Genes and environment

Some cases of hearing impairment result primarily from a single gene mutation inherited in a Mendelian fashion, and other cases are the consequence of a known environmental insult such as meningitis or cisplatin administration. However, in many (maybe most) cases, both the genome of an individual and the environment interact to lead to deafness. For example, not all cases of meningitis lead to hearing loss, and people working in the same noisy environment do not all develop the same degree of hearing impairment, and the genetic susceptibility of the individuals probably accounts for these differences. We already know one mutation, A1555G in the mitochondrial genome, which makes carriers especially sensitive to aminoglycoside-induced hearing loss. This same mutation is associated with age-related progressive hearing loss in some families, irrespective of exposure to any drug. Gene variants that make carriers more susceptible to noise-induced deafness are difficult to find in humans, because of the difficulty in determining the exact level of historical exposure, but we do know of a number of such variants from work with animal models. These genes include Cu/Zn-superoxide dismutase (Sodl) and glutathione peroxidase (Gpxl), which are both involved in reducing reactive oxygen species. Mice with either of these genes knocked out showed increased susceptibility to noise-induced hearing loss (Ohlemiller et al., 1999; 2000). Heterozygotes for the Sodl knockout showed intermediate levels of the enzyme in blood and intermediate susceptibility to noise damage, but overexpression of Sodl did not lead to extra protection from damage (Ohlemiller et al., 1999; Coling et al., 2003). Mutations in two genes known to be involved in function of the stereocilia of sensory hair cells are reported to enhance noise sensitivity in heterozygotes: cadherin 23 (Cdh23), which has been proposed as a component of the extracellular tip links found between adjacent stereocilia of the hair bundle, and the plasma membrane calcium ATPase isoform 2 (Atp2b2), which encodes a calcium pump (Holme and Steel, 2004; Kozel et al., 2002). Vasodilator-stimulated phosphoprotein (Vasp) which is expressed in pillar cells of the organ of Corti and is thought to be involved in cytoskeletal dynamics also appears to have a protective effect because mice with no functional Vasp gene have increased sensitivity to noise-induced damage (Schick etal., 2004). Mice with an inactivated heat shock factor 1 gene (Hsfl) suffer increased degeneration of sensory hair cells in the cochlea (Sugahara et al., 2003). Three genes involved in neuronal function have a protective role, as mutants have increased sensitivity to noise: the glutamate transporter GLAST encoded by Slc1a3, the nociceptin/orphaninFQ receptor encoded by Oprll, and the a9 nicotinic acetylcholine receptor encoded by Chrna9 (Hakuba et al., 2000; Nishi et al., 1997; Maison et al., 2002). In contrast, mice with no acid-sensing ion channel 2 (Accnl/Asic2) are more resistant to temporary (but not permanent) threshold shifts following noise exposure (Peng et al., 2004). All of these genes represent good candidates for involvement in human sensitivity to noise-induced damage to hearing.

Despite the observation that susceptibility to noise-induced hearing loss often parallels age-related hearing loss in mice (Holme and Steel, 2004; Vazquez et al., 2004), this is not always the case (Yoshida et al., 2000), suggesting that some specific pathological mechanisms may be involved as well as common pathways to hearing loss.

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