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Review Hearing Molecules: Contributions from Genetic Deafness

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Review Hearing Molecules: Contributions from Genetic Deafness Cell. Mol. Life Sci. DOI 10.1007/s00018-007-6417-3 Cellular and Molecular Life Sciences Birkhuser Verlag, Basel, 2007 Review Hearing molecules: contributions from genetic deafness M.D. Eisena and D.K. Ryugoa,b Departments of aOtolaryngology-Head and Neck Surgery and bNeuroscience, Center for Hearing and Balance, Traylor 510, 720 Rutland Avenue, Baltimore, Maryland 21205 (USA), Fax: +4106144748, e-mail: [email protected] Received 20 September 2006; received after revision 24 October 2006; accepted 5 December 2006 Abstract. Considerable progress has been made over decade that address the function of the proteins the past decade identifying many genes associated implicated in genetic deafness and to place them in the with deafness. With the identification of these heredi- context of basic molecular mechanisms in hearing. tary deafness genes and the proteins they encode, The first part of this review highlights structural and molecular elements of basic hearing mechanisms functional features of the cochlea and auditory nerve. emerge. As functional studies of these molecular This background will provide a context for the second elements become available, we can put together the part, which addresses the molecular mechanisms pieces of the puzzle and begin to reach an under- underlying cochlear function as elucidated by genetic standing of the molecular mechanisms of hearing. The causes of deafness. goal of this review is to discuss studies over the past Keywords. Genetic deafness, auditory, cochlea, hearing, hair cell. Introduction auditory processing, whereas sensorineural’ hearing loss refers to malfunction of the electrochemical arm. Normal mammalian auditory function relies on two Conductive hearing loss typically results from middle broad categories of function – mechanical and electro- ear pathology – tympanic membrane perforation, chemical. First, sound must be directed to the cochlea, ossicular discontinuity or fixation, or middle ear analyzed into its frequency components, and then into infections that are often amenable to improvement oscillations of the cochlear hair cell hair bundle. with either amplification (i.e. hearing aids) or surgical Second, hair bundle oscillations must be converted procedures – and is not addressed further in this into an electrochemical signal of the auditory neuro- review. Sensorineural hearing loss, on the other hand, nal pathway. Malfunction of either of these auditory can result from malfunction anywhere along the processing components results in hearing loss, an auditory pathway, from the hair cell to higher-order affliction that affects an estimated 70 million people central auditory processing loci. Known etiologies of worldwide [1]. The hearing loss associated with these sensorineural hearing loss are abundant. Nearly half two broad components of auditory processing has of the cases of congenital deafness can be attributed to considerably disparate clinical presentation, diagno- genetic causes. One-third of these defects we accom- sis, and management. panied by identified disorders in other systems, and we In the clinic, the two types of hearing loss are typically considered as syndromic’ deafness. The remaining considered as separate entities. Conductive’ hearing two-thirds, however, are isolated to hearing loss and loss refers to malfunction of the mechanical arm of considered non-syndromic.’ 2 M.D. Eisen and D.K. Ryugo Genes and deafness Considerable progress has been made over the past decade identifying genetic loci and genes associated with mammalian deafness. The list of loci is well over 100 as of the submission of this review, and there are approximately 45 genes identified from these loci. An updated database of the non-syndromic deafness genes and loci is maintained at the Hereditary Hearing Loss Homepage (http://webhost.ua.ac.be/ hhh/). With the identification of hereditary deafness genes and the proteins they encode, molecular ele- ments of basic hearing mechanisms emerge. With studies of the function of these identified molecular elements we can put together the pieces of the puzzle and begin to reach an understanding of the molecular mechanisms of hearing. The goal of this review is to discuss studies of the function of the proteins impli- cated in genetic deafness in the context of basic molecular mechanisms in hearing. Understanding molecular mechanisms of deafness Figure 1. Schematic demonstrating the basic anatomy of the begins with a basic understanding of the normal cochlea. A. Cross section through one turn of the cochlea. St = Stria anatomy and physiology of the auditory pathway. The vascularis, SM = scala media, SV = scala vestibuli, ST = scala tympani, IHC = inner hair cell, OHC = outer hair cell, TM = first part of this review thus briefly highlights struc- tympanic membrane, RM = Reisners membrane, SG = spiral tural and functional features of the cochlea and ganglion. B. Schematic of an inner (left) and outer (right) hair cell. auditory nerve. This background will provide a con- AT = afferent terminal and synapse, HB = stereociliary (hair) text for the second part of this review that addresses bundle, ET = efferent terminal. C. Schematic of two stereocilia within a hair bundle. SL = side links, CP = cuticular plate, R = the molecular mechanisms underlying cochlear func- rootlet, TL = tip link. tion as elucidated by genetic causes of deafness. We are interested in cochlear function, rather than devel- opment, and as such will focus on the developed cochlea. Since the intracellular resting potential of hair cell receptors is around –70 mV, the potential difference across the hair cell apex is a remarkable 150 mV. This Cochlear anatomy and physiology large potential difference represents a tremendous ionic force and serves as the engine driving the Figure 1 is a schematic diagram showing the anatomic mechanoelectrical transduction process of the hair details of the cochlea at different levels of magnifica- cell. tion; it should be used to reference anatomical Several cellular and extracellular specializations with- structures throughout the text. The cochlea is a in the cochlea function to decompose the mechanical spiraled bony tube housing three fluid-filled chambers stimulus of sound into its frequency components and that run along its length. Highly specialized cells to convert these stimuli into an electrochemical signal within the cochlea regulate the ionic composition of conveyed by discharges along auditory nerve fibers. these chambers. The outer chambers (scala tympani The stiffness gradient of the basilar membrane along and scala vestibuli) contain perilymph, a filtrate of the length of the cochlea functions like a bank of cerebrospinal fluid of similar composition to extrac- frequency band-pass filters aligned from the highest ellular fluid (high sodium, low potassium). The middle frequency at the cochlear base to the lowest frequency chamber (scala media) contains endolymph, a high- at its apex. Atop the basilar membrane rests the organ potassium, low-sodium fluid of similar composition to of Corti, which contains sensory hair cells and intracellular fluid. The outer wall of the scala media is supporting cells. Specialized supporting cells in the lined by the stria vascularis, a vascular epithelial layer organ of Corti complement the hair cells and play a that serves as the metabolic control center of the vital role in maintaining the integrity and function of cochlea. the hair cells. A final component of the cochlea As a result of the differences in ionic composition functional apparatus is the tectorial membrane, a between the compartments, the potential difference gelatinous ribbon of extracellular matrix attached between endolymph and perilymph is about +80 mV. medially and contacting the outer hair cell hair This positive potential is the largest found in the body. bundles. Cell. Mol. Life Sci. Review Article 3 Hair cells are polarized. From their apex protrude a spirals medially and in parallel to the organ of Corti. bundle of sensory hairs called stereocilia, which are The central axons of the spiral ganglion cells then composed of actin filaments. The synaptic machinery coalesce within the central core of the cochlea to populates the basolateral cell surface. Interconnecting course through the internal auditory canal towards the links between the stereocilia have two functions – brainstem as the auditory nerve. side-to-side links between stereocilia seem to provide structural stability to the sensory hair bundle, while links from the tip of a shorter stereocilia to the shaft of Mechanisms of hereditary sensorineural hearing loss a longer neighbor (i.e. “tip links”) attach to the mechanoelectric transduction channel [2, 3]. With In reviewing the identified genetic deafness genes, we mechanical oscillations of the basilar membrane, will focus on the gene product and attempt to use the stereocilia within hair bundles are displaced relative identified gene products to create a framework for a to each other. This displacement puts the tip links better understanding of basic mechanisms of hearing. under tension and pulls open cation channels. Driven Identification and characterization of genes associat- by the endocochlear potential, the flow of cations into ed with deafness is a progressive field. Our goal is to the hair bundle depolarizes the hair cell membrane summarize advances made in the “post-genomic” potential. The intracellular processes that then re- aspects of hereditary deafness, and to create a frame- spond to these changes
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