SFN: The genetic approach to the auditory system

Fred Kavli Distinguished International Scientist Lecture Understanding Sound Processing in the Auditory System: Advances Rooted in the Genetic Approach

Christine Petit, MD, PhD, College de France and Pasteur Institute

Yesterday morning, Dr. Christine Petit of Paris’ Pasteur Institute explained what genetic studies of families with early-onset deafness have told us about auditory processing. After giving an overview of what we know about the physiology of audition, particularly the cochlea, she described her work on the molecular basis of congenital early-onset deafness, and finally discussed advances in our understanding of the molecular basis of hearing that has come out of this approach.

Dr. Petit began by pointing out that auditory communication takes up more than 20% of our lifetimes, and perhaps more for some people! (I can't believe that never occurred to me before.) Humans can communicate not only with speech, but also can somehow convey emotion through music. Information is contained in the frequency composition of both these types of sounds—in the example she gave, “son” (French for “sound”), the “s” is broadband and contains higher frequencies, while the “on” phoneme is composed of lower frequencies and shows a cleaner harmonic structure. We know that the left auditory cortex is involved in speech and language, while the right auditory cortex tends to be associated with voice, prosody and music processing.

The cochlea performs several steps in the analysis that allows us to extract information from auditory inputs. It performs mechano-electrical transduction, changing sound waves into neural activity; frequency analysis (AKA Fourier transformations!); amplification; generation of distortions known as Tortini sounds or effects; and generation of suppressive masking, which increases the contrast between sounds and is necessary to make speech intelligible.

Next, the speaker gave an overview of cochlear anatomy and how mechanotransduction occurs. People in the audience might have caught a shout out to Stanford’s own Tony Ricci, for whom it is unclear whether auditory physiology or softball is a bigger obsession. I’ll spare you the nitty-gritty of the basilar membrane et al. for the moment, and simply say that critical steps in mechanotransduction occur at the delicate connections between hair cells and the basilar and tectorial membranes that sandwich them. Almost all congenital deafness, it turns out, involves cochlear defects in processes such as ionic homeostasis, inner hair cell synaptic defects, or mechanotransduction defects.

Isolating components of hair bundles is difficult due to their small size and the difficulty of extracting them. To get around this barrier, the speaker has taken the tack of finding large, intramarrying families with different types of congenital deafness and looking for mutations they share. This search took her to Tunisia, Lebanon and several other countries. They have identified several genes of interest, different ones causing deafness in different families. For example, they found defects in connexin26, a gap junction protein. Mutations in this gap junction are apparently responsible for a large proportion of inherited deafness, up to 30-50% (in Caucasian populations).

At this point the focus shifted to describing several genes that have come out of this work. First came otoferlin, a member of the ferlin family. Otoferlin^-/- mice have defective synaptic exocytosis, probably due to vesicle priming or fusion issues. Dr. Petit attributed the incredible temporal reliability and precision of auditory transduction in part to the huge volume of vesicular release in the cochlea (as many as 1000 vesicles/synapse – compare that with the single vesicle released at a typical central synapse!). This points to an explanation for why otoferlin mutations result specifically in deficits in hearing and not all processes requiring synaptic exocytosis.

Next she described components of tip links that have been identified by this approach. For the uninitiated, tip links are molecular ties, heretofore of unknown structure and composition, that connect the delicate protrusions from the apical surface of a hair cell known as stereocilia. Stereocilia, which are grouped into “hair bundles”, are part of how mechanical deflection of hair cells by sound waves opens ion channels and generates electric currents.

She named two classes of relevant genes, Usher I and Usher II, and focused on Usher I genes, which she said are “the heart of the mechanotransduction machinery”. We now know that tip links are composed of two Usher I proteins, protocadherin15 and cadherin23. Another Usher I gene she discussed was harmonin b, a knockout of which appears to prevent full relaxation of the tip link. A few other genes were discussed more briefly - readers are welcome to contribute details!