Identifying the genes of hearing, deafness, and dysequilibrium.

Hearing loss affects more than 25 million Americans and costs over 50 billion dollars each year, surpassing the combined financial impact of multiple sclerosis, stroke, epilepsy, spinal injury, Huntington’s, and Parkinson’s disease (1). Inherited deafness affects one child in 2,000, and equal numbers of children are born with a significant loss of hearing from other causes (2). In the general population, losses acquired through trauma and disease are even more frequent. A representative sample of 2,000 people would include over 300 who have a significant hearing impairment (3). More than 25% of people suffer from such a condition by the age of 65 and nearly 50% by the age of 80 (2). Infections and diseases of the external and middle ear are treatable, but the majority of significant hearing loss is permanent ‘‘nerve deafness’’, a misnomer for conditions that typically result from loss of hair cells (4). Like the rods and cones in the retina, hair cells in the inner ear convert physical stimuli into neural signals. Our sense of hearing originates from 16,000 hair cells in each cochlea (5). The rapid and critical reflex stabilization of our visual gaze and our sensitivity to head rotation depend on the hair cells in the inner ear’s three semicircular canals. Hair cells in the two other end organs of the vestibular portion of the inner ear lie beneath masses of calcium carbonate crystals and provide part of our sensitivity to gravity. Purely scientific interests provide justification for efforts to understand the mechanisms of the inner ear. The cochlea is sensitive to vibrations so minute that they approach the diameter of an atom, and it achieves temporal resolution on the level of 10 ms (1). It does this while providing excellent resolution of sound frequency across broad bandwidths and deep dynamic range. Yet, for many years the inner ear was effectively ‘‘off limits’’ to protein identification because its small number of detector cells located deep within the temporal bone was unsuited for conventional biochemistry. A few genes were identified via biochemical methods, but the efforts were limited to abundantly expressed genes (6, 7). Now, methods for amplifying small quantities of nucleic acids permit small samples from the sensory transducers in the ear to be investigated effectively. An article in a previous issue of the Proceedings illustrates this point. Heller et al. (8) have identified 120 clones in a cDNA library from auditory epithelia that code for 12 genes that are ear-specific or highly expressed in the ear. Three of the genes had been reported in the ear previously. Two are related to known forms of inherited nonsyndromic deafness. Two are highly expressed in cell types that are unique to the ear, and five others encode collagen isoforms. Such results are heartening in an area of sensory research in which only a limited number of genes had been identified. The type of approach that Heller et al. (8) have taken should continue to provide rapid identification of genes in the ears of chickens and other species. Important progress has been made before this in the identification of mutant genes that are responsible for inherited forms of deafness, but those genes have come to light one at a time (G. Van Camp and R. J. H. Smith, http:yydnalab-www.uia.ac.beydnalabyhhhy). Not surprisingly the first success came in identifying the cause of a syndromic form of inherited deafness, in which hearing impairment is accompanied by other phenotypes. In 1990, a mutation in the COL4A5 collagen gene was identified as the cause of Alport syndrome (9). In 1992, Waardenburg’s syndrome type 1 was identified with a mutation in a homologue of the Pax-3 gene (10). In 1993, a mutation in mitochondrial rRNA was identified with x-linked nonsyndromic and antibiotic-induced deafness (11). In 1995, the first genes in which mutations result in autosomal recessive forms of deafness were identified in mice. Analysis of Snell’s waltzer and shaker-1 demonstrated mutations in the genes for unconventional myosins 6 and 7, respectively (12, 13). Approximately 60 mutant loci in mice are candidates for involvement in the auditory system (14). Mapping of loci for deafness and balance dysfunction in mice already has speeded the identification of several genes that cause inherited deafness in humans. Such information should continue to be of great value in the analysis of the genes discovered in a range of species. In the case of shaker-1, the defects mapped to a site in the mouse genome that is homologous to a region on human chromosome 11 near the locus for Usher syndrome 1B. Based on that indication, reverse transcription-PCR analysis of affected families was undertaken and it showed that the human mutations were indeed in the gene for myosin 7a (15). These findings and the recent discovery that the phenotypes of shaker-2 mice and the human nonsyndromic deafness DFNB3 arise from mutations in myosin 15 (16, 17) have focused attention on the presence of unconventional myosins in hair cells themselves (18). These motor proteins are essential for maintenance of hearing and nonredundant in their actions, but their actual roles in the ear remain to be determined. Successes continued in 1997 with evidence supporting the conclusion that mutations in connexin-26, a gap junction protein, are responsible for a major form of nonsyndromic recessive deafness, DFNB1, and for a more limited form of nonsyndromic dominant hearing loss, DFNA3 (19, 20). In the same year, nonsyndromic dominant deafness DFNA1 was identified with a mutation in the human homologue of the Drosophila gene diaphanous. That gene encodes a protein ligand for profilin, which is a target for regulation of actin polymerization by Rho GTPases. Those facts suggest a possible role for the diaphanous product in the formation of or in dynamic changes that may occur within the cuticular plate or the stereocilia bundle, actin-rich cytoskeletal elements that are unique to hair cells (21). Also in 1997, mutations in the human a-tectorin gene were shown to cause nonsyndromic dominant hearing impairment in one Belgian (DFNA12) and one Austrian (DFNA8) family (22). In 1998, mutations in the transcription factor POU4F3, which is known to be highly expressed in hair cells of mice, were shown to cause a nonsynThe publication costs of this article were defrayed in part by page charge payment. 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