We are interested in identifying and studying mammalian genes that are involved in the development of the neuroepithelium of the inner ear. The molecular analysis of the neuroepithelial class of hearing loss mutations in the mouse is an ideal way of gaining access to such genes. One particular mouse mutation, called Ames Waltzer (av), causes deafness and a degeneration of the Organ of Corti; it also causes defects in other neuroepithelial components of the inner ear. Therefore, cloning and characterization of the gene directly associated with this mutation should provide some insights into the molecular roles of genes that are involved in the maintenance and function of the neuroepithelium. Since many deafness disorders in humans are associated with the degeneration of the neuroepithelium, it is possible that our findings in the mouse may provide some molecular insights into auditory disorders in humans. In this proposal we are planning to study four different alleles of av and to clone and study the normal temporal and spatial expression of the gene directly responsible for the phenotype conferred by these mutant alleles. We will analyze the phenotype associated with three new alleles of av utilizing histology and audiometric techniques. The approach that we will take to clone the gene will be based on the molecular analysis of a new allele of av that arose by insertional mutagenesis in one of our lines of transgenic mice. The mutant locus of this new insertional mutation is tagged with the transgene, which already has allowed us to clone and begin a molecular characterization of the mutant locus. In our preliminary data, we have determined that there are no major structural alterations associated with the transgene insertion site that would complicate the use of this mutation for our experiments. We also plan to clone and map the human homologue of the Ames Waltzer gene utilizing the mouse gene as a probe.
| Alagramam, K N; Murcia, C L; Kwon, H Y et al. (2001) The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nat Genet 27:99-102 |
| Alagramam, K N; Yuan, H; Kuehn, M H et al. (2001) Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum Mol Genet 10:1709-18 |
| Murcia, C L; Woychik, R P (2001) Expression of Pcdh15 in the inner ear, nervous system and various epithelia of the developing embryo. Mech Dev 105:163-6 |
| Alagramam, K N; Zahorsky-Reeves, J; Wright, C G et al. (2000) Neuroepithelial defects of the inner ear in a new allele of the mouse mutation Ames waltzer. Hear Res 148:181-91 |
| Alagramam, K N; Kwon, H Y; Cacheiro, N L et al. (1999) A new mouse insertional mutation that causes sensorineural deafness and vestibular defects. Genetics 152:1691-9 |
| Woychik, R P; Alagramam, K (1998) Insertional mutagenesis in transgenic mice generated by the pronuclear microinjection procedure. Int J Dev Biol 42:1009-17 |
