This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Non-syndromic neuroepithelial deafness occurs in a line of pointer dogs that were originally investigated for a behavioral abnormality (Klein et al (1988) Physiol. Behav. 43:307). Both the behavioral abnormality and coat color are independent of the hearing disorder (Steinberg et al (1994) J. Hered. 85:56). Deafness is always bilateral and the mode of inheritance is as an autosomal recessive trait. In affected pups, apparently normal hearing (assayed by the Brainstem Auditory Evoked Response, or BAER) gradually disappears, and a BAER is absent by approximately 100 days of age. Vestibular signs are absent. Preliminary histologic examination revealed the normal appearance of Reissner s membrane and the stria vascularis while the Organ of Corti is severely damaged. The endolymphatic potential, which is absent in cochleo-saccular form of deafness (Dalmatians), was +47 mV in a single deaf dog. Because these dogs hear normally, then progress to profound deafness, they may provide a valuable model for the study of hearing loss and methods to prevent this process. To further characterize the model, a whole-genome scan was performed on fifty-nine animals from the deaf pointer pedigree, of which nearly half were affected. Linkage between the deafness locus and markers on canine chromosome 4 (CFA4) was detected by two-point analysis, with LOD scores greater than 6 for three markers. The CFA4 region identified is flanked by markers FH3310 and FH2412. A single human recessive deafness gene locus, cadherin-23 (CDH23; see the Hereditary Hearing Loss Homepage, HHH, at www.uia.ac.be/dnalab/hhh/), is predicted to reside on CFA4. CDH23 encodes a member of the cadherin family of glycosylated transmembrane proteins. The protein is composed of 27 cadherin extracellular repeats, a transmembrane domain, and a cytoplasmic domain. In humans, mutant alleles of CDH23 give rise to both non-syndromic deafness and Usher s syndrome type 1D, depending on the type of mutation (see HHH). Sequencing the 69 exons of the CDH23 gene from an affected dog revealed one silent and one missense substitution in the open reading frame of the gene. The missense mutation is a proline to serine substitution of a highly conserved proline residue that is a signature residue of the cadherin domain. This substitution correlates completely with deafness in over 80 dogs in the pedigree and was not seen in the DNA of 25 German short-haired pointer dogs. The association of pointer deafness with this substitution, its similarity to CDH23 mutations found in deaf people, and the evolutionary conservation of the residue provide strong evidence that the serine substitution constitutes a deafness-causing allele.
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