Mutant ion channel in cochlear hair cells causes deafness.

T sensation of balance and hearing is initiated by the conversion of the movement of stereocilia in hair cells of the inner ear into electrical signals in nerve fibers leading to the brain. Driven by pressure waves that are generated by sound, head movement, or gravity, this transformation of energy occurs in structures of exceptional delicacy and intricacy, where movements of atomic dimensions result in perception (1). Not surprisingly, these sensory modalities may be easily and irreversibly damaged by, for example, chemical agents, noise, or head trauma. Because sensory transduction requires the performance of single molecules, it is also sensitive to mutation, and there is now a growing list of genetic loci for deafness that have been successfully traced to genes coding for membrane, regulatory, or structural proteins of the inner ear. In this issue of PNAS, Kharkovets et al. (2) report the expression pattern of a novel potassium channel, KCNQ4, in subtypes of hair cells and neurons of the auditory and vestibular systems. As mutations in the gene encoding KCNQ4 appear to cause one form of nonsyndromic dominant deafness, the results of this paper may lead to a refined molecular understanding of transduction, of the central processing of signals generated by hair cells, and of treatment of deafness and balance disorders. Although the mechanism of mechanotransduction is largely the same throughout the inner ear, hair cells are used in remarkably diverse ways (1). The apex of the hair cell features a bundle of stereocilia, which, when moved in a preferred direction, causes the opening of ion channels in the tips of the stereocilia and the consequent depolarization of the hair cell. A single row of inner hair cells in the organ of Corti, a structure that runs along the middle of the cochlea (Fig. 1), is arranged to transduce sound-driven movements of the cochlear basilar membrane into the release of the neurotransmitter glutamate onto the dendrites of spiral ganglion cells, resulting in signals in the auditory nerve. In mammals, the movement of the basilar membrane is ‘‘tuned,’’ so that progressively higher pitches cause maximal movement of more basal regions of the cochlea; in this way, select populations of inner hair cells are excited by specific frequencies of sound. This mechanical tuning is thought to be critically improved or amplified by a feedback mechanism involving several rows of outer hair cells. Movements of their stereocilia, and depolarization of their cell bodies, result in contractile movements of the outer hair cells, which are widely believed to feed back into movements of the organ of Corti, thus enhancing the resonant behavior of the entire structure. Although the inner hair cells receive afferent innervation, the outer hair cells are innervated by cholinergic efferent axons that cause damping of hair cell activity, a protective response to intense noise. In the vestibular hair cells of the utricular and saccular maculi, and the crista ampularis of each semicircular canal, position and movement of the head causes deflection of hair cell stereocilia, resulting in release of transmitter onto dendrites of the vestibular ganglion neurons. Here, too, there are two varieties of hair cell, Type I and Type II, but the functional significance of this distinction is unclear. Unlike Type II cells, the Type I hair cell has a remarkable amphora-like shape and is almost entirely encased by the huge calyciform dendritic terminal of the ganglion cell (Fig. 1). Ion channels of specialized composition figure critically in the performance of the auditory and vestibular systems. As noted, the purpose of hair cell stereocilia is to activate mechanosensitive ion channels. The flow of ions through these channels is driven by an elevated potassium concentration in the endolymph, the fluid overlying the hair cells. Once depolarized, calcium and potassium channels in the hair cells may mediate tuned electrical oscillations, and the release of neurotransmitter (3). Efferent feedback onto the outer hair cells utilizes a novel acetylcholine receptor subunit, a-9, which gates a channel of exceptionally high calcium permeability (4). In the central nervous system (CNS), specialized neural circuits extract specific aspects of auditory and vestibular information. The precise complement of ion channels they express enables these neurons to preserve temporal aspects of electrical signals coming from the inner ear (5). For example, spherical bushy cells and octopus cells of the ventral cochlear nucleus express a low-threshold potassium channel, probably composed of the Kv1.1 and -1.2 subunits, which is essential for their ability to respond with microsecond precision. Transmission through these circuits often relies on an unusually fast-gating glutamate-activated channel containing GluR4-flop subunits. Clearly, mutations in genes encoding specific ion channels could have highly selective effects on sensory function. A wide variety of inherited deafness disorders have been described, and recent efforts have determined many of the loci and gene products involved (see http:yy dnalab-www.uia.ac.beydnalabyhhhy for a comprehensive description of deafness loci). One family of potassium channel, termed KCNQ, figures in syndromic and nonsyndromic deafness disorders, suggesting that these channels are both susceptible to mutation and important in sensory transduction. For example, mutations in KCNQ1, or an accessory protein KCNE1, may lead to lethal distortions in cardiac action potentials, causing long QT syndrome (LQTS); when additional mutations are present, patients may also show congenital deafness, collectively termed Jervell and Lange-Nielsen syndrome (6). Loss of potassium channel function in this disorder may inhibit the generation of a potassiumrich endolymph, leading to hearing impairment. In 1999, Jentsch and colleagues reported the determination of the gene responsible for another form of hereditary deafness, DFNA2 (7). DFNA refers to the class of nonsyndromic autosomal dominant deafnesses. The gene mapped to this locus was KCNQ4, a new member of the KCNQ family of potassium channel, which in DFNA2 families features a missense mutation, G285S, that eliminates