Ion Channel Defects Minireview in Hereditary Hearing Loss

taken into the supporting cells, then diffuses through two syncytial networks back to the marginal cells of the stria vascularis, and is pumped by marginal cells to the Jeffrey R. Holt and David P. Corey* Howard Hughes Medical Institute and Department of Neurobiology endolymph. With such a complex and regulated flux of Harvard Medical School and K, it should perhaps come as no surprise that five Massachusetts General Hospital of the recently identified deafness genes encode ion Boston, Massachusetts 02114 channels and that most of these channels are expressed by specific components of the K recycling pathway. KCNQ1 and KCNE1 Approximately 1 in 1000 children is born with a signifiDefects in two related K channel genes occur in Jervell cant hearing deficit, which critically affects language and Lange-Nielsen Syndrome (JLNS; see references in development. By old age, nearly 1 in 3 of us will have OMIM *192500 and *176261 at http://www.ncbi.nlm.nih. impaired hearing and the resulting difficulty in communigov/omim/). This recessively inherited disorder is charcating with family and friends. Some portion of both the acterized by congenital bilateral deafness and by carcongenital and the progressive hearing loss has a basis diac abnormalities, including a prolonged QT interval in genetic defects. Fortunately, there has been extraorand arrhythmia that can lead to sudden death. Perhaps dinary progress in identifying genes defective in hearing the first description of a JLNS patient was recorded in and balance disorders: nearly 40 such genes have been 1856 by Meissner, involving a deaf girl who was called described, with 10 of them appearing in just the past before the director of her school for a reprimand and year (see G. Van Camp and R. J. H. Smith, Hereditary fell dead. One can imagine the director trying to explain Hearing Loss Homepage at http://dnalab-www.uia.ac.be/ the circumstances to the parents, but the parents were dnalab/hhh/). These are exhilarating times for a field that not surprised: they had lost two other deaf children has sometimes felt like a quiet backwater of neurounder similar circumstances of stress. The genetic bascience. sis, the deafness, and the arrhythmia are all apparent Some of these hearing and balance disorders are synin this incident. dromic, in which deafness occurs along with additional In some families with JLNS, mutations were found in symptoms, such as blindness. Others are nonsyndromic, the K channel gene KCNQ1 (also known as KvLQT1). presenting only with loss of hearing and/or balance. KCNQ1 is expressed in the heart, and mutations in this Hearing loss can be recessively inherited (these are most gene had previously been found in families with long often congenital and more severe), dominantly inherited QT syndrome without deafness. In the inner ear, the (usually progressive), or X linked. Mitochondrial mutaKCNQ1 channel is expressed in the apical surface of tions often produce hearing loss as well, and six such the marginal cells of the stria vascularis and in similar mutations have been identified. Different mutations in cells of the vestibular system (Shen and Marcus, 1998, the same gene can cause both syndromic and nonsynand references therein). The channel is tonically active dromic forms of hearing loss, or dominant and recessive and is thought to pass K into the endolymph. disorders, with several recent examples of each. Associated with KCNQ1 is a smaller subunit encoded The mammalian hearing apparatus, housed in the by KCNE1 (a.k.a. minK, IsK), that does not form part of snail-shaped cochlea (Figure 1), relies on a unique systhe conducting pore (Kaczmarek and Blumenthal, 1997). tem of ion transport among fluid spaces. The scala Mutations in KCNE1 have recently been found in other tympani and scala vestibuli contain perilymph, with an JLNS families that do not have a defect in KNCQ1. Moreionic composition much like typical extracellular fluid over, a null mutation in the mouse ortholog of KCNE1 (low K, high Na). However, the scala media contains causes a loss of K secretion by the stria vascularis of an endolymph with an ionic composition almost like the cochlea and related cells of the vestibular epithelium, cytoplasm (high K, low Na, low Ca1). Ion flux from eventual death of the hair cells, and concomitant loss the marginal cells of the stria vascularis maintains these of both hearing and balance (Vetter et al., 1996). Thus, concentrations and sets the endolymphatic potential to the cells that generate the high K concentration in enabout 180 mV. Any drop in this potential diminishes dolymph require KCNQ1 and KCNE1 to perform that sensitivity to acoustic stimuli. The sensory hair cells function. have their apical, ciliated surfaces facing endolymph GJB2 (Connexin 26) and their basolateral surfaces bathed by perilymph. Another critical element in the pathway for recycling K When the sensory cilia of hair cells are deflected by back to marginal cells has been described by Kikuchi acoustic vibrations, nonselective cation channels in the et al. (1995). Electron microscopy reveals an extensive cilia open and allow K to pass from the endolymph network of gap junctions in two sets of cochlear cells: into the hair cell cytoplasm. Efflux from the hair cell an epithelial cell system that surrounds the hair cells, basolateral membrane passes the K to the perilymph; and an adjacent connective tissue system of fibrocytes from the perilymph, K must somehow get back to the positioned under and around the marginal cells of the endolymph. Kikuchi et al. (1995) suggest that the K is stria (Figure 1). Immunostaining demonstrates that the connexin 26 protein (encoded by GJB2) is expressed by both sets of cells. Cells of the epithelial system have * To whom correspondence should be addressed (e-mail: corey@