Genetic entities are responsible for 30-50% of the total burden of deafness. The elucidation of gene products responsible for deafness, and their expression patterns, will help dissect the molecular events underlying both deafness and normal hearing. In a large family with progressive and profound deafness associated with Charcot-Marie-Tooth disease (CMT; and inherited peripheral neuropathy), a unique mutation in the PMP22 gene was determined responsible for the clinical presentation. The protein encoded by the PMP22 gene (peripheral myelin protein) is a component of the nervous system. The biological function of the PMP22 protein is not completely understood, but it is necessary for the proper myelination of nerve axons. The myelin sheath acts as an insulator of the electrical signal that is transmitted through nerve cells, and it is thought that abnormal myelin formation results in the symptoms of CMT. The role of PMP22 in hearing loss remains unclear, although it is interesting that PMP22 expression has been localized to neural and non-neural tissues and individuals affected by CMT and deafness exhibit both neural and cochlear components to hearing loss. PMP22 is a member of the family of Growth arrest specific (Gas) genes, which have been shown to regulate gene expression, cell death and cell division. It has been speculated that in non-neural tissue the PMP22 gene plays a role in cell differentiation and tissue development because of its characteristic expression pattern at times of cellular growth arrest and terminal differentiation. Thus PMP22 expression has been proposed to have two functions: a role in peripheral nerve myelination and a role in cell growth regulation in non-neural tissues. It is hypothesized that a similar dual expression of PMP22 is necessary for normal hearing. This study proposes to dissect the molecular pathology of deafness associated with PMP22 mutations using the Trembler-J mouse as a model. The Trembler-J mouse carries a point mutation in the PMP22 gene that, when expressed in the heterozygous state, exhibits a neuropathic phenotype with auditory dysfunction. This study proposes a comparative evaluation of expression patterns of the murine PMP22 gene and protein in the cochlear duct for both normal mice and mice with a mutant PMP22. Through this examination a potential role of PMP22 in hearing development will by formulated based on the types of cells and cochlear structures that express PMP22. In addition, overall gene expression patterns will be examined in normal and mutant mice to identify genes differentially expressed relative to functional levels of PMP22. Determining the differences in gene expression profiles through comparative analysis of control and experimental groups should contribute to the general understanding of PMP22 function and its interactions with other genes and gene products, and specifically shed light on its influence of inner ear development and function.
