Identifying Genes for Non-syndromic Recessive Deafness-A Collaborative Study

鉴定非综合征性隐性耳聋基因——一项合作研究

• 批准号: 8264891
• 负责人: Saima Riazuddin
• 金额: $ 32.51万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264891
• 关键词: Affect; Age; Apoptosis; Apoptotic; Biological; Cell Line; Cells; Cessation of life; Clinical; Counseling; Data; Development; Diagnosis; Disease; Early Diagnosis; Epithelium; Etiology; Evaluation; Experimental Designs; Family; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Determinism; Genetic Variation; Goals; Hearing; Hearing Impaired Persons; Human; Individual; Inherited; Intervention; Knockout Mice; Knowledge; Labyrinth; Link; Maps; Measures; Molecular; Molecular Epidemiology; Molecular Genetics; Morphology; Mutant Strains Mice; Mutate; Mutation; Neurons; Oxidative Stress; Pathway interactions; Population; Population Heterogeneity; Positioning Attribute; Prevention; Process; Proteins; Research; Role; Scientific Advances and Accomplishments; Sensory; Severities; Structure; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Variant; Work; Zebrafish; base; deafness; disability; embryo cell; gene function; hearing impairment; improved; insight; interest; methionine sulfoxide reductase; mouse model; mutant; next generation; novel; positional cloning; prevent; recessive genetic trait; spiral ganglion; trait

DESCRIPTION (provided by applicant): Hearing loss is a genetically heterogeneous disorder that can occur at any age, with any degree of severity, and in any population. Worldwide, 1.33 per 1000 individuals are affected by prelingual severe or profound deafness. Eighty-six distinct recessive genetic loci (DFNB) have been linked to nonsyndromic hearing impairment. To date, however, only 38 mutated genes have been identified from the 86 loci. Thus, despite the significant role of genetic factors in the etiology of recessive deafness and the dramatic progress in mapping of the DFNB loci, much remains to be uncovered regarding the identification of the genes involved in the hearing process as well as the molecular and cellular basis of hearing impairment. Gaining such knowledge is pivotal for the advancement of clinical interventions, including early diagnosis and novel treatments. The major goals of this application are to identify and characterize three deafness genes (DFNB74, DFNB85 and DFNB94) through comprehensive and systematic genetic and functional analyses. In our preliminary data we have already identified the DFNB74 mutant gene (MSRB3) and have developed a knockout mouse model for characterization studies. In addition, we have identified and mapped two new deafness loci (DFNB85 and DFNB94) segregating among 19 human families, and we are positioned to identify the specific gene variants on both of these loci. The proposed experimental design includes two overall aims: In Aim 1 we will identify causative genes on two novel DFNB loci (DFNB85 and DFNB94) using next-generation sequencing. We will also determine the expression and localization of the proteins encoded by the newly identified genes in the inner ear. In Aim 2, we will fully characterize the function of the known gene (MSRB3, locus DFNB74) in the inner ear, using a mouse model. Our experimental approach in Aim 2, based on extensive preliminary data, is to define the consequences of loss of MSRB3 on inner ear function, morphology, oxidative stress, and expression of genes involved in the apoptotic pathway. Our studies proposed through these two aims will employ state-of-the art genetic, molecular, and cell biological techniques. We anticipate that the completion of these studies will identify and provide information about two new genes responsible for nonsyndromic hearing loss in humans, and elucidate the function of the recently identified MSRB3 gene in the inner ear This work will advance the scientific understanding of deafness and it will have important clinical impact by enabling improved genetic diagnosis, counseling and the development of therapeutic interventions. PUBLIC HEALTH RELEVANCE: Advancing our understanding of molecular mechanisms in the inner ear is a prerequisite to developing therapeutic strategies for hearing impairment. The studies outlined in this proposal seek to identify genes for two additonal recently identified deafness loci and to charcterize the function of the known DFNB74 gene by utilizing mouse models. The proposed reserch is directly relevant to the NIH's interest in developing fundamental knowledge that will help to reduce the burdens of human disability.

描述（由申请人提供）： 听力损失是一种遗传异质性疾病，可以发生在任何年龄，任何严重程度，任何人群。在世界范围内，每1000人中有1.33人患有语前重度或极重度耳聋。86个不同的隐性遗传位点（DFNB）与非综合征性听力障碍有关。然而，迄今为止，仅从86个位点中鉴定出38个突变基因。因此，尽管遗传因素在这一过程中起着重要作用， 隐性耳聋的病因学以及DFNB基因座定位的巨大进展，有关参与听力过程的基因的鉴定以及听力障碍的分子和细胞基础还有很多有待发现。获得这些知识对于临床干预措施的进步至关重要，包括早期诊断和新型治疗。本申请的主要目标是通过全面和系统的遗传和功能分析来鉴定和表征三个耳聋基因（DFNB 74、DFNB 85和DFNB 94）。在我们的初步数据中，我们已经鉴定了DFNB 74突变基因（MSRB 3），并开发了一种用于表征研究的敲除小鼠模型。此外，我们已经确定和定位了两个新的耳聋基因座（DFNB 85和DFNB 94）分离的19个人类家庭，我们定位，以确定这两个基因座上的特定基因变异。所提出的实验设计包括两个总体目标：在目标1中，我们将使用下一代测序鉴定两个新DFNB基因座（DFNB 85和DFNB 94）上的致病基因。我们还将确定由新鉴定的基因编码的蛋白质在内耳中的表达和定位。在目标2中，我们将使用小鼠模型充分表征已知基因（MSRB 3，基因座DFNB 74）在内耳中的功能。我们在目标2中的实验方法，基于广泛的初步数据，是确定MSRB 3丢失对内耳功能，形态，氧化应激和参与凋亡途径的基因表达的后果。通过这两个目标，我们提出的研究将采用最先进的遗传，分子和细胞生物学技术。我们预计，这些研究的完成将确定并提供有关两个新基因的信息，负责人类非综合征性听力损失，并阐明最近确定的MSRB 3基因在内耳中的功能。这项工作将推进对耳聋的科学认识，并将通过改进遗传诊断，咨询和治疗干预措施的发展产生重要的临床影响。 公共卫生关系： 提高我们对内耳分子机制的理解是开发听力障碍治疗策略的先决条件。本研究拟利用小鼠模型对两个新发现的耳聋基因进行鉴定，并对已知的DFNB 74基因的功能进行研究。这项研究直接关系到美国国立卫生研究院对发展基础知识的兴趣，这将有助于减轻人类残疾的负担。