The aim of this application is to elucidate the biochemical basis for the maternally transmitted deafness. Hearing loss is the most frequent sensory disorder. One in 1000 children is born deaf, an equal number lose their hearing by adulthood and half the population experience significant hearing impairment by the age of 65 years. Deafness can be due to genetic or environmental causes or a combination of both. About 50% of the deafness cases have a genetic etiology or predisposition with autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns of inheritance. Despite the recent progress in molecular characterization of deafness, the biochemical and molecular pathogenic mechanisms underlying the maternally inherited deafness remain poorly understood. Recent results of genetic studies showed that an African-American family with maternally inherited nonsyndromic hearing loss have been associated with the mitochondrial T7511C mutation in the tRNA Ser(UCN) gene, which is commonly related to deafness. In addition, homoplasmic mutations T3308C in the ND1 gene and T5655C in the tRNA Ala gene have been found in all members of this pedigree and also in some controls. Thus, we hypothesize that the T7511C mutation in the tRNA Ser(UCN) gene is a primary mutation responsible for deafness phenotype and that T3308C and T5655C mutations play synergistic roles in the biochemical defect leading to deafness /phenotype. To test this hypothesis, we have constructed a disease cell model by transferring mitochondria from lymphoblastoid cell lines derived from deaf individuals with mtDNA mutations or from controls lacking mutations, into human mtDNA-less (rho o) cells. This application proposes two aims: 1). These transmitochondrial cell lines will be analyzed for the presence and severity of mitochondrial dysfunction associated with mtDNA mutations. 2). To study if over- expression of human mitochondrial Seryl-tRNA synthetase in these transmitochondrial cell lines can suppress the biochemical phenotype associated with T7511C mutation. Success of this project will enhance the understanding of pathogenic mechanisms of maternally inherited deafness, lead to the future therapies directed toward specific underlying abnormalities, and the development of animal models to test
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