Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D

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Abstract
Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing loss1 (Ahl). The human region that is orthologous to the mouse 'waltzer' region is located at 10q21–q22 and contains the human deafness loci DFNB12 and USH1D (refs. 2,3). Numerous mutations at the waltzer locus have been documented causing erratic circling and hearing loss4,5,6,7. Here we report the identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes a very large, single-pass transmembrane protein, that we have called otocadherin. It has an extracellular domain that contains 27 repeats; these show significant homology to the cadherin ectodomain. In v6J, a GT transversion creates a premature stop codon. In vAlb, a CT exchange generates an ectopic donor splice site, effecting deletion of 119 nucleotides of exonic sequence. In v2J, a GA transition abolishes the donor splice site, leading to aberrant splice forms. All three alleles are predicted to cause loss of function. We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v2J homozygotes. Our data indicate that otocadherin is a critical component of hair bundle formation. Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D.