Hearing Impairment: A Panoply of Genes and Functions
Authors: Amiel A. Dror, Karen B. Avraham
Journal: Neuron (2010)

Research in the genetics of hearing and deafness has evolved rapidly over the past years, providing the molecular foundation for different aspects of the mechanism of hearing. Considered to be the most common sensory disorder, hearing impairment is genetically heterogeneous. The multitude of genes affected encode proteins associated with many different functions, encompassing overarching areas of research. These include, but are not limited to, developmental biology, cell biology, physiology, and neurobiology. In this review, we discuss the broad categories of genes involved in hearing and deafness. Particular attention is paid to a subgroup of genes associated with inner ear gene regulation, fluid homeostasis, junctional complex and tight junctions, synaptic transmission, and auditory pathways. Overall, studies in genetics have provided research scientists and clinicians with insight regarding practical implications for the hearing impaired, while heralding hope for future development of therapeutics. Research in the genetics of hearing and deafness has evolved rapidly over the past years, providing the molecular foundation for different aspects of the mechanism of hearing. Considered to be the most common sensory disorder, hearing impairment is genetically heterogeneous. The multitude of genes affected encode proteins associated with many different functions, encompassing overarching areas of research. These include, but are not limited to, developmental biology, cell biology, physiology, and neurobiology. In this review, we discuss the broad categories of genes involved in hearing and deafness. Particular attention is paid to a subgroup of genes associated with inner ear gene regulation, fluid homeostasis, junctional complex and tight junctions, synaptic transmission, and auditory pathways. Overall, studies in genetics have provided research scientists and clinicians with insight regarding practical implications for the hearing impaired, while heralding hope for future development of therapeutics. Similar to other sensory loss, hearing impairment has a wide spectrum of etiologies originating from both environmental and genetic factors. Prolonged exposure to high intensity sound poses high risk for auditory function and can lower hearing thresholds. Acoustic trauma, as a result of a sudden loud noise, can lead to temporary and/or permanent hearing impairment. Among environmental factors, different viral infections, as well as neonatal anoxia and hyperbilirubinemia, can also cause permanent hearing defects. Long-term augmentation of ototoxic drugs such as aminoglycoside and gentamicin antibiotics has an adverse effect on the auditory system and accounts for hearing defects (Yorgason et al., 2006Yorgason J.G. Fayad J.N. Kalinec F. Understanding drug ototoxicity: molecular insights for prevention and clinical management.Expert Opin. Drug Saf. 2006; 5: 383-399Crossref PubMed Scopus (32) Google Scholar). Unlike the genetics factors dictated by hereditary information, some of the environmental factors can be reduced or prevented by raising awareness for appropriate protection. Genetic insults contributing to hearing defects poses greater challenges. The clinical heterogeneity of hearing loss is characterized by common classifications based on several parameters such as onset, severity, and the presence of additional clinical manifestations other than deafness. Hearing loss that occurs prior to speech acquisition is termed prelingual deafness, either congenital or appearing after birth. A hearing disability that appears early in childhood can have a major consequence on language acquisition. Age-related hearing loss (ARHL) affects the elderly population with high prevalence, and its appearance and progression is influenced by both genetic and environmental factors (Cruickshanks et al., 1998Cruickshanks K.J. Wiley T.L. Tweed T.S. Klein B.E. Klein R. Mares-Perlman J.A. Nondahl D.M. Prevalence of hearing loss in older adults in Beaver Dam, Wisconsin. The epidemiology of hearing loss study.Am. J. Epidemiol. 