MOLECULAR GENETICS OF USHER SYNDROME III, IIB, AND IA

Usher综合征是一种遗传性疾病，会导致先天性听力损失和视网膜色素变性。三种主要临床类型：Usher综合征(USH1)、II型(USH2)和III型前庭功能障碍。现在，至少有10个不同的基因座被确定与三种临床类型的疾病有关。在这10个Usher基因座中，已鉴定出USH1B和USH2A两个基因。USH1B编码一种非传统的肌球蛋白MYO7A，USH2A编码一种可能的细胞外基质蛋白。这些不同类别的分子之间有什么关系，它们与其他Usher基因的产物有关。为了解决这个问题，我们希望确定更多的Usher基因。我们有家庭资源来发起这样的项目。在本提案中，我们希望鉴定Usher综合征1A型、2B型和3型基因及其产物。我们将在构建序列标记位点(STS)图、整合的YAC/BAC/PAC重叠群图和转录图的基础上应用标准的位置克隆策略。Usher1A型、2B型和3型基因将被鉴定为携带疾病的基因，在受影响的个人中会导致其编码或调节区的突变。各种Usher基因的鉴定不仅提供了对一组基因的洞察，这些基因的产物在正常的听力、视觉和前庭功能中发挥着重要作用，而且建立了基于基因的疾病基因诊断的可能性。它将提供对内耳和视网膜的发育以及时间和空间组织的洞察，据信这些缺陷起源于这些缺陷，并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.