Targeted disruption of Otog results in deafness and severe imbalance

Genes specifically expressed in the inner ear are candidates to underlie he reditary nonsyndromic deafness(1). The gene Otog has been isolated from a m ouse subtractive cDNA cochlear library(2). It encodes otogelin, an N-glycos ylated protein that is present in the acellular membranes covering the six sensory epithelial patches of the inner ear: in the cochlea (the auditory s ensory organ), the tectorial membrane (TM) over the organ of Corti; and in the vestibule (the balance sensory organ), the otoconial membranes over the utricular and saccular maculae as well as the cupulae over the cristae amp ullares of the three semi-circular canals. These membranes are involved in the mechanotransduction process. Their movement, which is induced by sound in the cochlea or acceleration in the vestibule, results in the deflection of the stereocilia bundle at the apex of the sensory hair cells, which in t urn opens the mechanotransduction channels located at the tip of the stereo -cilia(3). We sought to elucidate the role of otogelin in the auditory and vestibular functions by generating mice with a targeted disruption of Otog. In Otog(-/-) mice, both the vestibular and the auditory functions were imp aired. Histological analysis of these mutants demonstrated that in the vest ibule, otogelin is required for the anchoring of the otoconial membranes an d cupulae to the neuroepithelia. In the cochlea, ultrastructural analysis o f the TM indicated that otogelin is involved in the organization of its fib rillar network. Otogelin is likely to have a role in the resistance of this membrane to sound stimulation. These results support OTOG as a possible ca ndidate gene for a human nonsyndromic form of deafness.