Mouse screen reveals multiple new genes underlying mouse and human hearing loss

Abstract

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

Abstract

This study uses an electrophysiological screen of over a thousand new mutant mouse lines to identify 38 new genes underlying deafness, some associated with human hearing function, revealing a wide range of molecular and pathological mechanisms.

Author summary

Progressive hearing loss with age is extremely common in the population, leading to difficulties in understanding speech, increased social isolation, and associated depression. We know it has a significant heritability, but so far we know very little about the molecular pathways leading to hearing loss, hampering the development of treatments. Here, we describe a large-scale screen of 1,211 new targeted mouse mutant lines, resulting in the identification of 38 genes underlying hearing loss that were not previously suspected of involvement in hearing. Some of these genes reveal molecular pathways that may be useful targets for drug development. Our further analysis of the genes identified and the varied pathological mechanisms within the ear resulting from the mutations suggests that hearing loss is an extremely heterogeneous disorder and may have as many as 1,000 genes involved.