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A gene in which mutations cause profound irreversible deafness in newborn children has been identified by the team led by Professor Christine Petit at the Pasteur Institute, in association with Inserm, the Pierre et Marie Curie University and the Collège de France. The discovery which has just been published in the journal Cell has led these researchers to uncover the role of its encoded protein, otoferlin. They have established, contrary to the generally accepted idea, that this deafness form that clinical exams classify as an auditory neuropathy, is due to a defect at the level of the cochlea, the auditory sensory organ. As a result, children diagnosed as carrying a mutation in the Otoferlin gene, can benefit from a cochlear implant, an electroacoustic device that substitutes for the function of the defective cochlea.
Researchers at the Sensory Deficits Genetics Unit of the Pasteur Institute, which is associated with Inserm, Pierre & Marie Curie University and the Collège de France and is a member of the EuroHear consortium, have studied the role of otoferlin encoded by a gene defective in a hereditary form of deafness. These researchers, working with the team of Dr Tobias Moser (University of Göttingen, Germany), Dr Antoine Triller (Inserm U497, ENS, Paris) and Prof Paul Avan (University of Clermont-Ferrand) have shown that otoferlin is necessary to stimulate the auditory nerve. Otoferlin is a protein of the synaptic vesicles required for the release of the neurotransmitter by the auditory sensory cells of the cochlea. Patients present with an auditory neuropathy that audiometric tests can’t distinguish from the other auditory neuropathies which are more generally due to defects affecting the neurons of the auditory system.
It is essential to know whether the defect lies in the cochlea and/or downstream in the neurons of the auditory system because there are electroacoustic protheses, cochlear implants, which can compensate for cochlear deficiencies by directly electrically stimulating the auditory nerve. Inserting this implant in deaf children who are likely to benefit from it must be decided early on; otherwise restoring quality hearing using this device will be less efficient.
Pr Christine Petit’s team has also developed a molecular diagnostic tool to detect mutations in the otoferlin gene which are frequent in certain countries. By using this tool, clinicians at the Trousseau Hospital in Paris have enabled two children suffering from this form of genetic deafness to receive cochlear implants that have restored their hearing (1).
This molecular diagnostic tool may be proposed in the future for all children suffering from an auditory neuropathy in order to help clinicians and families to make a decision with regard to the surgical cochlear implantation.
Professor Christine PETIT’s group, which have played a pioneering role in the study of hereditary deafness, have also recently developed a molecular diagnostic tool for genetic deafness which is not due to a damaged cochlea and which would enable clinicians to assess the advantages of a cochlear implant for this form of deafness (see press release of 22 June 2006).
" Otoferlin, defective in DFNB9 deafness, is essential for synaptic vesicle exocytosis at the auditory ribbon synapse " Cell, 20 octobre 2006
Isabelle Roux (1), Saaid Safieddine (1), Régis Nouvian (2), M’hamed Grati (1,3), Marie-Christine Simmler (4), Amel Bahloul (1), Isabelle Perfettini (1), Morgane Le Gall (5), Philippe Rostaing (6), Ghislaine Hamard (5), Antoine Triller (6), Paul Avan (7), Tobias Moser (2), Christine Petit (1)
1. Unité de Génétique des Déficits Sensoriels, Collège de France, Institut Pasteur & Inserm UMRS 587
2. Department of Otolaryngology and Center for Molecular Physiology of the Brain, University of Goettingen, Allemagne
3. Welcome Trust Sanger Institute, Cambridge, UK
4. Institut Jacques Monod, Paris, France
5. École Normale Supérieure, Inserm U497, Paris
6. Institut Jacques Monod, Paris, France
6. Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Clermont-Ferrand
(1) « Results of cochlear implantation in two children with mutations in the OTOF gene ». International Journal of Pediatric Otorhinolaryngology, avril 2006
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