1998; 148: 879-886Crossref PubMed Google Scholar, Gates et al., 1999Gates G.A. Couropmitree N.N. Myers R.H. Genetic associations in age-related hearing thresholds.Arch. Otolaryngol. Head Neck Surg. 1999; 125: 654-659Crossref PubMed Google Scholar). About 60% of the population over the age of 65 suffers from different degrees of hearing loss, with a decline in sensitivity to sound, accompanied with reduced speech perception. Hearing loss is also categorized based on the frequency loss and the severity of hearing thresholds. High tone loss refers to reduced sensitivity of high-frequency acoustic stimulus, as opposed to low tone loss for the low frequencies. The terms profound, mild, and moderate describe the descending order of different severity levels of hearing impairments. When hearing loss is the only apparent abnormality, it is referred to as nonsyndromic hearing loss (NSHL). In other cases hearing loss occurs along with a variety of other malformations and thus is designated as syndromic hearing loss (SHL). The auditory system bears one of the most intricate mechanisms of sensation ability in humans. The inner ear, a fluid-filled organ, is responsible for transforming the mechanical energy of the sound waves into electrical stimuli, which will eventually be translated in the brain. Anatomically, the inner ear is divided into the auditory and vestibular systems. While the auditory system is responsible for sound sensation, the vestibular system is responsible for three-dimensional orientation and gravity perception. The similarities between these two systems often lead to balance disorders in hearing impaired individuals (Gresty and Brookes, 1997Gresty M. Brookes G. Deafness and vertigo.Curr. Opin. Neurol. 1997; 10: 36-42Crossref PubMed Google Scholar). The auditory system is composed of a snail-shaped cochlea. The cochlea is a fluid-filled tube coiled in a spiral shape around the modiolus (Figure 1). Upon viewing a longitudinal cross-section, the cochlear canal is divided into three compartments (scalae). The scala media filled with endolymph lies between two larger perilymphatic filled compartments, the scala vestibuli and scala tympani. The scala media contains the cochlear sensory epithelium, the organ of Corti, which sits on top of the basilar membrane (Corti, 1851Corti A. Recherches sur l'organe de l'ouiė des mammifères.Ztschr. wissensch. Zool. 1851; 3: 109-169Google Scholar). The organ of Corti contains specialized sensory cells, known as hair cells, arranged in three rows of outer hair cells (OHCs) and one row of inner hair cells (IHC). The tectorial membrane, which sits on top of the organ of Corti, is an extracellular auxiliary structure contributing to hair-cell excitation (Lukashkin et al., 2010Lukashkin A.N. Richardson G.P. Russell I.J. Multiple roles for the tectorial membrane in the active cochlea.Hear. Res. 2010; 266: 26-35Crossref PubMed Scopus (12) Google Scholar). Sound-induced mechanical vibration of the middle ear is transmitted to the cochlea, generating movements of its associated fluids (Lawrence et al., 1961Lawrence M. Wolsk D. Litton W.B. Circulation of the inner ear fluids.Ann. Otol. Rhinol. Laryngol. 1961; 70: 753-776Crossref PubMed Google Scholar). As a consequence, deflection of the basilar membrane activates the sensory cells that transduce the mechanical stimulation into electrical signal. The number of cochlear turns, combined with the graded length and stiffness of the basilar membrane along the length of the cochlea, contributes to the determination of the audible range of frequencies (Manoussaki et al., 2006Manoussaki D. Dimitriadis E.K. Chadwick R.S. Cochlea's graded curvature effect on low frequency waves.Phys. Rev. Lett. 2006; 96: 088701Crossref Scopus (24) Google Scholar). The cochlear hair cells have a substantial role in translating mechanical forces evoked by sound into an electrical signal. The apical surface of each hair cell contains protrusions of actin-rich filaments known as stereocilia, which play a pivotal role in this mechanism. These membrane-bound filaments form a typical staircase arrangement, stabilized by a rich network of interconnections. Most significant, a tip link is present between the tops of stereocilia in the upper row of the hair bundle to the tips of stereocilia on the next lower row (Kazmierczak et al., 2007Kazmierczak P. Sakaguchi H. Tokita J. Wilson-Kubalek E.M. Milligan R.A. Müller U. Kachar B. