Cells and Stereocilia Proteins Top


Sound-induced vibrations of the organ of corti lead to deflections of the stereociliary bundles of HCs, which cause the opening of mechanically gated ion channels in stereocilia and HC depolarization. The HCs are divided into two groups by an arch known as the tunnel of corti. Those on the side of the arch closest to the outside of the spiral shape are known as OHCs, and they are arranged in up to five rows in humans.[51] The HCs on the other side of the arch form a single row, and are known as IHCs. The stereocilia on each OHC form a V- or W-shaped pattern, and they are arranged in rows (usually about three) that are graded in height, the tallest stereocilia lying on the outside of the V or W. IHCs transmit the sound information along afferent neurons to the central nervous system. In contrast, OHCs act as amplifiers that increase the motion of the organ of corti.[52] The coupling of OHCs to the TM is critical for them to be properly stimulated to create the forces of cochlear amplification necessary for the proper transmission of sound information to IHCs.[51],[52]


  Stereocilin Top


Stereocilia are microvillar-like projections supported by actin bundles. Stereocilial protein is expressed in the sensory ear HCs and associated with the stereocilia. Stereocilia contains the channels that convert vibration and motion into electric current, which in turn alters the cross-membrane potential, and is fundamental for hearing. One protein that has been implicated in this process is stereocilin, which may be a secreted protein without a noticeable transmembrane domain.[52],[53] In mature HCs, stereocilin localizes to the horizontal top connectors that link adjacent stereocilia to each other and to the tips of stereocilia near the TM. Stereocilin can also be detected within TMs that have been mechanically detached from HCs, suggesting that the protein might be secreted and deposited into the TM.[53] Genetic studies in mice have demonstrated that stereocilin is required for the maintenance of hair bundle integrity and the coupling of stereocilia to the TM.[53] The movement of stereocilia significantly reduces, thus causing reduced influx of K+ ions into the cells. Alteration of stereocilin protein is known to cause bilateral, nonprogressive, sensorineural hearing loss. The hearing impairment occurs between the range 125 and 1000 Hz, but severe in higher frequencies.[54],[55]

NIHL occurs due to damage in the organ of corti (OC), particularly IHCs and OHCs are affected. Although OHCs loss is considered as a major contributor for NIHL, hearing deficits are not closely correlated with OHCs damage, suggesting that the death of other cell type in the cochlea has significant role in the development of NIHL.[54],[55] Current study approach can be generalized to examine the targeting, interactions and activities of a wide variety of HC proteins. It reveals a great deal of new information about the HC proteins cadherin 23, harmonin, myosin XVa, espin, prestin, etc., which are crucial for HC structure and function. There are certain important proteins present in stereocilia and HCs, which overexpressed during NIHL are described in the following.


  Prestin Top


The most impressive property of OHCs is their ability to change their length at high acoustic frequencies, thus providing the exquisite sensitivity and frequency-resolving capacity of the mammalian hearing organ. Prestin, a transmembrane protein found in the OHCs of the cochlea, is related to a sulfate/anion transport protein.[56] In contrast to enzymatic-activity-based motors, prestin is a direct voltage-to-force converter, which uses cytoplasmic anions as extrinsic voltage sensors and can operate at microsecond rates. Intracellular anions such as chloride or bicarbonate are essential for prestin to function as the OHC motor molecule.[57] Additionally, the voltage sensitivity of prestin is markedly temperature-dependent. It is an inbuilt amplifier that plays a significant role for electromotility, drives cochlear amplification, and produces acute sharp turning curves which is associated with human hearing. After noise exposure, prestin is upregulated (30–40%) and intracellular anions act as extrinsic voltage sensors that bind to these proteins and trigger the conformational modifications required for rapid length changes in OHC.[58] Each OHC intensifies a bit of the signal, where sounds become amplified. The amplified sounds are then detected by the IHC and messages are sent to the brain. Prestin is functional in OHCs but does not result in any detectable enhancement in cochlear function. Loss of prestin disturbs the balance in cochlea, characterized by moderate-to-severe degree of hearing loss, and deterioration of frequency selectivity which is voltage-dependent across the OHCs.[56],[57],[58]


  Whirlin Top


Whirlin is a cytoplasmic PDZ domain containing protein that plays a role in elongation and maintenance of stereocilia, mechanosensory organelles located in HCs of the inner ear. Whirlin colocalizes with actin filaments and is primarily detected in cochlear HCs.[59] It is an organizer of submembranous molecular complexes that controls and coordinates actin polymerization of stereocilia, especially in IHC and OHC. Hearing in mammals depends on the proper development of actin-filled stereocilia at the HC surface in the inner ear. Whirlin is expressed at stereocilial tips associated with hearing loss.[54] It is connected to the dynamic Usher protein interactome and has a pleiotropic function in both the retina and the inner ear. Myosin XVa is a motor protein that associates with the second and third PDZ domain of whirlin through its C-terminal PDZ-ligand. Myosin XVa then delivers whirlin to the tips of stereocilia, which are subsequently elongated. p55 also interacts with whirlin, and mutations in DFNB31, the whirlin gene, leading to an early ablation of p55 labeling of stereocilia, which may cause recessive hearing loss in humans.[60]


