Molecular Genetics of Non-Syndromic Deafness

描述(调查人员摘要)：本提案的目标是确定 多学科研究非综合征性耳聋的分子基础 在来自远东人口的几个独特的患者/家庭资源中。 我们有来自患者/家属的大量且不断扩大的基因组DNA收集 非综合征性耳聋首先来自中国和日本，原因是遗传 异质性、多代大家庭和血缘家庭 已经被选中进行研究，能够独立地产生 有关联的证据。然后，我们将寻求识别并最终克隆 相关基因采用位置候选基因的方法。第二，一部小说 将使用顺序筛查策略来识别耳聋的新基因 在来自多个家庭的先驱中。待筛选的候选基因将 包括小鼠耳聋基因的人类同源基因和其他成员 基因家族，其中一些已知是导致耳聋的原因。这项研究 将产生关于种族频率和种族差异的重要信息 目前公认的非综合征患者基因突变的分布 耳聋。使用有关结果变量的现有信息，如年龄 失聪人群的发病、听力学发现和交配结构， 这些数据将允许搜索临床相关的基因-表型。 相关关系和对长期变化原因的更清晰理解 遗传性耳聋的特定形式的频率。最后，我们将使用酵母 2-杂合系统和免疫亲和层析寻找蛋白质 与MYO7A和USH1C基因的产物相互作用。这个 识别这种相互作用可能导致识别潜在的 修饰剂和令人兴奋的新治疗方法以减轻特定的 突变对耳蜗的影响。拟议的工作将确定新的 基因(S)用于非综合征性耳聋，使我们更好地了解细胞 以及遗传性耳聋的分子基础。我们的学习将发展出更多的 非综合征性耳聋的基因参与研究综述 进一步了解这些基因在内耳中的功能。这 知识是发展和提供知识的必要前提。 为非综合征性耳聋家庭提供分子诊断服务。

DESCRIPTION (Investigator's abstract): The goal of this proposal is to identify molecular basis of non-syndromic deafness by using a multidisciplinary Approach in several unique resources of patients/families from Far Eastern populations. We have a large and expanding collection of genomic DNA from patients/families with non-syndromic deafness from China and Japan First, because of genetic heterogeneity, large multigenerational families and consanguineous families have been selected for study that are independently capable of yielding evidence of for linkage. We will then seek to identify and ultimately clone the relevant genes by the positional candidate gene approach. Second, a novel sequential screening strategy will be used to identify new genes for deafness in probands from multiplex families. Candidate genes to be screened will include the human orthologs of murine genes for deafness and other members of gene families in which some are known to be the cause of deafness. The research will yield important information o ethnic differences in the frequency and distribution of mutations at currently recognized genes for non-syndromic deafness. Using available information on outcome variables such as age of onset, audiologic findings, and the mating structure of the deaf population, these data will permit a search for clinically relevant genotype-phenotype correlations and a clearer understanding of the cause for secular changes in the frequency of specific forms o genetic deafness. Finally, we will use yeast 2-hybrid systems and the immunoaffinity chromatography to search for proteins that interact with the products of the MYO7A and USH1C genes. The identification of such interactions could lead to identifying potential modifiers and exciting new therapeutic approaches to attenuate the specific effects of mutations on the cochlear. The proposed work will identify the new gene (s) for non-syndromic deafness and enable us to understand better cellular and molecular basis of genetic deafness. Our studies will develop a more comprehensive picture of the involvement of genes in non-syndromic deafness to gain further insight into the function of these genes in the inner ear. This knowledge is an essential prerequisite to the development and provision of molecular diagnostic services for families with non-syndromic deafness.