Characterization of the Kyoto circling (KCI) rat carrying a spontaneous nonsense mutation in the protocadherin 15 (Pcdh15) gene.

Protocadherin-15 (Pcdh15) plays important roles in the morphogenesis and cohesion of stereocilia bundles and in the maintenance of retinal photoreceptor cells. In humans, mutations in PCDH15 cause Usher syndrome type 1F (USH1F) and non-syndromic deafness DFNB23. In mice, repertories of Pcdh15 mutant alleles have been described as Ames waltzer mutations. For further understanding of Pcdh15 function in vivo and to develop better clinical treatment for the disabling symptoms of USH1F and DFNB23 patients, animal models suitable for clinical as well as pharmacological studies are required. Here we report the characterization of a Pcdh15 mutant allele, Kyoto circling, (Pcdh15(kci)) in the rat. Rats homozygous for Pcdh15(kci) display circling and abnormal swimming behaviors along with the lack of an auditory-evoked brainstem response at the highest intensities of acoustic stimulation. Positional cloning analysis revealed a nonsense mutation (c. 2911C>T, p. Arg971X) in the Pcdh15 gene, which is predicted to result in the truncation of the PCDH15 protein at the 9th domain of cytoplasmic cadherin domains. Histological study revealed severe defects in cochlear hair cell stereocilia, collapse of the organ of Corti, and marked reduction of ganglion cells in adult Pcdh15(kci) mutants. Severe reduction of sensory hair cells was also found in the saccular macula. Since the rat is more advantageous for clinical and pharmacological studies than the mouse, the KCI rat strain may be a better disease model for Pcdh15-deficit USH1F and DFNB23.