Molecular Genetics of autosomal dominant non-syndromic hearing loss

描述(申请人提供)：大多数遗传性听力损失(HL)是非综合征性的，通常起源于神经上皮细胞，由器官功能缺陷引起 科尔蒂--内耳的听觉传导部位。在这些人中，高达30%是常染色体显性遗传性非综合征性耳聋(ADNSHL)(Liu和Xu，1994)。尽管在过去的几年里，使用基于基因组学的方法，HL基因的列表迅速扩大，但有证据表明，还有更多的HL基因和基因座有待发现。首先，在为ADSNHL定位的65个基因中，只有26个基因被确定。其次，许多聋人家系仍然无法显示出与这些已知基因中的任何一个有关联，这表明还有其他基因参与其中。第三，尽管最近在识别非综合征性HL(NSHL)的基因方面取得了进展，但进行性听力损失的小鼠模型仍然相对较少。大量的耳聋小鼠突变体也存在，没有明显的人类同源基因，人类耳聋基因的定位或鉴定没有相应的小鼠模型可用，这表明我们仍然有很多关于人类耳聋的遗传学方法需要了解。因此，有必要定位和识别ADNSHL的新基因，以便为耳聋的遗传原因提供准确的诊断。DNA浓缩和下一代测序(NGS)技术的进步使快速且经济高效地对基因组的所有基因进行测序，然后快速识别导致孟德尔疾病的变异成为可能。我们的长期目标是更好地了解遗传性耳聋的遗传和分子基础，以便开发有效的遗传咨询和成功的治疗策略。我们最近发现了几个新的ADNSHL基因，并定位了几个新的基因座。我们已经成功地为其中一些基因建立了动物模型。此外，我们收集了15个ADNSHL与已知的ADNSHL基因座无关的多代大家系，为本建议的基因鉴定(短期目标)(特定目标1和2)以及体外和体内功能提供了基础 对当前建议中新发现的两个ADNSHL基因进行研究(具体目标2和3)。我们这次捐赠的具体目标是：1.为ADNSHL定位新的基因座。2.利用传统技术和创新技术寻找ADNSHL的新基因。3.研究人类Smac基因S71L突变对Smac基因敲除小鼠的结构和功能的影响。4.完成了P2XR2_V60L突变的体内外功能研究。拟议目标的完成不仅将增加我们对听力和耳聋生物学的理解，而且将通过增加遗传检测的可用性、改进分子诊断以及因此遗传咨询而具有高度的转化性。

DESCRIPTION (provided by applicant): The majority of inherited hearing loss (HL) is non-syndromic, and is often neuroepithelial in origin arising from defects in the function of the organ of Corti - the site of auditory transduction in the inner ear. Of these, up to 30% are autosomal dominant non-syndromic hearing loss (ADNSHL) (Liu and Xu, 1994). Although the past few years have witnessed a rapidly expanding list of HL genes using genomics based approaches, there is evidence that there are more HL genes and loci to be discovered. First, of the 65 mapped genes for ADSNHL, the gene has been identified for only 26. Second, many deaf pedigrees still fail to show linkage to any of these known loci, indicating that additional genes are involved. Third, despite recent progress in identifying genes underlying non syndromic HL (NSHL), there are still relatively few mouse models for progressive hearing loss. A large number of deaf mouse mutants also exist with no obvious human homologue, and human deafness genes localized or identified with no equivalent mouse model available, indicating that we still have much to learn about deafness from a genetic approach in humans. Therefore, there is an established need for mapping and identifying new genes for ADNSHL in order to provide accurate diagnosis of the genetic cause of deafness. Advances in DNA enrichment and Next Generation Sequencing (NGS) technology have made it possible to quickly and cost-effectively sequence all the genes of the genome, and then to rapidly identify variants responsible for Mendelian disorders. Our long-range goal is to better understand the genetic and molecular basis of hereditary deafness so that effective genetic counseling and successful treatment strategies can be developed. We have recently identified several new genes and mapped several novel loci for ADNSHL. We have successfully generated the animal models for some of these genes. In addition, we have collected 15 large multi-generational families with ADNSHL not linked to known ADNSHL loci, providing the basis for the present proposal for gene identification (Short-term objective) (Specific Aims 1 and 2) and for in vitro and in vivo function studies on both newly identified ADNSHL genes in the current proposal (Specific Aims 2 and 3). Our Specific Aims in this grant are: 1. Map new loci for ADNSHL. 2. Identify new genes for ADNSHL using traditional and innovative technologies. 3. Characterize the structural and functional consequences of the human S71L mutation of the SMAC gene in the smac knock-in mice. 4. Complete in vitro and in vivo functional studies of the P2XR2_V60L mutation. Completion of the proposed aims will not only increase our understanding of the biology of hearing and deafness, but will be highly translational by increasing availability of genetic testin, improving molecular diagnosis and, consequently, genetic counseling.