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

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Small Research Grants (R03)
Project #
5R03DC004958-02
Application #
6516301
Study Section
Special Emphasis Panel (ZDC1-SRB-O (27))
Program Officer
Watson, Bracie
Project Start
2001-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$74,000
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Tang, Xiaowen; Li, Ronghua; Zheng, Jing et al. (2010) Maternally inherited hearing loss is associated with the novel mitochondrial tRNA Ser(UCN) 7505T>C mutation in a Han Chinese family. Mol Genet Metab 100:57-64
Zhang, Minglian; Zhou, Xiangtian; Li, Chengwu et al. (2010) Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation. Mol Genet Metab 101:192-9
Lu, Jianxin; Qian, Yaping; Li, Zhiyuan et al. (2010) Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation. Mitochondrion 10:69-81
Tong, Yi; Sun, Yan-Hong; Zhou, Xiangtian et al. (2010) Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation. Mol Genet Metab 99:417-24
Li, Ronghua; Liu, Yuqi; Li, Zongbin et al. (2009) Failures in mitochondrial tRNAMet and tRNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese Family. Hypertension 54:329-37
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
Young, Wie-Yen; Zhao, Lidong; Qian, Yaping et al. (2005) Extremely low penetrance of hearing loss in four Chinese families with the mitochondrial 12S rRNA A1555G mutation. Biochem Biophys Res Commun 328:1244-51
Li, Zhiyuan; Li, Ronghua; Chen, Jianfu et al. (2005) Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss. Hum Genet 117:9-15
Li, Xiaoming; Zhang, Linda S; Fischel-Ghodsian, Nathan et al. (2005) Biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) A7445G mutation in osteosarcoma cell cybrids. Biochem Biophys Res Commun 328:491-8
Li, Ronghua; Ishikawa, Kotaro; Deng, Jian-Hong et al. (2005) Maternally inherited nonsyndromic hearing loss is associated with the T7511C mutation in the mitochondrial tRNASerUCN gene in a Japanese family. Biochem Biophys Res Commun 328:32-7

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