Molecular Genetics of autosomal dominant non-syndromic hearing loss

常染色体显性非综合征性听力损失的分子遗传学

• 批准号: 8346327
• 负责人: XUE Z LIU
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8346327
• 关键词: Affect; American; Animal Model; Apoptosis; Architecture; Area; Auditory; Auditory system; Behavioral; Biology; Candidate Disease Gene; Cells; Chinese People; Chromosome Mapping; Clinical Management; Clinical Treatment; DNA; Data; Defect; Diagnosis; Disease; Dominant-Negative Mutation; Exclusion; Family; Foundations; Gene Transfer Techniques; Generations; Genes; Genetic; Genetic Counseling; Genetic screening method; Genome; Genomics; Genotype; Goals; Grant; Hearing; Hearing Impaired Persons; Hearing Tests; Homologous Gene; Human; In Vitro; Inherited; Knock-in Mouse; Knowledge; Labyrinth; Learning; Light; Link; Maps; Membrane Potentials; Messenger RNA; Microscopic; Modeling; Molecular; Molecular Diagnosis; Molecular Genetics; Mutant Strains Mice; Mutation; National Institute on Deafness and Other Communication Disorders; Neuroepithelial; Organ of Corti; Partial Hearing Loss; Prevalence; Relative (related person); Research; Single Nucleotide Polymorphism; Site; Societies; Technology; Tissues; Transgenic Organisms; United States National Institutes of Health; Variant; Zebrafish; age related; base; cost; deafness; exome; gene discovery; gene function; genetic linkage analysis; genetic pedigree; hearing impairment; human morbidity; improved; in vivo; innovative technologies; mitochondrial membrane; mouse model; mutant; next generation; novel; overexpression; tool; treatment strategy

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. PUBLIC HEALTH RELEVANCE: The current studies will identify and characterize novel genes involved in hearing and responsible for late onset hearing impairment using large multi-generational families and state-of-the-art genomic tools such as massively parallel sequencing technologies. This will enhance our understanding of the normal hearing and the genetic aberrations that result in age-related hearing impairments. A more complete knowledge of genes involved in the auditory system will provide a foundation for better genetic counseling, clinical management and treatment options for hearing loss.

描述（由申请人提供）：大多数遗传性听力损失（HL）是非综合征性的，通常是由器官功能缺陷引起的神经上皮起源 Corti的-在内耳听觉传导的网站。其中，高达30%为常染色体显性非综合征性听力损失（ADNSHL）（Liu和Xu，1994）。虽然在过去的几年里，已经见证了一个快速扩大的HL基因的名单，使用基因组学为基础的方法，有证据表明，有更多的HL基因和基因座被发现。首先，在65个定位的ADSNHL基因中，该基因仅被鉴定出26个。第二，许多耳聋家系仍然没有显示出与这些已知基因座中的任何一个的连锁，这表明还有其他基因参与其中。第三，尽管最近在确定非综合征型HL（NSHL）相关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物，人类耳聋基因定位或鉴定，没有等效的小鼠模型可用，这表明我们仍然有很多要了解耳聋的遗传方法在人类。因此，有一个既定的需要定位和识别新的基因ADNSHL，以提供准确的诊断耳聋的遗传原因。DNA富集和下一代测序（NGS）技术的进步使得快速且具有成本效益地对基因组的所有基因进行测序，然后快速鉴定导致孟德尔疾病的变体成为可能。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，以便制定有效的遗传咨询和成功的治疗策略。我们最近已经确定了几个新的基因，并绘制了几个新的位点ADNSHL。我们已经成功地为其中一些基因建立了动物模型。此外，我们还收集了15个与已知ADNSHL基因座不连锁的ADNSHL多代大家族，为目前的基因鉴定（短期目标）（具体目标1和2）以及体外和体内功能提供了基础 对当前提案中两个新鉴定的ADNSHL基因的研究（具体目标2和3）。我们在这个补助金的具体目标是：1。绘制ADNSHL的新基因座。2.使用传统和创新技术鉴定ADNSHL的新基因。3.表征smac基因敲入小鼠中SMAC基因的人S71 L突变的结构和功能后果。4.完成P2XR2_V60L突变的体外和体内功能研究。完成拟议的目标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测试的可用性，改善分子诊断以及遗传咨询来实现高度转化。 公共卫生关系：目前的研究将使用大型多代家族和最先进的基因组工具（如大规模并行测序技术）来识别和表征与听力相关的新基因，并负责晚发型听力障碍。这将加强我们对正常听力和导致与年龄相关的听力障碍的遗传畸变的理解。对听觉系统相关基因的更全面了解将为更好的遗传咨询、临床管理和听力损失治疗方案提供基础。