  Myosin Top


In the cochlea, myosin is localized along with stereocilia in IHCs, OHCs, supporting cells, as well as in the synaptic terminals that are responsible for intracellular movements. Myosin moves to actin filaments during the dynamic movements of stereocilia.[61] Myosin is required for normal stereocilia bundle organization and has a role in the function of cochlear HCs. Myosin was strongly expressed in sensory epithelia of the vestibular system from the earliest stage of the disease. The shape of the hair bundle relies on a functional unit composed of myosin, harmonin-b, and cadherin 23, which is essential to ensure the cohesion of the stereocilia.[62] Studies implicated that harmonin, cadherin 23, and myosin is a single functional network that underlies the formation of a coherent HC bundle. Recently, myosin and cadherin 23 were both shown to bind to harmonin, suggesting that these molecules form a functional complex within the stereocilia.[62] Cadherin 23 may form links between adjacent stereocilia, with myosin anchoring the whole complex to the actin core. Because cadherin 23 and myosin are required for the proper organization of the stereocilia bundle, these structures are damaged by intense noise. The earliest connections between growing stereocilia are critical for shaping the hair bundle as a coherent unit, and that this relies on cooperation between the three aforementioned proteins.[63] Structural defects in myosin protein cause alterations in the auditory function. A failure in this process would lead to the hair bundle disorganization. Finally, an attractive hypothesis is that the functional network formed by harmonin-b, cadherin 23, and myosin also implicates the proteins defective to cause deafness in the human population with predisposition to noise-induced hearing loss.[61],[62]


  Harmonin Top


In the cochlea, harmonin (a multi-PDZ domain containing scaffold protein) is restricted to IHCs, OHCs, stereocilia, and also expressed in the ribbon synapses.[59] Alternatively, spliced Usher syndrome type 1C (USH1C) transcripts predict at least 10 protein isoforms which can be grouped into three subclasses, hereafter referred to as harmonin a, b, and c, and collectively as harmonin. Both harmonin and cadherin 23 are present in the growing stereocilia and that they bind to each other.[63] Moreover, it demonstrates that harmonin-b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microelements, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Harmonin-b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin-b along the actin core of the developing stereocilia.[64] It proposes that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin-b, and cadherin 23 that is essential to ensure the cohesion of the stereocilia. Harmonin bridges cadherin 23 to cytoskeletal actin core of the stereocilium that is essential for the developmental differentiation of stereocilia. Harmonin is associated with the other tip link proteins. Defects in the protein cause prelingual and moderate-to-severe degree of hearing loss.[61],[63],[64]


  Cadherin 23 Top


Cadherin 23 represents the first in this family of calcium-binding proteins of which mutations in the extracellular calcium binding domain contributes to an inherited disorder, USH1D. Patients with USH1D exhibit congenital sensorineural hearing loss, vestibular dysfunction, and visual impairment due to early onset of retinitis pigmentosa. In the inner ear, cadherin 23 interacts with myosin VIIIa and harmonin to form a functional network during HC differentiation, and in the retina to assemble a supramolecular complex contributing to the organization of the cytoskeletal matrices of the pre- and postsynaptic region. A number of cadherin 23 splice variants exist in association with various phenotypic expressions, indicating that differential mutations result in variable presentation of the disease.

The cadherin 23 protein is expressed in IHCs, OHCs, promoting strong adhesion in Reissner's membrane. It is important for delivering mechanical signals to the mechanoelectric transducer channels. It is one of the components of the tip link, which connects the top of shorter stereocilium to the sites of its taller neighbor. The average hearing loss is reported at 84.0 dB for CDH 23.[22] Similar interacting proteins have been reported that include protocadhrein-15, harmonin, and MAGI-1. Protocadherin-15 binds to CDH 23 through its extracellular domain.[60] MAGI-1 is a stereociliary scaffolding protein, whereas the cytoplasmic region of CDH 23 interacts with MAGI-1 and harmonin through its PDZ domain-binding interfaces. Alterations in cadherin 23 are known to cause moderate to profound high-frequency progressive sensorineural prelingual hearing loss.[61]


  Connexons 26 Top


The connexin family of proteins forms hexameric complexes called “connexons” that facilitate movement of low molecular weight proteins between cells via gap junctions. Connexin proteins share a common topology of four transmembrane α-helical domains, two extracellular loops, a cytoplasmic loop, and cytoplasmic N and C termini. Many of the key functional differences arise from specific amino acid substitutions in the most highly conserved domains, the transmembrane and extracellular regions.

There are 21 identified members of this protein, in the sequenced human genome, making the connexin gene family a wide-ranging membrane protein. The MW varies between 25 and 60 kDa and have an average length of 380 amino acids. The various connexins have been observed to combine into both homomeric and heteromeric gap junctions, each of which may exhibit different functional properties, including pore conductance, size selectivity, charge selectivity, voltage gating, chemical gating, etc.[47],[62] The association between connexin proteins and the inner ear cells is well documented. The abundant expression of connexins in the auditory system of the inner ear demonstrates their importance in the development and hearing process. The changes in connexins are associated with hearing loss, neurodegenerative disorders, and skin diseases.

Connexin 26 is required for maintenance of K+ ions concentration in the endolymph of inner ear. As the sound waves stimulate the ossicular chain, it causes vibration in the endolymph, resulting in entry of K+ ions into the HCs; consequently the vibration signal is converted into a neural signal. As the K+ ions releases from the HCs to the supporting cells, the system is regenerated. In this way, the K+ ions pass from cell to cell by gap junctions and then released into the endolymph. It controls ions movement from channels, allowing inflow of potassium from endolymph to IHCs and OHCs of cochlea causing depolarization of cell membrane. Connexin 26 connects all cell types in the cochlea, including spiral limbus, supporting cells, the spiral ligament, and basal and intermediate cells of striavascularis, and this involved in K+ homeostasis and intercellular signaling within the organ of corti. Although this protein is involved in signal transduction in the organ of corti, but exposure to high-frequency sound may cause permanent damage to the functioning of this protein, resulting in mutation of the gene coding for connexin 26. A mutation in the gene (GJB2) that codes for connexin 26 synthesis may lead to nonsyndromic deafness. This alters the normal functioning of this protein, resulting in cessation of K+ ion signal transduction due to exposure to noise. Extensive OHC loss and severe destruction of basal organ of corti are noted after noise exposure. Connexin 26 is a remarkable protein that shows involvement in hearing loss. The subsequent influx of calcium causes release of neurotransmitters from the synaptic vesicles to the primary afferent nerve ending synapses. Absence of connexin will be responsible for severe to profound nonsyndromic hearing loss.[63],[64]


