Conférence magistrale du Grand Prix Scientifique 2026

What have mouse mutants told us about hearing loss?
Karen P Steel, King’s College London
 

As the human inner ear is so difficult to access, much of our knowledge about its development, function and pathology has come from animal models. The mouse is particularly useful because of the similarities with human ears in structure, pathology and genetics, and because mice can readily be genetically manipulated. Each mouse mutant can give us insights into the molecular and cellular mechanisms underlying hearing loss. 

We have built up a considerable resource of mouse mutants and knowledge about each one over the years. Starting with spontaneous deaf mutants and mice from chemical mutagenesis, we used positional cloning to identify the mutations causing deafness in these lines (phenotype-driven approach). Many of these mutants showed early developmental defects, useful for providing candidate genes and mechanisms for childhood deafness in humans but we needed more examples of later-onset, progressive hearing loss to gain insight into this widespread sensory deficit in the human population. Therefore, we used a sensitive physiological test, Auditory Brainstem Responses, to screen a large panel of mouse mutants that we generated from stem cells with specific genes targeted (genotype-driven approach); of 1211 genes screened, 38 had raised ABR thresholds and a further 27 had abnormal ABR waveforms. In many of these mutants, the hearing loss was progressive, providing candidate genes for adult-onset hearing loss in humans. 

Analysis of these mouse mutants suggests that a wide range of classes of pathology lead to hearing loss, with many different cell types of the middle or inner ear showing the first sign of dysfunction. In support of this finding, many genes involved in deafness are expressed in places other than hair cells. Hair cell degeneration appears as a common secondary feature, after the initial dysfunction. The genes underlying deafness also showed a wide range of functions and would not have been guessed from existing knowledge, emphasising the importance of genetics in uncovering the molecular basis of auditory function. The wide variety of molecular and pathological mechanisms means that diagnosis of the cause of deafness will be critical to choice of treatments.

The panel of mouse mutants we have generated has provided us with the tools to establish that some forms of deafness can be reversed while others cannot, and to develop methods for diagnosing some key sites-of-lesion in the inner ear. These findings provide a proof-of-concept that will give a foundation for future development and application of therapies for progressive hearing loss in humans.