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

基本信息

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
项目类别：
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

项目摘要

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）是非综合性的，并且通常是由器官功能缺陷引起的神经上皮的。 Corti-内耳中听觉转导的位点。其中，高达30％的是常染色体显性占非综合性听力损失（ADNSHL）（Liu和Xu，1994）。尽管过去几年使用基于基因组学的方法见证了HL基因的快速扩展列表，但有证据表明，有更多的HL基因和基因座可以发现。首先，在ADSNHL的65个映射基因中，该基因仅被鉴定出26。第三，尽管最近在识别非综合征HL（NSHL）的基因方面取得了进展，但仍有相对较少的小鼠模型用于进行性听力损失。也存在大量聋小鼠突变体，没有明显的人类同源物，人类耳聋基因本地化或鉴定而没有可用的等效小鼠模型，这表明我们仍然可以从人类的遗传方法中了解耳聋。因此，为了准确诊断聋哑遗传原因，既定需要映射和识别ADNSHL的新基因。 DNA富集和下一代测序（NGS）技术的进步使得能够快速，成本效率地序列基因组的所有基因，然后迅速识别负责Mendelian疾病的变体。我们的远程目标是更好地了解遗传性耳聋的遗传和分子基础，以便可以制定有效的遗传咨询和成功的治疗策略。我们最近确定了几个新基因，并为ADNSHL绘制了几个新颖的基因座。我们已经成功地为其中一些基因生成了动物模型。此外，我们已经收集了15个具有ADNSHL的大型多代家族，与已知的ADNSHL基因座无关，为当前基因鉴定的建议提供了基础（短期目标）（特定目的1和2）以及体外和体内功能对当前建议中新鉴定的ADNSHL基因的研究（特定目的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确定ADNSHL的新基因。 3。表征SMAC敲入小鼠中SMAC基因的人类S71L突变的结构和功能后果。 4。P2XR2_V60L突变的体外和体内功能研究。提出的目标的完成不仅会增加我们对听力和耳聋的生物学的理解，而且通过增加基因测试的可用性，改善分子诊断以及因此，从而高度转化。公共卫生相关性：当前的研究将确定和表征与听力有关的新型基因，并使用大型多代家族和最先进的基因组工具（例如众多平行的测序技术）造成迟到的听力障碍。这将增强我们对正常听力的理解以及导致与年龄相关的听力障碍的遗传畸变。对听觉系统涉及的基因的更完整的了解将为更好的遗传咨询，临床管理和治疗选择提供基础。