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells.Nature. 2007; 449: 87-91Crossref PubMed Scopus (226) Google Scholar, Pickles et al., 1984Pickles J.O. Comis S.D. Osborne M.P. Cross-links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction.Hear. Res. 1984; 15: 103-112Crossref PubMed Scopus (299) Google Scholar). Upon mechanical stimulation that force deflections of the hair bundles, the tip links trigger the opening of the mechanoelectrical transduction (MET) channels that are located at stereocilia tips across the bundle. The synchronized opening of the MET channels depolarizes the cells and initiates electrical signals to the auditory nerve. The hair bundles of the cochlear hair cells face the scala media immersed in its fluid, the endolymph. Unlike other physiological fluids in the human body, the endolymph has a unique electrolyte composition with high potassium (K+) and low sodium (Na+) concentrations (Wangemann and Schacht, 1996Wangemann P. Schacht J. Cochlear homeostasis.in: Dallos P. Popper A.N. Fay R.R. The Cochlea. Handbook of Auditory Research. Springer, New York1996: 130-185Google Scholar). When hair cells are mechanically excited, an influx of potassium (K+) and calcium (Ca2+) ions depolarize the cell and trigger the release of neurotransmitter at the basal pole of the hair cell (Dallos, 1996Dallos P. Overview: cochlear neurophysiology.in: Dallos P. Popper A.N. Fay R.R. Springer Handbook of Auditory Research: The Cochlea. Springer, Berlin1996: 1-43Google Scholar). The afferent auditory pathway connects the sensory machinery of the cochlea to the brain, paving the route for propagation of neuronal electrical signals evoked by an acoustic stimulus. The apical side of cochlear hair cells is responsible for their mechanosensory role mediated by hair bundles, whereas the basolateral side of the cell is responsible for synaptic transmission. Thus, IHCs also function as presynaptic terminals, by coding acoustic signals to neurotransmitter release onto auditory afferent nerve fibers (Fuchs, 2005Fuchs P.A. Time and intensity coding at the hair cell's ribbon synapse.J. Physiol. 2005; 566: 7-12Crossref PubMed Scopus (62) Google Scholar). Specialized ribbon synapses located at presynaptic active zones of IHCs are tethered by synaptic vesicles and are sufficient for their precise temporal release in response to sound (Glowatzki et al., 2008Glowatzki E. Grant L. Fuchs P. Hair cell afferent synapses.Curr. Opin. Neurobiol. 2008; 18: 389-395Crossref PubMed Scopus (35) Google Scholar). IHCs serve as the major acoustic sensors, whereas the OHCs increase amplification sensitivity and frequency selectivity of the cochlea (Dallos, 1992Dallos P. The active cochlea.J. Neurosci. 1992; 12: 4575-4585Crossref PubMed Google Scholar). Each IHC is innervated by more than 15 afferent sensory neurons, providing efficient parallel channels for transmission of an acoustic stimulus to the central nervous system (Rubel and Fritzsch, 2002Rubel E.W. Fritzsch B. Auditory system development: Primary auditory neurons and their targets.Annu. Rev. Neurosci. 2002; 25: 51-101Crossref PubMed Scopus (304) Google Scholar). The primary electrical signal initiated by the IHCs is processed in the spiral ganglia, the auditory nerve, and integrated in the afferent auditory pathway. Further downstream to the auditory nerve, the auditory pathway contains four major intermediate stations, including the cochlear nuclei, superior olive, inferior colliculus, and medial geniculate body (Webster, 1992Webster D.B. An overview of mammalian auditory pathways with an emphasis on humans.in: Webster D.B. Popper A.N. Fay R.R. The Mammalian Auditory Pathway: Neuroanatomy. Springer-Verlag, New York1992: 1-26Crossref Google Scholar). In the brain, the collected auditory inputs are decoded and analyzed within the auditory cortex in the temporal lobe. The cochlear hair cells are arranged in a tonotopic gradient that enables acquisition of sensory transduction of the audible range of frequencies. This organization is characterized by a gradient along the length of the cochlea, sensing high frequencies at the base and low frequencies at the apex (Romand, 1997Romand R. Modification of tonotopic representation in the auditory system during development.Prog. Neurobiol. 