DFNA1 IN INHERITED HEARING LOSS

说明： 调查人员研究了一个常染色体哥斯达黎加大家庭。 显性进行性非综合征性耳聋(DFNA1)，最近 通过定位克隆鉴定了一种蛋白质截断突变。 果蝇透明基因的人类同源物。这种突变被发现了 在所有聋人家庭成员中，而在正常听力家庭成员或以上的人中 300名控制者。此应用程序的目标是 (1)为该突变的致病性提供功能支持 通过a)通过同源重组和 表明这些小鼠突变体具有耳聋表型(特异性目标1 3)和b)说明蛋白质异常导致异常 稳定性或细胞内定位(特定目标2和4)，(2)至 启动与透明蛋白相互作用的研究，这将澄清 致病途径并为其他耳聋基因提供候选基因 (具体目标5)， (3)对其他三个耳聋家系进行新耳聋的鉴定研究 耳聋基因(特定目标6)，以及(4)收集200名聋人 与一些来自凯撒永久制度的家庭成员作为将军 资源，并筛查透明系统中的突变(特定 目标7)。

DESCRIPTION: The investigators have studied a large Costa Rican family with autosomal dominant progressive non-syndromic hearing loss (DFNA1), and have recently through positional cloning identified a protein truncation mutation in the human homologue of the Drosophila diaphanous gene. This mutation was found in all deaf family members, and not in normal hearing family members or over 300 control individuals. The goals of this application are (1) to provide functional support for the pathogenicity of this mutation through a) generating mutant mice through homologous recombination and showing that these mouse mutants have a deafness phenotype (specific aims 1 and 3) and b) demonstrating that the protein abnormality leads to abnormal stability or intracellular localization (specific aims 2 and 4), (2) to start the study of proteins interacting with diaphanous which will elucidate the pathogenic pathway and provide candidate genes for other deafness genes (specific aim 5), (3) to study three other deafness families toward the identification of new deafness genes (specific aim 6), and (4) to collect 200 deaf individuals with some family members from the Kaiser Permanente system as a general resource, and screen them for mutations in the diaphanous system (specific aim 7).