权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
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/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

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.

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，通常起源于神经上皮，由器官功能缺陷引起