  Tip Links and Mechanoelectrical Transducer Channel Proteins Top


Tip links are thought to be an essential element of the mechanoelectrical transduction (MET) apparatus in sensory HCs of the inner ear. It helps in the conversion of mechanical stimuli arising from sound and head movements into electrochemical signals. The dynamic properties and molecular composition of tip links have been the subject of intense debate over the past two decades. Tip links proteins include cadherin 23, protocadhrein-15, harmonin, and MAGI-1. Cadherins belong to the family of calcium-dependent adhesion molecules that function to mediate cell–cell binding to the maintenance of structure and morphogenesis. It is also involved in stereocilia organization and hair bundle formation.[59] The identification CDH 23 and PCDH 15 as constituents of the tip links and the molecular asymmetry formed by heterophilic interaction of these molecules provides novel opportunities for understanding MET at the molecular level, and for determining the extent to which defects in MET cause hearing impairment. MET is a key element in the transduction process, which is the mechanoelectric transducer apparatus located near the top of the stereocilium. Cations, mainly potassium and calcium, flow through MET channel and alter the membrane potential that pass signal to the brain.[65],[66] The molecules that form tip links have recently been identified, and the analysis of their properties has not only changed the view of MET but also suggests that tip link defects can cause hearing loss.[67]


  Espins Top


Espins are more potent than other actin-bundling proteins at eliciting microvillar elongation, possibly owing to their high affinity for F-actin and their highly cooperative effects on actin filament twist. Collections of parallel actin-bundle containing finger-like protrusions that more closely resemble stereocilia in length affect the espin C terminal actin-bundling module and are associated with recessive deafness and vestibular dysfunction in humans.[68]


  Ezrin–radixin–moesin Protein Top


Ezrin–radixin–moesin (ERM) proteins are collectively composed of ezrin, radixin, and moesin and belong to the band 4.1 superfamily, whose members share a common N-terminal FERM domain.[68] The ERM protein family has been proposed to play structural and regulatory roles in many plasma membrane-based processes, viz., transmembrane signaling, growth regulation, differentiation, and the determination of cell shape, adhesion, etc., by functioning as membrane–cytoskeletal crosslinkers in actin-rich cell surface structures.[69] The ERM protein functions as a regulated cross-linkers in between the plasma membrane and F-actin in the underlying cytoskeleton.[68] In human, the genes for the ERM proteins present on different chromosomes: radixin is on chromosome 11 (11 exons); ezrin is on chromosome 6 (13 exons); and moesin is on the X chromosome (12 exons), which produces ~80, ~82, and ~75 kDa proteins, respectively.[69] Among ERM protein, ezrin and moesin display 74%, radixin and ezrin display 75%, and 81% protein sequence identity with radixin and moesin.[68]

Ezrin plays an essential role in microvillar generation and dynamics, which is confirmed by the knockout of the ezrin gene in mice and fruit fly. At the initial stage of the stereocilia development, ezrin localizes aberrantly to the stereocilia but later it will be replaced by the radixin. The loss of radixin cannot be fully compensated by the ezrin.[68] The expression of moesin shows tissue specificity, and it is predominantly found in microvilli of endothelial cells.[69]

Radixin is actin and/or plasma membrane linking protein that anchors filaments to membrane.[70] Occurrence of the radixin was determined by immunolabeling of HCs in fish, amphibians, birds, and mammals, and it was unveiled that the highest concentration of radixin was situated in the lower shaft of each stereocilium, just above its basal taper.[71] In human, radixin protein is expressed in cochlear HCs, and it is also expressed in vestibular stereocilia with ezrin.[72] Radixin deficiency may cause hearing impairment, mainly deafness.[70] The expression of radixin is specifically found along with the length of stereocilia in both the organ of corti and in the vestibular system[73] where it diminishes gradually in prevalence toward the stereociliary tip.[71] Han et al.[73] found that the knockout of the radixin gene (Rdx) in mouse is associated with early postnatal progressive degeneration of cochlear stereocilia and subsequent deafness.


  Wolframin Top


Wolframin is a product of WFS1 gene found in chromosome 4p16.1.[74] Wolframin is a type II transmembrane protein consisting of 890 amino acids having nine helical transmembrane segments, and has been believed that it might play a role in homeostasis of K+ and Ca2+ in endoplasmic reticulum calcium channel or a regulator of channel activity.[74],[75] Studies reveal that wolframin localized to the ER in the pancreatic β-cells, brain hippocampus, and several cell types in the inner ear. In primates like mouse and marmoset (Callithrix jacchus), it is predominantly expressed in cochlea (striavascularis, organ of corti, and spiral ganglion neurons).[76] Mutations in both alleles of a single gene located of WFS1 cause an autosomal recessive disorder called Wolfram syndrome, while heterozygous mutations are associated with the dominantly inherited disease, low frequency sensorineural hearing loss that leads to deafness.[76],[77]


