Molecular Genetics of Non-Syndromic Deafness

描述（研究者摘要）：本提案的目标是确定 非综合征性耳聋的分子基础 来自远东人群的患者/家庭的几个独特资源。 我们从患者/家庭中收集了大量不断扩大的基因组DNA 中国和日本的非综合征性耳聋患者 异质性、多代大家庭和血缘家庭 被选来进行研究， 联系的证据。然后，我们将设法确定并最终克隆 通过位置候选基因方法确定相关基因。第二，小说 序贯筛选策略将用于鉴定耳聋的新基因 在多重家族的先证者中。待筛选的候选基因将 包括人类耳聋鼠基因的直系同源物和其他成员， 基因家族，其中一些已知是耳聋的原因。研究 将产生重要的信息，即频率上的种族差异， 目前公认的非综合征性疾病基因突变的分布 耳聋使用关于结果变量的现有信息，例如年龄 发病，听力学结果，和聋人人口的交配结构， 这些数据将允许搜索临床相关的基因型-表型 相关性和更清楚地了解长期变化的原因， 遗传性耳聋的特殊形式的频率。最后，我们将使用酵母 2-杂交系统和免疫亲和层析来寻找蛋白质 与MYO 7A和USH 1C基因的产物相互作用。的 识别这种相互作用可以导致识别潜在的 修饰剂和令人兴奋的新的治疗方法，以减轻特定的 基因突变对耳蜗的影响拟议的工作将确定新的 非综合征性耳聋的基因，使我们能够更好地了解细胞 和遗传性耳聋的分子基础。我们的研究将发展出一种 基因参与非综合征性耳聋的全面情况， 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 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.