Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice

Mutations at the waltzer (v) locus result in deafness and vestibular dysfun ction due to degeneration of the neuroepithelium within the inner ear. Here , we use a positional cloning approach to show that waltzer encodes a novel cadherin (Cdh23), which is most closely related to the Drosophila Fat prot ein. A single nucleotide deletion in the v(J) allele and a single nucleotid e insertion in the v allele are predicted to truncate each protein near the N-terminus and produce a functional null allele. In situ hybridization ana lysis showed that Cdh23 is expressed in the sensory hair cells of the inner ear, where it has been suggested to be a molecule critical for crosslinkin g of the stereocilia. In addition, Cdh23 is expressed in the urticulo-saccu lar foremen, the ductus reuniens, and Reissner's membrane, suggesting that Cdh23 may also be involved in maintaining the ionic composition of the endo lymph. Finally, mutations in human CDH23 have recently been described for t wo loci, DFNB12 and USH1D, which cause nonsyndromic deafness, identifying w altzer as a mouse model for human hearing loss. (C) 2001 Academic Press.