The broad long term objectives of this research proposal are to elucidate the molecular basis of maternally inherited deafness, and globally to shed light on the mechanism(s) of phenotypic expression of pathogenic mitochondrial DNA mutations.
The specific aims of this proposal mainly revolve around the identification and functional characterization of a nuclear gene that is responsible for modifying the clinical expression of the A1555G mitochondrial DNA mutation associated with hearing impairment in humans. The health-relatedness of these aims is to provide the basis for the rational design of therapeutic interventions to prevent, correct, or circumvent the clinical expression of maternally transmitted hearing impairment specifically and mitochondrial DNA diseases more generally. The experimental approach will focus on the identification of a modifier gene on chromosome 8 using genetic mapping and the analysis of candidate genes in the region. In parallel, genetic linkage and candidate gene analysis will be used to identify additional loci and genes that may be modifiers of the clinical phenotype. Once the chromosome 8 modifier gene has been identified, the gene and its functional pathway will be functionally characterized using expression studies, cellular localization, identification of proteins binding to the modifier, and binding assays of both the mutated and non-mutated forms of the modifier protein.
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