Hearing, visual and molecular phenotypes of Ames waltzer and waltzer mice
Description
Usher syndrome (USH) affects an estimated 1/16,000 to 1/50,000 people worldwide and has been reported to underlie a majority of deaf-blindness. There are three generally accepted clinical subtypes of Usher syndrome, which is a recessively inherited neurosensory disorder. Usher syndrome type 1 is characterized by profound congenital deafness, retinitis pigmentosa and vestibular abnormalities in humans. Seven USH1 loci have been mapped and genes for five of them have been identified. Mutations in CDH23, the gene encoding cadherin 23, were found in both USH1D and DFNB12 patients. Missense mutations of CDH23 also cause nonsyndromic recessive deafness, while more severe mutations (truncating mutations and some missense mutations) are associated with an USH1D phenotype. Protein truncating mutations in the gene encoding protocadherin 15 (PCDH15) cause Usher syndrome type 1 (USH1F) while less disabling mutant alleles of PCDH15 are associated with nonsyndromic recessive hearing loss (DFNB23). This suggests that the retina is somehow resistant to the effects of altered or reduced levels of protocadherin 15 due to particular missense mutations, which nevertheless cause profound deafness. In the waltzer (v) and Ames waltzer (av) mouse, recessive mutations of Cdh23 and Pcdh15, respectively, are associated with profound deafness and circling behavior, but not retinal degeneration. In this study of Pcdh15av-5J mice and mice either double heterozygous or double homozygous for the Cdh23v-6J and Pcdh15av-Jfb alleles, we extended the characterization of the auditory phenotype and initiated a study of the retinal phenotype of these mice. We have shown that two alleles of young Ames waltzer mice have (Pcdh15av-5Jfb, Pcdh15av-5J ) have significantly reduced electroretinogram (ERG) potentials and provide evidence suggesting that splice variants of Pcdh15 may compensate for the mutant allele in the eye but not in the ear. Furthermore, we show that there are no obvious genetic interactions between the Cdh23v-6J and Pcdh15av-Jfb alleles using double heterozygous as well as double homozygous mice