  Claudin 14 Top


Claudin proteins are mainly located at the tight junction, where it act as ionic barriers between cells.[78] Tight junction plays a crucial part in the normal hearing process in cochlear function because any mutations or lack of tight junction associated proteins, like claudin 9, 11, 14, and occluding, cause deafness in humans and/or mice.[79] Out of 24 different mammal claudins, claudin-14 has been identified as an important molecule for normal hearing process, where it is expressed in the supporting cells in the organ of corti, OHCs and IHCs. Here it acts as a selective barrier between endolymph and perilymph.[78],[80] In humans, a nonsyndromic hearing loss (congenital deafness DFNB29) occurred predominantly in higher frequencies due to the mutations in the claudin-14 gene.[81],[82] A rapid degeneration of cochlear HCs is found in knockout mice for claudin-14 gene, which make mice deaf.[83]


  Tricellulin Top


Tricellulin protein belongs to tetramembrane-spanning TAMP family and is one of the constituents of tricellular tight junctions and barrier of tight junctions.[84],[85] With the help of immunofluorescence staining, it was observed that the tricellulin concentration at tricellular contacts is ubiquitous in various epithelial cells in tissues, and in the mouse organ of corti, tricellulin localizes specifically to the tricellular junctions.[85],[86] In humans, five different mutations are reported in TRIC gene, and that which encode tricellulin has been reported to cause autosomal recessive nonsyndromic deafness DFNB49.[86] Kamitani et al.[79] reported that mice having tricellulin-knockout (Tric-/-) or mutation in TRIC gene shows an early onset of progressive hearing loss without any other significant morphological changes in other organs, which are similar to the phenotype reported in human DFNB49. They also reported that cochlea of tricellulin-knockout mice developed normally, although they progress into functional and histological degeneration later.


  Cochlin Top


Cochlin protein is a product of the COCH gene found in humans on chromosome 14q12-q13. Five missense mutations in the FCH/LCCL domain of COCH gene cause DFNA9, an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular dysfunction pathology.[87],[88] Defect in cochlin also leads to Meniere's disease and presbycusis. The occurrence of cochlin is in the cochlea and the vestibular system where it presents as a part of the extracellular matrix. Cochlin offers structural support to cochlea and also it interacts with other molecules in the extracellular matrix.[89] Cochlin is predominantly expressed in the inner ear with three glycosylated isoforms with molecular weights of 40, 46, and 60 kDa, whereas cochlin-tomo protein, a smaller 16 kDa isoform has been identified in the perilymph.[87],[89]


  Collagen Ix Top


In the TM, type IX collagen is reported as one of the very well-known components, along with type II and V collagens.[90] Collagen IX belongs to the fibril-associated collagen and is the integral component of type-A fiber of TM, where it cross-linked with type-II collagen. In TM, type-A fibers is a straight, unbranched and running radially in parallel bundles with type-B, which is a loosely packed, wavy, and highly branched, and combining it forms striated sheet matrix. It was suggested that collagen IX plays a crucial role in the rigidity of structure and integrity of inner ear.[90],[91],[92]


  Otoferlin Top


Otoferlin localized at the IHCs of the cochlea acts with one of the myosins VI, and is mainly involved in the synaptic vesicle-membrane fusion and in the membrane trafficking having the HC-specific Ca2+ sensor for exocytosis.[93],[94] The otoferlin protein encoded by OTOF gene belongs to ferlin family, a C2-domain-containing protein and is considered one of the relevant genes associated with nonsyndromic deafness (DFNB9). Genetic mutation in otoferlin leads to severe hearing impairment resulting from improper HC synaptic development and lack of synaptic vesicle exocytosis.[95],[96]


  Protocadherin-15 Top


Protocadherin-15 belongs to the cadherin superfamily of Ca2+-dependent adhesion glycoproteins, and is believed to establish the regular building of the HC stereocilia bundles and inner ear function in humans, mice, and zebrafish. Protocadherin-15 is associated with the tip-link complex of HCs as an ankle links.[97] In humans, mutated protocadherin-15 (PCDH15, encoded by USH1F/PCDH15) generate Usher syndrome, which is a hereditary deafness and blindness disease and it is also responsible in the nonsyndromic deafnesses, DFNB12 and DFNB23.[98],[99]


  Actin-Gamma 1 Top


Gammacyto-actin (γcyto-actin) is mainly distributed in the inner ear sensory epithelial cells and is an essential component of the stereocilia core. The localization of γcyto-actin includes HC stereocilia and their rootlets, the cuticular plate where it anchored, adherens junctions, and OHC lateral walls.[100] Mutations in various actin and actin-interacting proteins cause defects in stereocilia structure and mutation in γ-actin (actg1). ACTG1 leads to dominant progressive hearing loss without other syndromic phenotypes.[101],[102]

From this extensive literature survey, authors made an attempt to understand the proteins associated with the pathophysiology and their mechanism in NIHL. It is obvious that aforesaid proteins are involved in the protection of inner ear's structural integrity. It is noteworthy to mention that collectively all these proteins may be considered as biomarkers for the identification of NIHL at early stage. In addition, proteomic approach may provide more insights on protein expression and downregulation due to noise exposure. Comprehensive understanding of inner ear proteome will accelerate the biomarkers study of NIHL for prevention.

