The functions of PDZ domain scaffold proteins in Usher syndrome

描述（由申请人提供）：人类Usher综合征是聋盲的最常见原因，其特征是由于感觉毛细胞丧失引起的先天性耳聋和由于色素性视网膜炎引起的进行性视网膜变性。12个不同的染色体位点与Usher综合征有关，其中9个基因已被鉴定。鉴定缺失的Usher基因对于诊断和患者咨询至关重要。这九个已知基因编码的蛋白质种类之多令人惊讶。虽然这些蛋白质的作用知之甚少，但最近的研究表明，它们在多分子复合物中共同发挥作用。该项目的重点是分析在组织复合物中起核心作用的两种支架蛋白，以及这种组织支架的新的潜在成员。该项目有三个主要目标：1）确定新发现的基因是否编码Usher支架蛋白，2）分析支架蛋白在将Usher蛋白组织成复合物中的功能，以及3）确定Usher蛋白复合物如何在内耳和视网膜细胞中发挥作用。 公共卫生相关性：Usher综合征是导致聋盲的主要原因，是一种遗传性疾病，影响着成千上万的美国人。Usher综合征的耳聋是由于内耳感觉毛细胞的损失，范围从中度到重度。失明是由于视网膜色素变性。至少有十几种不同基因中的任何一种突变都可能导致Usher综合征，其中只有九种基因被确定。最近的研究表明，由Usher基因编码的各种蛋白质在多分子复合物中共同作用，尽管当复合物有缺陷时导致内耳和视网膜细胞丧失的过程尚不清楚。这个项目将阐明如何和在哪里复杂的功能和机制，它的组装。该项目还将确定Usher基因家族的新成员。这些信息对于Usher患者的诊断，遗传咨询和治疗设计非常重要。

DESCRIPTION (provided by applicant): Human Usher syndrome, the most frequent cause of deaf blindness, is characterized by congenital deafness, due to loss of sensory hair cells, and progressive retinal degeneration, due to retinitis pigmentosa. Twelve different chromosomal loci have been linked to Usher syndrome and nine of the genes have been identified to date. Identification of the missing Usher genes is crucial for diagnosis and patient counseling. The nine known genes encode a surprisingly broad range of different types of proteins. Although the roles of these proteins are poorly understood, recent studies suggest that they function together in a multimolecular complex. This project focuses on analysis of the two scaffold proteins that play a central role in organizing the complex, and a new potential member of this organizing scaffold. The project has three main aims: 1) to determine whether the newly discovered gene encodes an Usher scaffold protein, 2) to analyze the functions of the scaffold proteins in organizing the Usher proteins into a complex, and 3) to determine how the Usher protein complex functions in cells of the inner ear and retina. PUBLIC HEALTH RELEVANCE: Usher syndrome, the leading cause of deaf blindness, is a genetically heritable disorder that affects tens of thousands of Americans. Deafness in Usher syndrome is due to loss of inner ear sensory hair cells and can range from moderate to profound. Blindness is due to retinitis pigmentosa. Mutations in any one of at least a dozen different genes can cause Usher syndrome, only nine of the genes have been identified. Recent research suggests that the various proteins encoded by the Usher genes act together in a multimolecular complex, although the processes that lead to loss of inner ear and retinal cells when the complex is defective are unknown. This project will elucidate how and where the complex functions and the mechanisms by which it assembles. The project will also identify new members of the Usher gene family. This information is important for diagnosis, genetic counseling, and design of therapies for Usher patients.