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

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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.

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A physiological place-frequency map of the cochlea in the CBA/J mouse.

Marcus Müller, Karen von Hünerbein, Silvi Hoidis … (2005)

Genetically manipulated mice have gained a prominent role in in vivo research on development and function of the auditory system. A prerequisite for the interpretation of normal and abnormal structural and functional features of the inner ear is the exact knowledge of the cochlear place-frequency map. Using a stereotaxic approach to the projection site of the auditory nerve fibers in the cochlear nucleus, we succeeded in labelling physiologically characterized auditory nerve afferents and determined their peripheral innervation site in the cochlea. From the neuronal characteristic frequency (CF) and the innervation site in the organ of Corti a place-frequency map was established for characteristic frequencies between 7.2 and 61.8 kHz, corresponding to locations between 90% and 10% basilar membrane length (base = 0%, apex = 100%, mean length measured under the inner hair cells 5.13 mm). The relation between normalized distance from the base (d) and frequency (kHz) can be described by a simple logarithmic function: d(%) = 156.5-82.5 x log(f), with a slope of 1.25 mm/octave of frequency. The present map, recorded under physiological conditions, differs from earlier maps determined with different methods. The simple logarithmic place-frequency relation found in the mouse indicates that mice are acoustic generalists rather than specialists.