Acknowledgement

All authors would like to acknowledge Ministry of Mines, Government of India for funding the project and to the Director, National Institute of Miners' Health for their constant support and guidance for this study. Anand Barapatre gratefully acknowledge the financial support by Science & Engineering Research Board - NPDF Fellowship (SERB, PDF/ 2016/1775/LS).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Topilla E, Pyykko I, Starck J, Kaksonen R, Ishizaki H. Individual risk factors in the development of noise-induced hearing loss. Noise Health 2000;2:59-70.  Back to cited text no. 1
    
2.
Robinson T, Whittaker J, Acharya A, Singh D, Smith M. Prevalence of noise-induced hearing loss among woodworkers in Nepal: A pilot study. Int J Occup Environ Health 2015;21:14-22.  Back to cited text no. 2
    
3.
Nelson DI, Nelson RY, Concha-Barrientos M, Fingerhut M. The global burden of occupational noise-induced hearing loss. Am J Ind Med 2005;48:446-58.  Back to cited text no. 3
    
4.
World Health Organization (WHO) report 2001. Available from www.who.int/quantifying_ehimpacts/global/ebdcountgroup/en/index.html 2001. [Last accessed on 2015 Jun 15].  Back to cited text no. 4
    
5.
Azizi MH. Occupational noise-induced hearing loss. Int J Occup Environ Med 2010;1:116-23.  Back to cited text no. 5
    
6.
Occupational Exposure to Noise: Evaluation, Prevention and Control: NIOSH Cooperative Agreement with WHO for 1994-1995. Available from: http://www.who.int/occupational_health/publications/noisebegin.pdf. [Last accessed on 2013 Nov 24].  Back to cited text no. 6
    
7.
Mcbride DI. Noise induced hearing loss and hearing conversation in mining: In depth review. Occup Med 2004;54:290-6.  Back to cited text no. 7
    
8.
Aas S, Tronstad VT. Diffusion-Based Model for Noise Induced Hearing Loss Master of Science in Electronics thesis, Department of Electronics and Telecommunications. Norwegian University of Science and Technology; 2007.  Back to cited text no. 8
    
9.
Fettiplace R, Hackney CM. The sensory and motor roles of auditory hair cells. Nat Rev Neurosci 2006;7:19-29.  Back to cited text no. 9
    
10.
Harrison VR. The prevention of noise induced hearing loss in children: A review article. Int J Pediatr 2012;473541:13.  Back to cited text no. 10
    
11.
Harding W, Baggot J, Bohne A. Height changes in the Organ of Corti after noise exposure. Hear Res 1992;63:26-36.  Back to cited text no. 11
    
12.
Engstrom B, Flock A, Borg E. Ultrastructural studies of stereocilia in noise-exposed rabbits. Hear Res 1983;12:251-64.  Back to cited text no. 12
    
13.
Zheng XY, Henderson D, Mcfadden, SL, Hu BH. The role of the cochlear efferent system in acquired resistance to noise-induced hearing loss. Hear Res 1997;104:191-203.  Back to cited text no. 13
    
14.
Zheng XY, Mcfadden SL, Ding DL, Henderson D. Cochlear differentiation and impulse noise-induced acoustic trauma in the chinchilla. Hear Res 2000;144:187-95.  Back to cited text no. 14
    
15.
Kurmis AP, Apps SA. Occupationally-acquired noise-induced hearing loss: A senseless workplace hazard. Int J Occup Med Environ Health 2007;20:127-36.  Back to cited text no. 15
    
16.
Yeo KN, Yun SY, Kim WJ, Choi HS, Lim CG, Chung WJ. Proteomic analysis of the protein expression in the cochlea of noise-exposed mice. Korean J Audiol 2011;15:107-13.  Back to cited text no. 16
    
17.
Cohen-Salmon M, Ott T, Michel V, Hardelin JP, Perfettini I, Eybalin M, et al. Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol 2002;12:1106-11.  Back to cited text no. 17
    
18.
Delprat B, Boulanger A, Wang J, Beaudoin V, Guitton MJ, Ventéo S, et al. Downregulation of otospiralin, a novel inner ear protein, causes hair cell degeneration and deafness. J Neurosci 2002;22:1718-25.  Back to cited text no. 18
    
19.
Etournay R, El-Amraoui A, Bahloul A, Blanchard S, Roux I, Pézeron G, et al. PHR1, an integral membrane protein of the inner ear sensory cells, directly interacts with myosin 1c and myosin VIIa. J Cell Sci 2005;118:2891-9.  Back to cited text no. 19
    
20.
Chen GD. Prestin gene expression in the rat cochlea following intense noise exposure. Hear Res 2006;222:54-61.  Back to cited text no. 20
    
21.
Yamashita D, Minami SB, Kanzaki S, Ogawa K, Miller JM. Bcl-2 genes regulate noise-induced hearing loss. J Neurosci Res 2008;86:920-8.  Back to cited text no. 21
    
22.
Kazmierczak P, Sakaguchi H, Tokita J, Wilson-Kubalek EM, Milligan RA, Müller U, et al. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 2007;449:87-91.  Back to cited text no. 22
    
23.
Bahloul A, Simmler MC, Michel V, Leibovici M, Perfettini I, Roux I, et al. Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells. EMBO Mol Med 2009;1:125-38.  Back to cited text no. 23
    
24.
Fetoni AR, Ralli M, Sergi B, Parrilla C, Troiani D, Paludetti G. Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs. Acta Otorhinolaryngol Ital 2009;29:70-5.  Back to cited text no. 24
    
25.
Wang B, Liu Y, Zhu X, Chi F, Zhang Y, Yang M. Up-regulation of cochlear Hes1 expression in response to noise exposure. Acta Neurobiol Exp 2011;71:256-62.  Back to cited text no. 25
    