1997; 51: 1-17Crossref PubMed Scopus (24) Google Scholar). Likewise, further communication of acoustic signals with the brain is tonotopically preserved within the different levels of the auditory pathway (Rubel and Fritzsch, 2002Rubel E.W. Fritzsch B. Auditory system development: Primary auditory neurons and their targets.Annu. Rev. Neurosci. 2002; 25: 51-101Crossref PubMed Scopus (304) Google Scholar). This high selectivity and sensitivity for frequency specific signals provides us with the ability of orchestrated perception to decipher between a rich spectrum of sounds. Given the complexity of the hearing mechanism, it should come as no surprise that a panoply of genes have been discovered to be involved in hearing loss. To date, more than 50 genes and 80 additional loci have been linked to various degrees of hearing impairment (Figure 2). Taking advantage of standardized nomenclature, a common classification of the loci and genes for hearing impairment has been established (HUGO Gene Nomenclature Committee, http://www.genenames.org/). Depending on the inheritance mode, the nonsyndromic genes or loci are classified accordingly: DFNA (dominant), DFNB (recessive), DFNX (x-linked), DFNY (y-linked), and DFNM (modifier). Additional specific symbols are used for different forms of hearing loss including otosclerosis (OTSC), auditory neuropathy (AUNA), and mitochondrial (MRTNR, MTTS) genes. For each locus, the relevant symbol is depicted with a number next to it, designated by the chronological order of its discovery. Routinely updated, the Hereditary Hearing Loss Homepage (http://hereditaryhearingloss.org/) provides an open and reliable resource for all listed genes and loci. Well-established genetic studies from the past years have highlighted the pathophysiologies underlying mutations in many of these genes (Dror and Avraham, 2009Dror A.A. Avraham K.B. Hearing loss: Mechanisms revealed by genetics and cell biology.Annu. Rev. Genet. 2009; 43: 411-437Crossref PubMed Scopus (77) Google Scholar). Several studies have successfully integrated groups of proteins encoded by these genes into common pathways of inner ear function, providing explanations for the similar phenotypes of affected individuals carrying mutations in different genes of the same network. One such example is the Usher network of proteins, with mutations in nine different genes underlying this most common syndrome of deafness and blindness (Saihan et al., 2009Saihan Z. Webster A.R. Luxon L. Bitner-Glindzicz M. Update on Usher syndrome.Curr. Opin. Neurol. 2009; 22: 19-27Crossref PubMed Scopus (68) Google Scholar) Nevertheless, human variants of the same gene may result in clinical heterogeneity. For example, mutations in the SLC26A4 gene are linked with either NSHL, DFNB4, or a syndromic form known as Pendred's syndrome (PS) with enlargement of the thyroid gland (Pera et al., 2008Pera A. Dossena S. Rodighiero S. Gandía M. Bottà G. Meyer G. Moreno F. Nofziger C. Hernández-Chico C. Paulmichl M. Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA.Proc. Natl. Acad. Sci. USA. 2008; 105: 18608-18613Crossref PubMed Scopus (51) Google Scholar). The attempt to identify genes for hearing impairment by conventional methods has led to great success over the past two decades. Linkage analysis with microsatellite markers has been used widely, allowing the chromosomal location of deafness genes to be mapped in families all over the world. Once the linkage region was elucidated, in the most recent years, mutation analysis by Sanger sequencing often led to the identification of the causative mutation. However, despite the great contribution of linkage analysis methods, many deafness genes remain to be elucidated. A long list