Molecular Pathology of Deafness
….Molecular analysis identified a unique point mutation in the candidate gene PMP22. The association of CMT with a point mutation in the PMP22 gene is not surprising since the duplication of this gene has long been implicated in the pathogenesis of this common peripheral neuropathy (Lupski, 1992). However, the unique co-presentation of CMT with deafness additionally points to PMP22 as playing an important part in the development of normal hearing.
In mammals, PMP22 is predominantly expressed by Schwann cells, where the protein is predicted to aid in the formation and maintenance of the compact myelin sheathes of the peripheral nervous system. It is also found in cells of non-neural tissues at lower levels, particularly those of the epithelium, lung and intestine (Jetten and Suter, 2000). 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. We hypothesize that a similar dual expression of PMP22 is necessary for normal hearing. In support, audiological studies of individuals with hearing loss associated with the PMP22 defect indicated both a neural and cochlear component. We predict that Schwann cell expression of PMP22 is required for auditory nerve myelination, and that dysfunction in this role leads to the abnormal auditory brainstem response (ABR) latencies observed in affected individuals. We also predict that we will find PMP22 expression in structures of the inner ear and cochlea during development, perhaps functioning in the maintenance of these structures, and that PMP22 mutations independently lead to cochlear dysfunction.
This study proposes to examine the expression and localization of the PMP22 gene and protein in the inner ear of both normal mice and mice with a mutant PMP22 and neuropathic phenotype (Trembler-J mice). In addition, gene expression profiles from control and mutant mice will be examined to identify genes whose transcription is influenced by PMP22 expression as well as provide insight to potential cellular functions and protein:protein interactions that involve PMP22. The study will help define the role of PMP22 in normal hearing and how the expression of the mutant form leads to deafness and could lead to the development of novel and effective treatments for deafness and additionally CMT.