26.
Savas JN. Proteome biology of noise induced hearing loss. NIH Project Research portfolio Online Reporting Tools (RePORT). 2014 Available from: https://projectreporter.nih.gov/project_info_description.cfm?aid=8678358. [Last accessed on 2014 Jun 14].  Back to cited text no. 26
    
27.
Hong O. Hearing loss among operating engineers in American construction industry. Int Arch Occup Environ Health 2005;78:565-74.  Back to cited text no. 27
    
28.
Kumar A, Mathur NN, Varghese M, Mohan D, Singh JK, Mahajan P. Effect of tractor driving on hearing loss in farmers in India. Am J Ind Med 2005;47:341-8.  Back to cited text no. 28
    
29.
Van Eyken E, Van Laer L, Fransen E, Topsakal V, Hendrickx JJ, Demeester K, et al. The contribution of GJB2 (Connexin 26) 35delG to age-related hearing impairment and noise-induced hearing loss. Otol Neurotol 2007;28:970-5.  Back to cited text no. 29
    
30.
Aslam JM, Aslam AM, Batool A. Effect of Noise Pollution on Hearing of Public Transport Drivers in Lahore City. Pak J Med Sci 2008;24:142-6.  Back to cited text no. 30
    
31.
Thorne PR, Ameratunga SN, Stewart J, Reid N, Williams W, Purdy SC, et al. Epidemiology of noise-induced hearing loss in New Zealand. N Z Med J 2008;121:33-44.  Back to cited text no. 31
    
32.
Rashtak S, Ettore MW, Homburger HA, Murray JA. Combination testing for antibodies in the diagnosis of coeliac disease: Comparison of multiplex immunoassay and ELISA methods. Aliment Pharmacol Ther 2008;28:805-13.  Back to cited text no. 32
    
33.
Jansen EJ, Helleman HW, Dreschler WA, de Laat JA. Noise induced hearing loss and other hearing complaints among musicians of symphony orchestras. Int Arch Occup Environ Health 2009;82:153-64.  Back to cited text no. 33
    
34.
Kerketta S, Gartia R, Bagh S. Occupational hearing loss of the workmen of an open cast chromite mines. Indian J Occup Environ Med 2012;16:18-21.  Back to cited text no. 34
[PUBMED]  [Full text]  
35.
Mostaghaci M, Mirmohammadi SJ, Mehrparvar AH, Bahaloo M, Mollasadeghi A, Davari MH. Effect of workplace noise on hearing ability in tile and ceramic industry workers in Iran: A 2-year follow-up study. ScientificWorldJournal 2013;2013:923731.  Back to cited text no. 35
    
36.
Lacerda A, Quintiliano J, Lobato D, Gonçalves C, Marques J. Hearing profile of Brazilian forestry workers' noise exposure. Int Arch Otorhinolaryngol 2015;19:22-9.  Back to cited text no. 36
    
37.
Ranga RK, Yadav S, Yadav A, Yadav N, Ranga SB. Prevalence of occupational noise induced hearing loss in industrial workers. Indian J Otol 2014;20:115-8.  Back to cited text no. 37
  [Full text]  
38.
Tahir N, Syed AM, Jamal HH, Begum J. Burden of Noise Induced Hearing Loss among Manufacturing Industrial Workers in Malaysia. Iran J Publ Health 2014;43:148-53.  Back to cited text no. 38
    
39.
Oliveira A, Cacodcar J, Motghare DD. Morbidity among iron ore mine workers in Goa. Indian J Public Health 2014;58:57-60.  Back to cited text no. 39
[PUBMED]  [Full text]  
40.
Whittaker JD, Robinson T, Acharya A, Singh D, Smith M. Noise-induced hearing loss in small-scale metal industry in Nepal. J Laryngol Otol 2014;128:871-80.  Back to cited text no. 40
    
41.
Musiba Z. The prevalence of noise-induced hearing loss among Tanzanian miners. Occup Med 2015;65:386-90.  Back to cited text no. 41
    
42.
Alexopoulos EC, Tsouvaltzidou T. Hearing loss in shipyard employees. Indian J Occup Environ Med 2015;19:14-8.  Back to cited text no. 42
[PUBMED]  [Full text]  
43.
Yadav M, Yadav KS, Netterwala A, Khan B, Desai NS. Noise-induced hearing loss (NIHL) and its correlation with audiometric observations in heavy vehicle operators suffering with metabolic disorders. Int J Med Clin Res 2015;6:0976-5549.  Back to cited text no. 43
    
44.
Haghighat-Nia A, Keivani A, Nadeali Z, Fazel-Najafabadi E, Hosseinzadeh M, Salehi M. Mutation spectrum of autosomal recessive non-syndromic hearing loss in central Iran. Int J Pediatr Otorhinolaryngol 2015;79:1892-5.  Back to cited text no. 44
    
45.
Thakkar LR, Pingle SK, Kumbhakar DV, Jawade AA, Tumane RG, Soni PN, et al. Expression of 16.2kDa protein in elderly population: A quest for the detection of age related hearing impairment. Indian J Otol 2015;21:248-53.  Back to cited text no. 45
  [Full text]  
46.
Fuente A, Hickson L. Noise-induced hearing loss in Asia. Int J Audiol 2011;50:S3-10.  Back to cited text no. 46
    
47.
Piatto VB, Secches LV, Arroyo MAS, Lopes ACP, Maniglia JV. Nonsyndromic Deafness Molecular Update. Open Biol J 2009;2:80-90.  Back to cited text no. 47
    
48.
Trivedi M, Pingle S. A review Noise Induced Hearing Loss (NIHL). Asiatic J Biotechnol Resources 2013;4:1-6.  Back to cited text no. 48
    