of human loci linked with hearing impairment is still pending for further gene discovery (Hereditary Hearing Loss Homepage). Furthermore, complex mutations such as duplications of an entire gene within a detective locus could not be assessed by standard sequencing approaches. For example, taking advantage of array comparative genomic hybridization (array CGH), geneticists can track chromosomal imbalances. Utilizing this platform, a tandem genomic duplication of the TJP2 gene was recently identified to be responsible for progressive NSHL in DFNA51 individuals (Walsh et al., 2010aWalsh T. Pierce S.B. Lenz D.R. Brownstein Z. Dagan-Rosenfeld O. Shahin H. Roeb W. McCarthy S. Nord A.S. Gordon C.R. et al.Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.Am. J. Hum. Genet. 2010; 87: 101-109Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Both the DFNB79 and DFNB82 genes, encoding taperin and GPSM2, respectively, were identified by targeted genome capture, combined with massively parallel sequencing (Rehman et al., 2010Rehman A.U. Morell R.J. Belyantseva I.A. Khan S.Y. Boger E.T. Shahzad M. Ahmed Z.M. Riazuddin S. Khan S.N. Riazuddin S. Friedman T.B. Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79.Am. J. Hum. Genet. 2010; 86: 378-388Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Walsh et al., 2010bWalsh T. Shahin H. Elkan-Miller T. Lee M.K. Thornton A.M. Roeb W. Abu Rayyan A. Loulus S. Avraham K.B. King M.C. Kanaan M. Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82.Am. J. Hum. Genet. 2010; 87: 90-94Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). With the development of advanced new technologies such as massively parallel sequencing, it is expected that more genes will be added to the list of human genes for hearing impairment in a relatively short period. Animal models have provided an invaluable tool for studying advanced hearing mechanisms in a way that could not have been achieved only by human studies. A wide array of organisms, including zebrafish, chick, and mouse, have complemented the human genetics field with an in-depth understanding of protein function. Among the models, the striking similarity between human and mouse inner ear structure and function has defined the mouse as a prominent animal model for human deafness. The ease of gene overexpression, depletion, and targeted mutagenesis has enabled researchers to create reliable animal models for genetic forms of hearing loss to mimic the corresponding mutation in humans. Once a novel human deafness gene is discovered, the generation of an animal model is optimal for studying its function. Thus, in parallel to gene discovery in human families, a long list of mouse models for hearing loss have been established (Leibovici et al., 2008Leibovici M. Safieddine S. Petit C. Mouse models for human hereditary deafness.Curr. Top. Dev. Biol. 2008; 84: 385-429Crossref PubMed Scopus (37) Google Scholar). This tight crosstalk between human and mouse genetics also benefits in the other directions, from mouse to human (Brown et al., 2008Brown S.D. Hardisty-Hughes R.E. Mburu P. Quiet as a mouse: Dissecting the molecular and genetic basis of hearing.Nat. Rev. Genet. 2008; 9: 277-290Crossref PubMed Scopus (72) Google Scholar). Mutants that have arisen due to spontaneous mutations and chemically induced mutants generated by N-ethyl-N-nitrosourea (ENU) mutagenesis have led to the discovery of new deafness genes in mice and subsequent discovery of their human orthologs (Brown et al., 2009Brown S.D. Wurst W. Kühn R. Hancock J.M. The functional annotation of mammalian genomes: The challenge of phenotyping.Annu. Rev. Genet. 2009; 43: 305-333Crossref PubMed Scopus (40) Google Scholar). For example, identification of a recessive mutation in the Loxhd1 gene of the samba deaf ENU mice led to the discovery of its human ortholog LOXHD1 within the previously mapped DFNB77 locus responsible for autosomal recessive NSHL (Grillet et al., 2009Grillet N. Schwander M. Hildebrand M.S. Sczaniecka A. Kolatkar A. Velasco J. Webster J.A. Kahrizi K. Najmabadi H. Kimberling W.J. et al.Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.Am. J. Hum. Genet. 