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: 8719084
• 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/8719084
• 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; Massive Parallel Sequencing; 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 sequencing; 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 sequencing; 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.

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，并且通常是由器官功能缺陷引起的神经上皮起源 柯蒂氏管 - 内耳听觉传导部位。其中，高达 30% 是常染色体显性非综合征性听力损失 (ADNSHL)（Liu 和 Xu，1994）。尽管过去几年使用基于基因组学的方法发现的 HL 基因列表迅速扩大，但有证据表明还有更多 HL 基因和基因座有待发现。首先，在 ADSNHL 的 65 个定位基因中，仅鉴定出 26 个基因。其次，许多聋人谱系仍然未能显示与任何这些已知基因座的连锁，这表明还涉及其他基因。第三，尽管最近在识别非综合征性 HL (NSHL) 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。大量耳聋小鼠突变体也存在，没有明显的人类同源物，并且人类耳聋基因定位或鉴定没有可用的等效小鼠模型，这表明我们仍然有很多东西需要从人类遗传方法中了解耳聋。因此，迫切需要绘制和鉴定 ADNSHL 的新基因，以便对耳聋的遗传原因提供准确的诊断。 DNA 富集和下一代测序 (NGS) 技术的进步使得快速且经济高效地对基因组的所有基因进行测序成为可能，然后快速识别导致孟德尔疾病的变异。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。我们最近鉴定了几个新基因并绘制了 ADNSHL 的几个新位点。我们已经成功地为其中一些基因生成了动物模型。此外，我们收集了 15 个与已知 ADNSHL 基因座无关的 ADNSHL 大型多代家族，为目前基因鉴定（短期目标）（具体目标 1 和 2）以及体外和体内功能的提议提供了基础 对当前提案中新发现的 ADNSHL 基因进行研究（具体目标 2 和 3）。我们在这笔赠款中的具体目标是： 1. 绘制 ADNSHL 的新基因座。 2. 使用传统和创新技术识别 ADNSHL 的新基因。 3. 表征 SMAC 基因的人类 S71L 突变在 smac 敲入小鼠中的结构和功能后果。 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，而且将通过增加基因测试的可用性、改善分子诊断以及因此的遗传咨询而实现高度转化。