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Lessons About Hearing Loss From Mice

Steel, Karen P. PhD

doi: 10.1097/01.HJ.0000575348.28940.d3
Editorial
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Dr. Steel is a professor of sensory function at King's College London. Her research uses genetics as a tool to understand the molecular, cellular, and physiological basis of deafness with a focus on progressive hearing loss.

Despite the difference in the size of the inner ear and the spectrum of frequencies detected, there are remarkable similarities in the anatomy, physiology, genetics, and pathology of the auditory system in mice and humans. A new study by Ingham, et al., analyzed the auditory brainstem response (ABR) thresholds and waveforms in a large set of new mouse mutants with mutations targeting 1,211 diverse genes—around six percent of the total number of genes in the genome (PLoS Biol. 2019 Apr 11;17(4):e3000194). The findings have direct relevance to human hearing loss.

First, 38 new genes, or 3.14 percent of the genes tested, were found to lead to raised thresholds for auditory responses. Extrapolating to the total number of genes in the mouse (and human) genome, this suggests that another 600 genes involved in auditory function remain to be found. Added to the 400 genes already known to underlie deafness, this indicates that there are a thousand genes involved in deafness. Deafness is, therefore, a highly heterogeneous disorder in mice and in humans. When people with hearing impairment are referred for genetic diagnosis, small panels of known “deafness genes” are often screened for mutations. Since many of the genes involved in deafness have not yet been discovered, maybe sequencing all genes (exomes or whole genomes) will be more likely to reveal potential genetic causes.

Second, a wide range of hearing loss types was found. Some mutant genes led to profound deafness, while others showed only mild effects, such as a consistent 20 dB increase in thresholds at certain frequencies. Some showed high-frequency hearing loss, while others showed low-frequency or flat impairment. The mutants analyzed in more detail revealed different pathologies underlying the raised thresholds. Several genes were associated with conductive hearing loss due to a predisposition to middle ear inflammation, which is not often thought of as a disorder that can be caused by a mutation in a single gene. Other mutants had abnormal inner hair cells, defects of inner and outer hair cells, synaptic defects, or reduced endocochlear potentials—all very different primary pathologies. A few mutant lines showed consistent thresholds over a range of ages, but, interestingly, many of those we studied showed normal early development of ABRs, followed by progressive hearing loss.

Finding these new genes will be invaluable in understanding age-related, progressive hearing loss in humans because most of the previously known deafness genes are required for early structural or functional development of the ear and do not tell us much about the maintenance of hearing. We cannot assume that all human hearing loss is due to hair cell degeneration. We will need to develop better diagnostic techniques to distinguish the different sites of lesion to prescribe the correct drug. Better diagnostic tools will allow better stratification of people for clinical trials, improving the chances of finding effective drugs.

Third, the 38 genes that were newly discovered to be involved in hearing loss in mice all represent good candidate genes for involvement in human deafness. We have already found evidence that two of these mouse genes are also mutated in human families with inherited deafness, and more evidence will follow. In addition, we found evidence that genomic variants in 11 of the 38 genes are associated with the range of hearing ability in the 1958 British Birth Cohort, a sample of people born during a specific week in the United Kingdom and whose hearing was tested by audiometry at the age of 44 and 45.

Finally, we found that an additional 27 mouse mutant lines had normal ABR thresholds but abnormal waveforms. This may align with the finding that many people report difficulty hearing in noisy environments but have normal audiometric thresholds. Should we consider central deficits as potential direct effects of genetic variants in key genes?

The analysis of mouse mutants has shown us a very wide range of underlying pathologies that lead to hearing loss and a large number of different genes likely to be involved. The genes identified provide clues about the molecular networks required for normal hearing and targets for drug discovery, and the mouse mutants are resources for the initial testing of candidate drugs to slow down or stop progressive hearing loss whatever the trigger.

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