2009; 85: 328-337Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). This phenotype-driven approach has not only enriched the list of known deafness genes, but also enabled scientists to further study the pathophysiology underlying different mutations. The availability of state-of-the-art scientific tools, including in vivo studies on animal models, has opened a new venue for understanding the complex mechanisms of proteins in the wide context of the auditory network. Gene discovery in humans and protein characterization in animal models have revealed numerous molecular pathways in the inner ear. These include but are not limited to gene regulation, fluid homeostasis, mechanotransduction, and structure (Figure 3). Gene regulation plays an essential role in development. It is therefore not surprising that numerous transcription factors, including EYA4, POU3F4, POU4F3, TFCP2L3, and ESRRB, have been linked with hearing loss. Recently, a mutation in the microRNA miR-96 was also implicated in progressive hearing loss in humans, introducing the first microRNA deafness gene (Mencía et al., 2009Mencía A. Modamio-Høybjør S. Redshaw N. Morín M. Mayo-Merino F. Olavarrieta L. Aguirre L.A. del Castillo I. Steel K.P. Dalmay T. et al.Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss.Nat. Genet. 2009; 41: 609-613Crossref PubMed Scopus (177) Google Scholar). miR-96 resides within a cluster of three miRNAs, while the other two, miR-183 and miR-182, are also expressed in the inner ear and participate in the regulation of gene expression (Figure 4; Weston et al., 2006Weston M.D. Pierce M.L. Rocha-Sanchez S. Beisel K.W. Soukup G.A. MicroRNA gene expression in the mouse inner ear.Brain Res. 2006; 1111: 95-104Crossref PubMed Scopus (91) Google Scholar). A wide number of genes encoding different transporters and channels are highly expressed in the ear and participate in maintaining the unique fluid homeostasis (Lang et al., 2007Lang F. Vallon V. Knipper M. Wangemann P. Functional significance of channels and transporters expressed in the inner ear and kidney.Am. J. Physiol. Cell Physiol. 2007; 293: C1187-C1208Crossref PubMed Scopus (88) Google Scholar). The critical nature of maintaining appropriate fluid homeostasis is highlighted by evidence that mutations in genes such as the solute carrier transporter gene SLC26A4 (pendrin) lead to prelingual deafness. Constant secretion of potassium into the endolymph and generation of endochlear potential is also paramount for inner ear physiology and requires potassium recycling machinery (Zdebik et al., 2009Zdebik A.A. Wangemann P. Jentsch T.J. Potassium ion movement in the inner ear: Insights from genetic disease and mouse models.Physiology (Bethesda). 2009; 24: 307-316Crossref PubMed Scopus (53) Google Scholar), with a network of connexin gap junction proteins suggested to support this process. The compartmentalization of the two distinct extracellular fluids of the inner ear, endolymph and perilymph, requires a network of epithelia to establish a tight junctional barrier surrounding the scala media (endolymph). In this regard, a group of genes encoding tight junction proteins, including CLDN14, TRIC, and TJP2, participates in the formation of the mechanical barrier between epithelial cells in the inner ear. These genes have also been implicated in different forms of hearing impairment and their functional significance in hearing is outlined, including barrier formation, cell polarization, and signal transduction. The inner ear is responsible for transforming the mechanical energy of the sound waves into electrical stimuli, and its function relies critically on the integrity of the extracellular matrix of the tectorial membrane and the basilar membrane in order to achieve proper mechanical stimulation of the cochlear sensory cells. This process depends upon on the appropriate temporal and spatial expression patterns of the participating matrix proteins (Richardson et al., 2008Richardson G.P. Lukashkin A.N. Russell I.J. The tectorial membrane: One slice of a complex cochlear sandwich.Curr. Opin. Otolaryngol. Head Neck Surg. 2008; 16: 458-464Crossref PubMed Scopus (26) Google Scholar). Accordingly, several extracellular matrix proteins encoded by TECTA (α-tectorin), COL11A2 (collagen, type XI, alpha 2), COCH (cochlin), OTOA (otoancorin), and STRC (stereocilin) have been associated with different forms of hearing impairment. The inner ear also expresses another prominent group of genes belonging to the myosin family of motor proteins, including MYO1A, MYO3A, MYO6, MYO7A, MYO15A, and MYH9 (Petit and Richardson, 2009Petit C. Richardson G.P. Linking genes underlying deafness to hair-bundle development and function.Nat. Neurosci. 