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7000多万儿童。在综合征性HL中，Usher综合征(USH)是一种神经感觉障碍，定义为双侧感觉神经性HL和由于视网膜色素变性(RP)而导致的视力丧失。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，每6000人中就有1人患有USH。已有14个不同的遗传座位与USH表型相关联，其中11个座位的基因已被鉴定。对USH基因/蛋白决定因素的遗传和功能研究已在阐明内耳和视网膜感觉上皮的共同分子成分方面取得了丰硕成果。然而，这两个感觉器官的许多基本成分的分子同一性仍然是未知的，这阻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/基因突变并不能解释所有已知的USH病例。这项研究的长期目标是全面了解遗传性Usher综合征的机制，并开发治疗USH和预防USH的药物。这项拟议研究的目的是识别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觉所必需的。这项拟议研究的基本原理是，识别致病基因并了解其正常功能对于预防听力和视力损失以及开发治疗这些损伤的治疗剂至关重要。该项目针对NIH的使命，即开发可翻译的基本知识，以减轻人类残疾的负担。在我们的初步数据中，我们已经鉴定了两个突变基因：USH1K和USH1M，并定位了另外两个对听觉和视觉功能至关重要的基因的染色体位置(USH1H和USH1N)。实验设计包括两个目标，包括确定分离尿促性腺激素的大家族成员及其临床表型；;鉴定新的尿促性腺激素基因，鉴定其在小鼠内耳和视网膜中的表达，并在模型系统中确定已识别的尿促性腺激素新基因变体对编码蛋白的影响。该项目将有利地将人类临床评估和基因分析与内耳和视网膜发育和功能相关的基因分析结合在一起。这对于改进USH的分子流行病学、基因诊断和咨询具有重要意义，为USH的分子流行病学、基因诊断和咨询提供有临床意义的基础知识。

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.