MOLECULAR GENETICS OF USHER SYNDROME TYPE I

Usher综合征（USH）是一种以进行性视网膜炎为特征的常染色体隐性遗传疾病 色素性（RP）和中度至重度感音神经性听力损失。USH是导致 全世界约有50%的耳聋和失明病例， 在美国，失明是由于Usher综合征。三种主要的临床亚型（USH I型， USH II型和USH III型）根据听力损失的严重程度以及是否存在 前庭功能障碍USH I型是遗传异质性的，表型是最严重的 USH的三种类型USH 1的7个基因位点已经被定位，其中5个基因已经被定位。 被识别。至少还有三个USH I型基因有待鉴定。在与 弗里德曼博士的实验室拥有前所未有的遗传资源，可以识别和研究 与非综合征型和综合征型听力损伤有关的基因。从这个资源中，1有 开发了一个独特的USH I型家族的集合，在已知的USH基因中没有突变， 与USH 1H基因座连锁或与已知USH 1基因座不连锁。作为首席研究员，我的目标是利用 这些USH I型家族用于定位和鉴定新的USH 1基因，包括USH 1H。我 USH的出版记录表明了我成功进行这项研究的能力。我的职业目标 是通过鉴定和功能解剖与耳聋有关的基因来了解听力过程的遗传和分子基础。该建议有三个具体目的：1）招募具有USHI表型的额外家庭和已知USH基因座的突变筛选，2）连锁分析以定位USHl的基因座，和3）定位克隆USHI H和额外USHI基因。 这些基因的鉴定和表征将提高诊断的准确性和改善遗传咨询。USH的分子解剖将揭示关于正常人常见的发育、代谢和/或调节途径的重要新信息。视网膜和听觉功能。

Summary: Usher syndrome (USH) is an autosomal recessive disorder characterized by progressive retinitis pigmentosa (RP) and moderate to profound sensorineural hearing loss. USH is the leading cause of combined deafness and blindness in the world and about 50% of all cases of combined deafness and blindness in the United States are due to Usher syndrome. The three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished by severity of hearing loss and by the presence or absence of vestibular dysfunction. USH type I is genetically heterogeneous and the phenotype is the most severe of the three types of USH. Seven genetic loci have been mapped for USH1 and genes for five of them have been identified. At least three more genes for USH type I remain to be identified. In collaborations with scientists around the world, Dr. Friedman's lab has an unprecedented genetic resource to identify and study the genes involved in nonsyndromic as well as syndromic hearing impairment. From this resource, 1 have developed a unique collection of USH type I families with no mutations in the known USH genes and are either linked to USH1H locus or unlinked to known USH1 loci. As the Principal Investigator, my goal is to use these USH type I families forthe mapping and identification of new USH1 genes, including USH1H. My publication record on USH is indicative of my abilities to successfully conduct this research. My career goals are to understand the genetic and molecular basis of hearing processes through the identification and functional dissection of the genes involved in deafness. There are three specific aims of this proposal: 1) enrollment of additional families with an USHI phenotype and mutational screening of known USH loci, 2) linkage analyses to map the loci for USH1, and 3) positionally cloning of USHI H and additional USHI genes. Identification and characterization of these genes will enhance diagnostic accuracy and improve genetic counseling. Molecular dissection of USH will reveal important new information about the developmental, metabolic and/or regulatory pathways common to norma! retinal and auditory function.