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Genetics & Physiology of Hearing

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Professor Christine PETIT

Hearing is the sense of communication. It is a necessary condition to the learning of any vocal exchange within a species, including oral language in humans.
The cochlea, the mammalian auditory sensory organ, is an electroacoustic organ with extreme potentials. The human cochlea detects an acoustic energy as low as about 10 times the thermal noise and covering 12 orders of magnitude. It responds to a spectrum of frequencies extending up to 10 octaves with a frequency discrimination that can reach 1/1000. The cochlea associates three functions: - a microphonic function, that is, an acoustico-electrical transduction operating in microseconds, - a frequency analyser activity and - an amplifier function. The working principles of the cochlea have been elucidated since the 19th century, mainly by physicists. However, at the beginning of the 1990s, the way in which it differentiates and works at the molecular level was still entirely unknown. Christine Petit considered the genetic approach as the fast track to gain access to the molecular mechanisms of the cochlear development and functioning and choose to address it in humans. As a result, she pioneered with her colleagues, the field of human hereditary deafness.

Human hereditary deafness

Severe to profound deafness affect one newborn out of 700. It affects an additional one child out of 1000 before adulthood, and 2.3% of the general population between 60 and 70. Moreover, 40% of people over 65 suffer from hearing loss impeding conversational exchanges.
Our laboratory solved that the specific difficulties encountered by linkage analysis for deafness, through the study of deaf families living in geographic isolates, and mapped to the human chromosomes the first two genes (DFNB1 and DFNB2) underlying childhood deafness. On the grounds of our expertise (i.e. the previous finding of the first gene causative for an olfactory defect, namely Kallmann syndrome), we initiated the search of the causative genes for deafness. We have now identified around twenty of these genes. We have been able to conclude that severe to profound deafness cases, without evidence clearly pointing at environmental causes are almost exclusively hereditary. Our lab has shown that connexin-26 accounts for one third to half cases of severe to profound congenital deafness in Mediterranean sea countries. All, but the gene encoding pejvakin, result in a primary cochlear defect. The deciphering of the pathogenesis of these various deafness forms, based on an in-depth study of mouse models, led us to reveal a variety of defective processes: (i) pure mechanical defect (as tectorial membrane anomalies), (ii) ionic homeostasis anomalies (as the rupture of the epithelial stria vascularis blood barrier), (iii) synaptic defect (as failure of synaptic vesicle fusion) and (iv) a large ensemble of anomalies of the hair bundle, the mechanoreceptive structure to sound. Notably, Usher syndrome type I and II have been found as resulting from the defect of proteins forming hair bundle links, essential to its cohesion at the earliest step for the formers, and essential to the unidirectionality of its stimulation for the latter.

Our present research interests and aims are focused on:

Molecular physiology of the auditory system

- the structure / function of the mechanotransduction machinery,
- the molecular composition and function of the hair bundle links from early developmental to adult stages,
- the molecular physiology of the inner hair cells synaptic trafficking and exocytosis,
- the molecular physiology of the spiral ganglion neurons.

To assess these questions, we are resorting to a multidisciplinary approach. Our laboratory is gathering biophysical, electrophysiological (mechanotransduction recording, capacitance measurements…), biochemical, imaging (electron microscopy, confocal and biphoton analyses), cell biology, genetics and molecular genetics expertises.

Human hereditary deafness

We keep researching genes responsible for early onset forms. The genes underlying late-onset forms are now explored as well.
For all these forms, an in-depth multidisciplinary investigation of the structure/function of the proteins encoded by these deafness genes and of the pathogenic processes involved, are developed that mainly rely on mouse models.

Therapeutic approaches

New avenues will focus on therapeutic research aiming at preventing or slowing down the occurrence and the progression of late-onset forms of deafness, at first, as well as at the prevention of the development of the retinitis pigmentosa in Usher syndrome (sensorineural deafness associated with retinitis pigmentosa leading to blindness).


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