Genetic Basis of Moderate to Severe Hearing Loss in Pakistan

巴基斯坦中度至重度听力损失的遗传基础

基本信息

批准号：
8139119
负责人：
Sadaf Naz
金额：
$ 5.39万
依托单位：
SCHOOL OF BIOLOGICAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139119
关键词：
Affect Attention Audiometry Blood specimen Candidate Disease Gene Child Childhood Clinical Clinical Markers Collection Communication impairment DNA Data Data Analyses Defect Diagnosis Disease Education Enrollment Etiology Family Family Relationship Future Gene-Modified Genes Genetic Genetic Counseling Genetic Screening Genotype Government Hearing Hearing Impaired Persons Hereditary Disease Human Individual Inherited Knowledge Labyrinth Maps Marriage Medical History Meiotic Recombination Mental Depression Microsatellite Repeats Mutation Nature Occupations Pakistan Participant Phenotype Population Population Study Proteins Recruitment Activity Research Research Personnel Residual state Resources Role Sampling Schools Sensory Simulate Societies Special Education Speech Tertiary Protein Structure Work base deafness early onset family structure gene cloning gene function genetic linkage genetic linkage analysis genome-wide linkage hearing impairment novel positional cloning programs sound

项目摘要

DESCRIPTION (provided by applicant): The overall objective of the proposed work is to map and positionally clone genes responsible for moderate to severe hearing loss. Deafness is one of the most prevalent sensory defects in humans and a majority of genetic hearing loss is recessively inherited and is the only clinical manifestation (nonsyndromic). Untreated hearing loss results in speech difficulties and often has a detrimental effect on family relations, occupation and education of these individuals and can contribute to depression. Although over 20 genes have been cloned for nonsyndromic, recessively inherited, severe-to-profound deafness, the genes responsible for recessive, moderate to severe hearing loss are largely unknown due to the scarcity of such families currently recruited in genetic linkage studies. To remove this bias, we plan to: a) Enroll large consanguineous families with recessively inherited moderate to severe hearing loss from Pakistan, b) Discover novel loci by performing genome-wide linkage analyses on the collected samples & c) Identify the causative genes by positional cloning. To achieve these aims we will recruit families with the help of audiologists, Pakistan Society for Communication Disorders, Department of Special Education and regular schools. After collection of blood samples and extraction of DNA, we will screen samples from affected individuals for shared homozygosity with markers flanking known deafness loci. If homozygosity at some of these markers segregates with the hearing loss, the appropriate genes will be sequenced in order to find mutations and determine genotype-phenotype correlations. Families in which hearing loss is negative for linkage to known loci will be selected for the identification of novel loci. Markers for genome-wide linkage analyses will be used and two-point LOD (Likelihood of Odds) scores calculated to identify the disease loci. After mapping and refining these loci, we will positionally clone the disease genes by mutational analyses of the genes in the mapped intervals. The knowledge gained by this study may provide clinical markers to assist in genetic diagnosis of hearing loss and will be useful in genetic counseling of the participants enabling them to make choices since cousin marriages are common in Pakistan. Identification of the genes underlying hearing loss due to genetic disorders will reveal the crucial molecules necessary for audition and will elucidate their normal function. This is a first step in developing treatments and cures for hearing loss in the future.

描述（由申请人提供）：拟议工作的总体目标是绘制和定位克隆导致中度至重度听力损失的基因。耳聋是人类最普遍的感觉缺陷之一，大多数遗传性听力损失是隐性遗传的，是唯一的临床表现（非综合征性）。未经治疗的听力损失会导致言语困难，通常会对这些人的家庭关系、职业和教育产生不利影响，并可能导致抑郁症。尽管已经克隆了 20 多个与非综合征性、隐性遗传性、重度至重度耳聋有关的基因，但由于目前在遗传连锁研究中招募的此类家族很少，导致隐性、中度至重度听力损失的基因在很大程度上是未知的。为了消除这种偏见，我们计划：a）招募来自巴基斯坦的患有隐性遗传的中度至重度听力损失的大型近亲家庭，b）通过对收集的样本进行全基因组连锁分析来发现新的基因座，以及c）通过以下方法识别致病基因：定位克隆。为了实现这些目标，我们将在听力学家、巴基斯坦沟通障碍协会、特殊教育部和普通学校的帮助下招募家庭。收集血样并提取 DNA 后，我们将筛选受影响个体的样本，以确定其与已知耳聋基因座两侧标记的共享纯合性。如果其中一些标记的纯合性与听力损失分离，则将对适当的基因进行测序，以发现突变并确定基因型-表型相关性。将选择听力损失与已知基因座连锁呈阴性的家庭来鉴定新基因座。将使用全基因组连锁分析的标记，并计算两点 LOD（赔率似然）分数来识别疾病位点。在对这些位点进行定位和细化之后，我们将通过对定位区间内的基因进行突变分析来定位克隆疾病基因。这项研究获得的知识可以提供临床标记来协助听力损失的基因诊断，并将有助于参与者的遗传咨询，使他们能够做出选择，因为表亲婚姻在巴基斯坦很常见。鉴定由于遗传性疾病导致听力损失的基因将揭示听力所需的关键分子，并阐明它们的正常功能。这是未来开发听力损失治疗方法的第一步。