MOLECULAR GENETICS OF USHER SYNDROME III, IIB, AND IA

Usher综合征是一种遗传性疾病，会导致先天性听力丧失和视网膜色素变性。临床主要分为Usher综合征型（USH1）、II型（USH2）和III型前庭功能障碍。现在至少有十个不同的基因位点被确定与三种临床类型的疾病有关。在10个Usher基因座中，已经确定了两个基因，USH1B和USH2A。USH1B编码MYO7A，一种非常规的肌球蛋白，而USH2A编码一种假定的细胞外基质蛋白。这些不同种类的分子与其他Usher基因产物之间有什么关系呢？为了解决这个问题，我们希望鉴定更多的Usher基因。我们有家庭资源来启动这样的项目。在本提案中，我们希望确定Usher综合征1A型、2B型和3型基因及其产物。我们将采用标准的定位克隆策略，构建序列标记位点（STS）图谱，整合YAC/BAC/PAC序列图谱和转录本图谱。Usher 1A、2B和3型基因将被鉴定为携带疾病的基因，导致受影响个体的编码区或调控区发生突变。各种Usher基因的鉴定不仅提供了对其产物在正常听力，视觉和前庭功能中起重要作用的一组基因的深入了解，而且建立了基于基因的疾病遗传诊断的可能性。它将为内耳和视网膜的发育以及时间和空间组织提供见解，这些缺陷被认为是起源于内耳和视网膜，这将使我们能够设计治疗方法。

Usher syndrome is a hereditary disorder that causes congenital hearing loss and retinitis pigmentosa. The three major clinical types, Usher syndrome type (USH1), type II (USH2) and type III of vestibular dysfunction. At least ten distinct genetic loci are now identified as being associated with the three clinical types of the disease. Of the ten Usher loci, two genes, USH1B and USH2A, have been identified. The USH1B encodes MYO7A, an unconventional myosin and USH2A encodes a putative extracellular matrix protein. What, if any, relation is there between these different classes of molecules and they relate to the other Usher genes' products. To address this question, we wish to identify additional Usher genes. We have the family resources to initiate such project. In the present proposal we wish to identify the Usher syndrome type 1A, type 2B and type 3 genes and their products. We will apply standard positional cloning strategy based on the construction of Sequence Tagged Site (STS) maps, integrated YAC/BAC/PAC contig maps and transcript maps for the respective critical regions. The Usher type 1A, 2B and 3 genes will be identified as genes carrying disease causing mutations in their coding or regulatory regions in the affected individuals. The identification of the various Usher genes not only provides an insight into a group of genes whose products play an important role in normal hearing, vision and vestibular function but establishes the possibility of gene based genetic diagnosis of the disease. It will provide insights into the development and the temporal and spatial organization of the inner ear and retina where the defect is believed to originate and will allow us to design therapies.