Gap junctions, assembled by connexins, mediate cell-cell communication and maintain cellular homeostasis. In human, mutations in genes encoding connexins are identified in a number of inherited diseases. Mutations in connexin-31 are associated with hearing impairment, erythrokeratodermia variabilis (EKV), and peripheral neuropathy. Little is known about the molecular basis for the distinct pathogenic processes associated with Cx31 mutants. In preliminary study, we have shown the expression of Cx31 in adult organ of corti. We also found that hearing impairment-associated Cx31 mutants show impaired channel function, loss of assembly at cell-cell contacts, and defective intracellular trafficking. Notably, EKV-associated Cx31 mutants promote apoptotic cell death, in addition to the defects found in hearing impairment-associated mutants. Moreover, expression of disease associated Cx31 mutants induces BiP expression. We hypothesize that Cx31 mutant-associated hearing impairment and skin disease are consequences of abnormal intracellular trafficking of mutant proteins. The trafficking defect of the mutant proteins results from UPR induced by abnormal conformation of mutant proteins. In this proposal we propose:
Specific aim 1. To define the intracellular trafficking defects of disease associated Cx31 mutants.
Specific aim 2. To determine the molecular mechanism of cell death caused by expressing EKV-associated Cx31 mutants.
Specific aim 3. To define the pathogenic mechanisms of disease-associated Cx31 mutants in vivo using transgenic mouse models. The results will facilitate both the understanding of the pathological mechanisms of Cx31 mutations and the design of potential treatments of these diseases.