49.
Verhoeven K, Van Laer L, Kirschhofer K, Legan PK, Hughes DC, Schatteman I, et al. Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet 1998;19:60-2.  Back to cited text no. 49
    
50.
Meyer NC, Alasti F, Nishimura CJ. Identification of three novel TECTA mutations in Iranian families with autosomal recessive nonsyndromic hearing impairment at the DFNB21 locus. American J Med Genet 2007;143:1623-9.  Back to cited text no. 50
    
51.
Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, et al. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol Genet 2003;12:1155-62.  Back to cited text no. 51
    
52.
Dallos P, Fakler B. Prestin, a new type of motor protein. Nat Rev Mol Cell Bio 2002;3:104-11.  Back to cited text no. 52
    
53.
Zheng J, Shen W, He DZ, Long KB, Madison LD, Dallos P. Prestin is the motor protein of cochlear outer hair cells. Nature 2000;405:149-55.  Back to cited text no. 53
    
54.
Hakizimana P, Brownell EW, Jacob S, Fridberger A. Sound-induced length changes in outer hair cell Stereocilia. Nat Commun 2012;3:1094.  Back to cited text no. 54
    
55.
Flock A, Cheung HC. Actin filaments in sensory hairs of inner ear receptor cells. J Cell Biol 1977;75:339-43.  Back to cited text no. 55
    
56.
Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, et al. Defects in whirlin, a PDZ domain molecule involved in steriocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet 2003;34:421-8.  Back to cited text no. 56
    
57.
Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, et al. A novel gene for Usher syndrome type 2: Mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum Genet 2007;121:203-11.  Back to cited text no. 57
    
58.
Boeda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, et al. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J 2002;21:6689-99.  Back to cited text no. 58
    
59.
Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, et al. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet 2001;68:26-37.  Back to cited text no. 59
    
60.
Alagramam NK, Stepanyan R, Jamesdaniel S, Daniel HC, Davis RR. Noise exposure immediately activates cochlear mitogen-activated protein kinase signalling. Noise Health 2014;16:400-9.  Back to cited text no. 60
[PUBMED]  [Full text]  
61.
Sengupta S, George M, Miller KK, Naik K, Chou J, Cheatham AM, et al. EHD4 and CDH23 Are Interacting Partners in Cochlear Hair Cells. J Biol Chem 2009;284:20121-9.  Back to cited text no. 61
    
62.
Muller DJ, Hand GM, Engel A, Sosinsky GE. Conformational changes in surface structures of isolated connexin 26 gap junctions. EMBO J 2002;21:3598-607.  Back to cited text no. 62
    
63.
Kemperman HM, Hoefsloot HL, Cremers WRJ. Cor, Hearing loss and connexin 26. J R Soc Med 2002;95:171-7.  Back to cited text no. 63
    
64.
Mukherjee M, Phadke SR, Mittal B Connexin 26 and autosomal recessive non-syndromic hearing loss. Indian J Hum Genet 2003;9:40-50.  Back to cited text no. 64
    
65.
Hongzhe LI, Jawon K, Douglas V, Steyger P. Met channel- Independent uptake of aminoglycosides by cochlear hair cells. Ninth International conference on Molecular Biology of Hearing and Deafness. Stanford University; 2013;22-25.  Back to cited text no. 65
    
66.
Stepanyan R, Indzhykulian A, Mclean J, Sinha G, Frolwnkov G. Acoustic overstimulation and mitochondrial Ca2+ overload in outer hair cells. Ninth International conference on Molecular Biology of Hearing and Deafness. Stanford University; 2013;22-25.  Back to cited text no. 66
    
67.
Sensory Perception. Available from the source: http://cnx.org/contents/b375ea7d-22d5-4f47-b10a-41dd93637896@4. [Last accessed on 2015 May 15].  Back to cited text no. 67
    
68.
Sauvanet C, Wayt J, Pelaseyed T, Bretscher A, Structure, regulation, and functional diversity of microvilli on the apical domain of epithelial cells. Annu Rev Cell Dev Biol 2015;31:593-621.  Back to cited text no. 68
    
69.
Hoeflic KP, Ikura M, Radixin: Cytoskeletal adopter and signaling protein. Int J Biochem Cell Biol 2004;36:2131-6.  Back to cited text no. 69
    
70.
Ciuman RR. Auditory and vestibular hair cell stereocilia: Relationship between functionality and inner ear disease. J Laryngol Otol 2011;125:991-1003.  Back to cited text no. 70
    
71.
Pataky F, Pironkova R, Hudspeth AJ. Radixin is a constituent of stereocilia in hair cells. PNAS 2004;101:2601-6.  Back to cited text no. 71
    
72.
Peng AW, Salles FT, Pan B, Ricci AJ. Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction. Nat Commun 2011;2:523.  Back to cited text no. 72
    
73.
Han Y, Wang X, Chen J, Sha SH. Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling. J Neurochem 2015;133:617-28.  Back to cited text no. 73
    
74.
Concetta A, Alessandro S, Lorenzo P, Francesca L, Katia P, Ramona T, et al. Wolfram Syndrome: New mutations, different phenotype. PLoS One 2011;7:e29150.  Back to cited text no. 74
    
75.
Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, et al. WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. FEBS Lett 2006;580:5635-40.  Back to cited text no. 75
    
76.
Noriomi S, Makoto H, Naoki O, Hideyuki O. Expression pattern of wolframin, the WFS1 (Wolfram syndrome-1 gene) product, in common marmoset (Callithrix jacchus) cochlea. Cell Mol Dev Neurosci 2016;1:833-6.  Back to cited text no. 76
    
