Deafness, the most common sensory disorder, often strikes in childhood. In many cases, a child initially identified with partial deafness develops profound hearing loss over a period of months to years, often because of a gradual degeneration of the outer hair cells, which are required to amplify sound vibrations, and are also responsible for the exquisite sensitivity and frequency selectivity of mammalian hearing. Over half the cases of childhood deafness are due to single-gene defects, but the specific mechanisms by which many of these mutations cause progressive sensorineural hearing loss are not clearly defined. The ease of genetic manipulation in mice enables the creation of mutant alleles and the detailed dissection of the degenerative process.

This manuscript uses a mouse model to study the pathophysiological mechanisms underlying deafness caused by an autosomal dominant mutation in the alpha tectorin gene (Tecta C1509G). Tecta protein localizes to the tectorial membrane, an acellular gelatinous structure that interacts with the sensory hair cell stereociliary bundles and transduces sound within the mammalian cochlea. Children with the TECTA C1509G mutation are born with partial hearing loss, which progressively worsens with age.

Tecta C1509G mice have hearing loss because the tectorial membrane is congenitally malformed, such that sound stimulates only the first row of outer hair cells, instead of all three rows. Thus, forward transduction (the process of converting sound pressure waves into voltage signals) is defective. Outer hair cells are also crucially important for amplifying and sharpening the tuning of the traveling soundwave, by a process termed reverse transduction. Surprisingly, reverse transduction was increased in Tecta C1509G mice, owing to upregulation of the outer hair cell electromotility motor protein prestin. Since Tecta is not expressed within hair cells, a non-cell-autonomous mechanism is responsible, which partially compensates for the hearing loss caused by defective forward transduction.

The Tecta C1509G mouse provides a unique opportunity to study how the targeted loss of outer hair cell stimulation alters cochlear physiology and cellular gene expression. Intriguingly, the increase in reverse transduction might also cause the progressive hearing loss associated with this mutation, perhaps by putting the outer hair cells at greater risk of damage from noise exposure or aging.

The findings from this study have general applicability to all the many forms of human hearing loss caused by deficient outer hair cell stimulation. Tecta C1509G mice may also be of use as a model system for the development of therapies to slow the rate of hearing loss. Such a therapy would be of great importance, allowing children with progressive hearing loss to lengthen their window of hearing while they are in the crucial process of learning speech and language, and reducing a major cause of societal isolation and depression in the elderly.

2010