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.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Watson, Bracie
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Cedars-Sinai Medical Center
Los Angeles
United States
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Ballana, Ester; Mercader, Josep Maria; Fischel-Ghodsian, Nathan et al. (2007) MRPS18CP2 alleles and DEFA3 absence as putative chromosome 8p23.1 modifiers of hearing loss due to mtDNA mutation A1555G in the 12S rRNA gene. BMC Med Genet 8:81
Guan, Min-Xin; Yan, Qingfeng; Li, Xiaoming et al. (2006) Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet 79:291-302
Yan, Qingfeng; Bykhovskaya, Yelena; Li, Ronghua et al. (2006) Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochem Biophys Res Commun 342:1130-6
Patton, Jeffrey R; Bykhovskaya, Yelena; Mengesha, Emebet et al. (2005) Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation. J Biol Chem 280:19823-8
Mathews, C E; Leiter, E H; Spirina, O et al. (2005) mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes. Diabetologia 48:261-7
Zeharia, Avraham; Fischel-Ghodsian, Nathan; Casas, Kari et al. (2005) Mitochondrial myopathy, sideroblastic anemia, and lactic acidosis: an autosomal recessive syndrome in Persian Jews caused by a mutation in the PUS1 gene. J Child Neurol 20:449-52
Bykhovskaya, Yelena; Casas, Kari; Mengesha, Emebet et al. (2004) Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 74:1303-8
Bykhovskaya, Yelena; Mengesha, Emebet; Wang, Dai et al. (2004) Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3. Mol Genet Metab 83:199-206
Li, Xiaoming; Fischel-Ghodsian, Nathan; Schwartz, Faina et al. (2004) Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness. Nucleic Acids Res 32:867-77
Casas, Kari; Bykhovskaya, Yelena; Mengesha, Emebet et al. (2004) Gene responsible for mitochondrial myopathy and sideroblastic anemia (MSA) maps to chromosome 12q24.33. Am J Med Genet A 127A:44-9

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