Biochemical Basis of Maternally Inherited Deafness

母系遗传性耳聋的生化基础

基本信息

批准号：
6634549
负责人：
MIN-XIN GUAN
金额：
$ 7.4万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2005-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6634549
关键词：
aminoacid tRNA ligase cell line complementary DNA congenital deafness gene expression gene mutation human genetic material tag mitochondrial DNA molecular cloning molecular genetics oxidative phosphorylation phenotype protein biosynthesis transfection /expression vector transfer RNA

项目摘要

DESCRIPTION (provided by applicant): 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

描述（由申请人提供）：本申请的目的是阐明母体传播耳聋的生化基础。听力损失是最常见的感觉障碍。 1000个儿童中有一个是聋人，平等数字因成年而失去听力，人口经验一半截至65岁的听力障碍。耳聋可能是由于遗传或环境原因或两者的组合。约有50％耳聋病例具有常染色体的遗传病因或易感性主体，常染色体隐性，X连锁或线粒体模式遗产。尽管最近的分子表征取得了进展耳聋，生化和分子致病机制母体遗传的耳聋仍然很少理解。最新结果遗传研究表明，具有母体继承的非裔美国人家族非综合性听力损失与线粒体T7511C有关 tRNA \ ser（UCN）基因中的突变，通常与耳聋有关。在此外，ND1基因中的同质突变T3308C和T5655C中的T3308C 在该血统的所有成员中都发现了tRNA \ ala基因，也发现了某些基因控件。因此，我们假设TRNA \ Ser（UCN）中的T7511c突变基因是负责耳聋表型和T3308C的主要突变和T5655C突变在生化缺陷中扮演着协同作用，导致耳聋 /表型。为了检验这一假设，我们构建了一个疾病细胞通过从源自淋巴细胞细胞系中转移线粒体的模型有mtDNA突变或缺乏突变的对照组的聋人进入人mtDNA无（Rho \ o）细胞。该应用程序提出了两个目标：1）。这些将分析蒙木膜软骨细胞系的存在和严重程度线粒体功能障碍与mtDNA突变有关。 2）。研究是否过度在这些中的人线粒体Seryl-tRNA合成酶的表达多蒙蒙膜软骨细胞系可以抑制与生化表型相关的生化表型带有T7511c突变。该项目的成功将增强对母体遗传的耳聋的致病机制，导致未来针对特定潜在异常的疗法和发展动物模型进行测试

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular pathogenetic mechanism of maternally inherited deafness.

母系遗传性耳聋的分子发病机制。

DOI：
10.1007/978-3-662-41088-2_25
发表时间：
2004
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Guan,Min-Xin
通讯作者：
Guan,Min-Xin

Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation.

DOI：
10.1016/j.mito.2009.09.007
发表时间：
2010-01
期刊：
MITOCHONDRION
影响因子：
4.4
作者：
Lu, Jianxin;Qian, Yaping;Li, Zhiyuan;Yang, Aifen;Zhu, Yi;Li, Ronghua;Yang, Li;Tang, Xiaowen;Chen, Bobei;Ding, Yu;Li, Yongyan;You, Junyan;Zheng, Jing;Tao, Zhihua;Zhao, Fuxin;Wang, Jindan;Sun, Dongmei;Zhao, Jianyue;Meng, Yanzi;Guan, Min-Xin
通讯作者：
Guan, Min-Xin

Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation.

DOI：
10.1016/j.ymgme.2009.12.004
发表时间：
2010-04
期刊：
MOLECULAR GENETICS AND METABOLISM
影响因子：
3.8
作者：
Tong, Yi;Sun, Yan-Hong;Zhou, Xiangtian;Zhao, Fuxin;Mao, Yijian;Wei, Qi-Ping;Yang, Li;Qu, Jia;Guan, Min-Xin
通讯作者：
Guan, Min-Xin

Biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) A7445G mutation in osteosarcoma cell cybrids.