Deafness is an important and common cause of human suffering, and mitochondrial mutations have been found to be responsible for both syndromic and non-syndromic hearing loss. Our efforts have concentrated on maternally inherited non-syndromic deafness, using a large Arab-Israeli pedigree with over 50 deaf family members with maternally inherited hearing loss as our paradigm. We described in this family in 1993 the first molecular defect linked to non-syndromic deafness, and were able to show that the same mitochondrial mutation surprisingly also predisposes to aminoglycoside induced hearing loss. The biochemistry and tissue specific expression of mitochondrial mutations in the cochlea remains in general an enigma, and our Arab-Israeli pedigree with inherited cochlear deafness due to the interaCtion of a mitochondrial and autosomal mutation, provides an opportunity to resolve it. This opportunity exists because the autosomal locus can be identified by either positional cloning and/or functional cloning. The broad long-term objectives and the health relatedness of this research proposal are (1) to elucidate the molecular basis of deafness in this particular pedigree, and to design therapeutic approaches to prevent, correct, or circumvent those defects, and (2) in a more general sense to shed light on the mechanism of tissue specific expression of mitochondrial mutations, in particular with respect to the cochlea, and to design therapeutic interventions to prevent, correct, or circumvent this abnormal expression.
The specific aims of this three year proposal all revolve around the elucidation of the putative autosomal locus in the Arab-Israeli pedigree, and include (1) characterization of the clinical phenotype in greater detail, including examination of the possibility of reduced penetrance in some of the hearing family members and environmental agents precipitating hearing loss in some of the deaf family members, and collection of additional nuclear families from the deafness pedigree; (2) characterization of the functional effect of the mitochondrial mutation in greater detail, in particular with respect to its interaction with nuclear factors, by both detailed biochemical assays of deaf and hearing family members, and the use of mitochondrial transfer experiments; (3) demonstration that the autosomal locus is linked to a specific chromosomal region of the human genome by a systematic genome-wide genetic mapping approach; (4) investigation of the possibility of direct cloning of the autosomal gene, by searching for a consistent difference in expression patterns between lymphoblastoid cell lines of deaf and hearing family members, and/or a significant survival difference between lymphoblastoid cell lines of deaf and hearing family members, when challenged with aminoglycoside metabolites and/or oxygen radicals.
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