Genetic influences in individual susceptibility to noise: a review.

Individual animals and humans show differing susceptibility to noise damage even under very carefully controlled exposure conditions. This difference in susceptibility may be related to unknown genetic components. Common experimental animals (rats, guinea pigs, chinchillas, cats) are outbred-their genomes contain an admixture of many genes. Many mouse strains have been inbred over many generations reducing individual variability, making them ideal candidates for studying the genetic modulation of individual susceptibility. Erway et al. (1993) demonstrated a recessive gene associated with early presbycusis in the C57BL/6J inbred mouse. A series of studies have shown that mice homozygous for Ahl allele are more sensitive to the damaging effects of noise. Recent work has shown that mice homozygous for Ahl are not only more sensitive to noise, but also are probably damaged in a different manner by noise than mice containing the wild-type gene (Davis et al., 2001). Recent work in Noben-Trauth's lab (Di Palma et al., 2001) has shown that the wild-type Ahl gene codes for a hair cell specific cadherin. Cadherins are calcium dependent proteins that hold cells together at adherins junctions to form tissues and organs. The cadherin of interest named otocadherin or CDH23, is localized to the stereocillia of the outer hair cells. Our working hypothesis, suggests that otocadherin may form the lateral links between stereocilia described by Pickles et al (1989). Reduction of, or missing otocadherin weakens the cell and may allow stereocilia to be more easily physically damaged by loud sounds and by aging.

Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2.

Plasma membrane Ca2+-ATPase isoform 2 (PMCA2) exhibits a highly restricted tissue distribution, suggesting that it serves more specialized physiological functions than some of the other isoforms. A unique role in hearing is indicated by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells. To analyze the physiological role of PMCA2 we used gene targeting to produce PMCA2-deficient mice. Breeding of heterozygous mice yielded live homozygous mutant offspring. PMCA2-null mice grow more slowly than heterozygous and wild-type mice and exhibit an unsteady gait and difficulties in maintaining balance. Histological analysis of the cerebellum and inner ear of mutant and wild-type mice revealed that null mutants had slightly increased numbers of Purkinje neurons (in which PMCA2 is highly expressed), a decreased thickness of the molecular layer, an absence of otoconia in the vestibular system, and a range of abnormalities of the organ of Corti. Analysis of auditory evoked brainstem responses revealed that homozygous mutants were deaf and that heterozygous mice had a significant hearing loss. These data demonstrate that PMCA2 is required for both balance and hearing and suggest that it may be a major source of the calcium used in the formation and maintenance of otoconia.