Molecular Determinants of Usher Syndrome Disorder in Humans

听力损失（HL）是一种高度可变的表型，影响全球超过7000万儿童。在综合征型HL中，Usher综合征（USH）是一种神经感觉障碍，由双侧感觉神经性HL和视网膜色素变性（RP）引起的视力丧失定义。Usher综合征分为三种临床亚型。一项分子诊断研究表明，在美国，USH的发病率为1/6000。14个不同的遗传位点已被链接到USH表型和基因的11个这些位点已被确定。USH基因/蛋白决定簇的遗传和功能研究在阐明内耳和视网膜感觉上皮细胞的共同分子组成方面取得了丰硕成果。然而，这两种感觉器官的许多重要成分的分子身份仍然是未知的，妨碍了我们对听觉和视觉的分子和细胞基础以及精确机制的理解。同样，已知的基因座/基因突变不能解释所有已知的USH病例。本研究的长期目标是充分了解遗传性Usher综合征的机制，并开发治疗和预防USH的治疗药物。这项研究的目的是鉴定和表征哺乳动物内耳发育、功能和视网膜感觉细胞长期维持所必需的蛋白质。我们的假设是，如果一个突变的基因导致耳聋和失明，那么该基因的正常功能将是听力和视力所必需的。这项研究的基本原理是，识别致病基因并了解其正常功能对于预防听力和视力丧失以及开发治疗这些损伤的治疗药物至关重要。该项目致力于国家卫生研究院的使命，即开发可用于减轻人类残疾负担的基本知识。在我们的初步数据中，我们已经确定了两个突变基因：USH 1 K和USH 1 M，并绘制了听觉和视觉功能所必需的另外两个基因的染色体位置（USH 1H和USH 1 N）。提出的实验设计包括两个目标，包括确定和临床表型分离USH的大家族成员;鉴定新的USH基因，表征它们在小鼠内耳和视网膜中的表达，并确定新USH基因的变体对模型系统中编码蛋白的影响。该项目将有利地将联合收割机人类临床评估和遗传分析与内耳和视网膜的发育和功能相结合。它将通过推进协调一致的方法和产生与临床相关的基础新知识而具有重要意义，具有很大的潜力来改善USH的分子流行病学，遗传诊断和咨询。

Hearing loss (HL) is a highly variable phenotype that affects more than 70 million children worldwide. Among syndromic HL is Usher syndrome (USH), a neurosensory disorder defined by a bilateral sensorineural HL and a loss of vision due to retinitis pigmentosa (RP). Usher syndrome is classified into three clinical subtypes. A molecular diagnosis study suggested a frequency of 1/6000 individuals afflicted with USH in the US. Fourteen distinct genetic loci have been linked to the USH phenotype and genes for eleven of these loci have been identified. Genetic and functional studies of the gene/protein determinants of USH have been fruitful in elucidating the common molecular components of inner ear and retinal sensory epithelia. However, the molecular identities of many essential components of these two sensory organs are still unknown, precluding our understanding of molecular and cellular basis and precise mechanism of hearing and vision in general. Likewise, the known loci/gene mutations do not account for all known cases of USH. The long-­term goal of this research is to fully understand the mechanisms of inherited Usher syndrome and to develop therapeutic agents for the treatment and prevention of USH. The objective of the proposed research is to identify and characterize proteins essential to mammalian inner ear development, function and long-­term maintenance of retinal sensory cells. Our hypothesis is that if a mutated gene causes deafness and blindness, then the normal function of that gene will be necessary for hearing and vision. The rationale for the proposed research is that identifying a causative gene and understanding its normal function is essential for preventing hearing and vision loss and for the development of therapeutic agents to treat these impairments. The project addresses NIH’s mission to develop basic knowledge that may be translatable to reduce the burdens of human disability. In our preliminary data we have already identified two mutant genes: USH1K and USH1M, and have mapped the chromosomal positions (USH1H and USH1N) of two additional genes essential for auditory and visual function. The proposed experimental design comprises of two aims that include the ascertainment and clinically phenotype members of extended families segregating USH;; identification of new USH genes, characterization of their expression in the mouse inner ear and retina and determine the effect of identified variant of novel USH gene on the encoded protein in model systems. The project will advantageously combine human clinical assessment and genetic analyses with relevant to inner ear and retina development and function. It will be significant by advancing concerted methods and yielding basic new knowledge that is clinically relevant, with high potential to improve the molecular epidemiology, genetic diagnosis and counseling for USH.