77.
Christine P, Eberhard F, Hans W. Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells. Exp Gerontol 2005;40:671-8.  Back to cited text no. 77
    
78.
Huihui X, Yang L, Guimei H, Rossiter SJ, Shuyi Z. Adaptive evolution of tight junction protein claudin-14 in echolocating whales. Gene 2013;530:208-14.  Back to cited text no. 78
    
79.
Kamitani T, Sakaguchi H, Tamura A, Miyashita T, Yamazaki Y, Tokumasu R, et al. Deletion of tricellulin causes progressive hearing loss associated with degeneration of cochlear hair cells. Sci Rep 2015;5:1-5.  Back to cited text no. 79
    
80.
Lal-Nag M, Morin PJ. The claudins. Genome Biol 2009;10:235.1-235.7.  Back to cited text no. 80
    
81.
Wattenhofer M, Reymond A, Falciola V, Charollais A, Caille D, Borel C, et al. Different mechanisms precludemutant CLDN14 proteins from forming tight junctions in vitro. Hum Mutat 2005;25:543-9.  Back to cited text no. 81
    
82.
Kitajiri S, Katsuno T. Tricellular tight junctions in the inner ear. Biomed Res Int 2016;6137541:1-5.  Back to cited text no. 82
    
83.
Ben-Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Itallie CMV, et al. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 2003;12:2049-61.  Back to cited text no. 83
    
84.
Riazuddin S1, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, et al. Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet 2006;79:1040-51.  Back to cited text no. 84
    
85.
Furuse M, Izumi Y, Oda Y, Higashi T, Iwamoto N. Molecular organization of tricellular tight junctions, Tissue Barriers 2014;2:e28960.  Back to cited text no. 85
    
86.
Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM, et al. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Investig 2013;12:4036-49.  Back to cited text no. 86
    
87.
Robertson NG, Hamaker SA, Patriub V, Aster JC, Morton CC. Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. J Med Genet 2003;40:479-86.  Back to cited text no. 87
    
88.
Baek MJ, Park HM, Johnson JM, Altuntas CZ, Jane-Wit D, Jaini R, et al. Increased frequencies of cochlin-specific t cells in patients with autoimmune sensorineural hearing loss. J Immunol 2006;177:4203-10.  Back to cited text no. 88
    
89.
Baruah P. Cochlin in autoimmune inner ear disease: Is the search for an inner ear autoantigen over?, Auris Nasus Larynx 2014;41:499-501.  Back to cited text no. 89
    
90.
Asamura K, Abe S, Imamura Y, Aszodi A. Type IX collagen is crucial for normal hearing. Neuroscience 2005;132:493-500.  Back to cited text no. 90
    
91.
Simmler MC, Cohen-Salmon M, El-Amraoui A, Guillaud L, Benichou JC, Petit C, et al. Targeted disruption of Otog results in deafness and severe imbalance. Nature Genet 2000;24:139-43.  Back to cited text no. 91
    
92.
Cohen-Salmon M, El-Amraoui A, Leibovici M, Petit C. Otogelin: A glycoprotein specific to the acellular membranes of the inner ear. PNAS 1997;94:14450-5.  Back to cited text no. 92
    
93.
Varga R, Kelley PM, Keats PJ, Starr A, Leal SM, Cohn E, et al. Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene. J Med Genet 2003;40:45-50.  Back to cited text no. 93
    
94.
Heidrych P, Zimmermann U, Kuhn S, Franz C, Engel J, Duncker SV, et al. Otoferlin interacts with myosin VI: Implications for maintenance of the basolateral synaptic structure of the inner hair cell. Hum Mol Genet 2009;18:2779-90.  Back to cited text no. 94
    
95.
Al-Wardy NM, Al-Kindi MN, Al-Khabouri MJ, Tamimi Y, Camp GV. A novel missense mutation in the C2C domain of otoferlin causes profound hearing impairment in an Omani familywith auditory neuropathy. Saudi Med J 2016;37:1068-75.  Back to cited text no. 95
    
96.
Frederick DG, Patricia MQ. Deciphering the Roles of C2-Domain-Containing Proteins (Synaptotagmins and Otoferlin) in the Inner Ear. J Neurosci 2011;31:4765-7.  Back to cited text no. 96
    
97.
Ahmed ZM, Goodyear R, Riazuddin S, Lagziel A, Legan PK, Behra M, et al. The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. J Neurosci 2006;26:7022-34.  Back to cited text no. 97
    
98.
Sotomayor M, Weihofen WA, Gaudet R, Corey DP. Structural determinants of cadherin-23 function in hearing and deafness, Neuron 2010;66:85-100.  Back to cited text no. 98
    
99.
Jianchao L, Yunyun H, Qing L, Mingjie Z. Mechanistic basis of organization of the harmonin/ush1c-mediated brush border microvilli tip-link complex. Dev Cell 2016;36:179-89.  Back to cited text no. 99
    
100.
Belyantseva IA, Perrin BJ, Sonnemann KJ, Zhu M, Stepanyan R, McGee J, et al. γ-actin is required for cytoskeletal maintenance but not development. PNAS 2009;106:9703-8.  Back to cited text no. 100
    
101.
Michalski N, Petit C. Genetics of auditory mechano-electrical transduction, Pflugers Archiv Eur J Physiol 2014;467:49-72.  Back to cited text no. 101
    
102.
Perrin BJ, Sonnemann KJ, Ervasti JM. β-Actin and γ-Actin are each dispensable for auditory hair cell development but required for stereocilia maintenance. PLoS Genet 2010;6:1-12.  Back to cited text no. 102
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
Print this article  Email this article