2009; 12: 703-710Crossref PubMed Scopus (73) Google Scholar). Hair cell-specific myosins were shown to have a crucial role in hair bundle organization and function. Human mutations of these myosins are associated with NSHL, while MYO7A mutations can also lead to a syndromic form of blindness and deafness known as Usher syndrome. Human mutations in several additional genes have also been linked to familial cases of Usher syndrome, while their encoded proteins are essential for the morphogenesis and cohesion of hair bundles of cochlear hair cells (Saihan et al., 2009Saihan Z. Webster A.R. Luxon L. Bitner-Glindzicz M. Update on Usher syndrome.Curr. Opin. Neurol. 2009; 22: 19-27Crossref PubMed Scopus (68) Google Scholar). Four of these genes, CDH23, PCDH15, USH2A, and VLGR1, encode adhesion proteins; three genes, WHRN, USH1C, and SANS, encode scaffolding proteins; and the USH3A gene encodes an integral protein. The cell-cell adhesion proteins cadherin 23 (CDH23) and protocadherin 15 (PCDH15) form the tip link between adjacent stereocilia (Kazmierczak et al., 2007Kazmierczak P. Sakaguchi H. Tokita J. Wilson-Kubalek E.M. Milligan R.A. Müller U. Kachar B. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells.Nature. 2007; 449: 87-91Crossref PubMed Scopus (226) Google Scholar) and support the mechanical tension of the hair bundle and its mechanotransduction, with mutations in these genes causing NSHL or Usher syndrome (Ahmed et al., 2003Ahmed Z.M. Riazuddin S. Ahmad J. Bernstein S.L. Guo Y. Sabar M.F. Sieving P. Riazuddin S. Griffith A.J. Friedman T.B. et al.PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23.Hum. Mol. Genet. 2003; 12: 3215-3223Crossref PubMed Scopus (137) Google Scholar, Bork et al., 2001Bork J.M. Peters L.M. Riazuddin S. Bernstein S.L. Ahmed Z.M. Ness S.L. Polomeno R. Ramesh A. Schloss M. Srisailpathy C.R. 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: 26-37Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). More details on these genes and their roles in deafness have been reviewed in detail elsewhere (Gillespie and Müller, 2009Gillespie P.G. Müller U. Mechanotransduction by hair cells: models, molecules, and mechanisms.Cell. 2009; 139: 33-44Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Finally, the normal function of the auditory system also depends critically on its ability to transduce mechanical stimuli into an electrical signal that appropriately propagates from the cochlea to the brain. Mutations in genes that are critical to this synaptic transmission process, such as SLC17A8 (VGLUT3) and OTOF (otoferlin), can lead to deafness, including a relatively rare hearing disorder, auditory neuropathy, associated with improper functioning of the auditory nerve. In the current review we have focused on a subgroup of genes encoding proteins associated with different aspects of auditory function, including gene regulation, fluid homeostasis, junctional complex and tight junctions, synaptic transmission, and the auditory pathway. Individual genes and pathways have been chosen as a way to highlight the types of processes critical for proper auditory function, and illustrates how alterations in these gene products can lead to hearing impairment. Temporal and spatial regulation of gene expression is fundamental for development, cellular proliferation and differentiation, morphogenesis, and drives the specific function of different cells and tissues (Latchman, 2007Latchman D. Gene Regulation. Taylor & Francis, Oxford2007Google Scholar). A large group of regulatory proteins, including transcript