CONNEXIN DEFECTS AND CONGENITAL HEARING LOSS

In developed countries deafness is mostly of generic origin: the pathology is inherited, at least, in 60% of the cases. The crucial role played by gap junctions in hearing has been recognized when mutations in the gene coding for connexin 26 (Cx26), underlying the DFNB1 form of deafness, have been found to be responsible for about half of all cases of human deafness in countries surrounding the Mediterranean Sea. DFNB1 is thus almost as frequent as cystic fibrosis. Since then other connexin genes have been implicated in inherited human hereditary hearing loss, but among these the most abundant connexins in the inner ear are Cx26 and Cx30, which form channels that permit the rapid exchange of ions and small molecules between adjacent cells. This research project aims at improving our (still limited) understanding of the role played by connexins in the inner ear. We shall use a combined approach involving cell and molecular biology studies, protein functionality assays and computer modelling of gap junction channel structure. We also intend to use two mouse models of DFNB1 in which either one of Cx26 or Cx30 has been genetically ablated from the inner ear. Using state of the art techniques for gene transfer, we shall endeavour to restore function by reinstate the missing connexin gene. This will help us to understand the underlying pathogenic mechanisms at a molecular level and will provide preliminary information on new potential therapeutical approaches.