Molecular Genetics of Non-Syndromic Deafness

描述（由申请人提供）：听力损失是人类发病的重要经济和社会原因。遗传因素是导致听力损失的主要原因之一。虽然已有100多个非综合征性听力损失（NSHL）基因被定位，并且越来越多的基因被克隆，但对遗传性内耳缺陷的分子机制知之甚少。长期目标是更好地了解遗传性耳聋的细胞和分子基础，以便开发有效的遗传咨询和成功的遗传性耳聋治疗策略。在之前的资助期间，我们已经确定了几个基因并绘制了两个新的非综合征性听力损失基因座，这为基因克隆和功能研究开辟了新的途径。鉴于人们对这些基因的突变如何产生相似的表型知之甚少，而且许多耳聋谱系仍然无法显示出与这些基因座的联系，因此，继续鉴定人类耳聋基因并研究鉴定基因的功能对我们来说很重要。有趣的是，在我们的前期研究中，我们进一步证实了NSHL的异质性，缩小了DFNA41和DFNA53位点的关键区域，成功建立了Ush1c敲除小鼠模型和Cdh23和Pcdh15的双突变小鼠，并鉴定了Slc26a5敲除小鼠模型的阳性ES细胞克隆。这些有趣的初步结果引导我们继续克隆NSHL的新基因，并充分研究NSHL的分子机制（短期目标），以确定遗传性内耳疾病的潜在治疗方法。目的1。定位和克隆NSHL的其他基因。目标2。克隆DFNA41/DFNA53基因。目标3。利用Ush1c敲除小鼠确定内耳缺陷的细胞和分子机制，以及Ush1c与其他Ush1基因在体内的功能相互作用。目标4。描述Slc26a5敲入小鼠中人类prestin基因IVS2-2A>G突变的结构和功能后果。

DESCRIPTION (provided by applicant): Hearing loss is an economically and socially important cause of human morbidity. The genetic factors are one of the main etiologies causing hearing loss. While more than 100 genes for non-syndromic hearing loss [NSHL) have been mapped and a growing number have been cloned, little is known about the molecular mechanisms underlying hereditary inner ear defect. The long-term objective is to better understand the cellular and molecular basis of hereditary deafness so that effective genetic counseling and successful treatment strategies for hereditary deafness can be developed. During the previous grant period, we have identified several genes and mapped two novel loci for non-syndromic hearing loss, which opened new avenues to genes cloning and functional investigations. Given the facts that little is known about how mutations in these genes produce similar phenotypes and that many deafness pedigrees still fail to show linkage to any of these loci, it is therefore important for us to continue identifying human deafness genes and to investigate function of identified genes. Interestingly, as shown in our preliminary studies, we have confirmed further heterogeneity of NSHL, narrowed the critical regions of the DFNA41 and DFNA53 loci, successfully created the Ush1c knockout mouse model and double mutant mice for Cdh23 and Pcdh15, and identified positive ES cell clones for the Slc26a5 knockin mouse model. These interesting preliminary results have thus led us to continue cloning novel genes for NSHL and fully investigate the molecular mechanisms underlying NSHL (short-term objective) towards identifying potential therapeutic approaches for hereditary inner ear diseases. Aim 1. Localize and clone additional genes for NSHL. Aim 2. Clone DFNA41/DFNA53 genes. Aim 3. Determine cellular and molecular mechanism underlying inner ear defects using the Ush1c knockout mice and functional interactions in vivo of Ush1c with other Ush1 genes. Aim 4. Characterize the structural and functional consequences of the IVS2-2A>G mutation of the human prestin gene in the Slc26a5 knockin mice. Significance: The studies proposed in the current proposal together with the studies completed during the previous grant period will provide new insights into the pathological mechanisms underlying genetic hearing loss in humans, which can uncover new development of strategies for therapeutic intervention of hearing impairment in NSHL.