MUTATIONS IN A NOVEL COCHLEAR GENE CAUSE DFNA9, A HUMAN NONSYNDROMIC DEAFNESS WITH VESTIBULAR DYSFUNCTION

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineura l hearing loss with vestibular pathology. Here we report three missens e mutations in human COCH (previously described as Coch5b2), a novel c ochlear gene, in three unrelated kindreds with DFNA9. All three residu es mutated in DFNA9 are conserved in mouse and chicken Coch, and are f ound in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human coc hlear and vestibular organs, occurs in the chicken inner ear in the re gions of the auditory and vestibular nerve fibres, the neural and abne ural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas corr espond to human inner ear structures which show histopathological find ings of acidophilic ground substance in DFNA9 patients.