Molecular Determinants of Usher Syndrome Disorder in Humans

人类亚瑟综合症的分子决定因素

• 批准号: 9899240
• 负责人: Zubair M. Ahmed
• 金额: $ 52.72万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899240
• 关键词: Address; Affect; Alleles; Ankle; Auditory; Bilateral; Biological Models; Blindness; Cells; Child; Clinical; Clinical assessments; Collaborations; Complex; Critical Pathways; Data; Development; Diagnosis; Disease; ERCC6 gene; Enrollment; Epithelial; Epithelium; Experimental Designs; Extended Family; Eye; Family; Family member; Frequencies; G-substrate; Gene Expression; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Counseling; Genotype; Goals; Hair Cells; Hearing; Human; Impairment; Individual; Inherited; Intervention; Knowledge; Labyrinth; Link; Lod Score; Maintenance; Maps; Medical Genetics; Methods; Mission; Molecular; Molecular Biology; Molecular Diagnosis; Molecular Epidemiology; Molecular Genetics; Mus; Mutate; Organ; Pakistan; Pathogenicity; Pathology; Pathway interactions; Pattern; Phenotype; Population Heterogeneity; Positioning Attribute; Prevention; Proteins; Reporting; Research; Retina; Retinitis Pigmentosa; SNP genotyping; Sampling; Sensorineural Hearing Loss; Sensory; Sensory Hair; Side; Structure; Syndrome; Testing; Therapeutic; Therapeutic Agents; Time; United States National Institutes of Health; Usher Proteins; Usher Syndrome; Usher Syndrome Type 1; Variant; Vision; Visual impairment; base; chromosomal location; clinical phenotype; clinical subtypes; clinically relevant; cohort; consanguineous family; deafness; disability; exome sequencing; experience; gene function; genetic analysis; genetic disorder diagnosis; genetic linkage analysis; genetic pedigree; genetic variant; genome sequencing; genome-wide linkage; genomic locus; hearing impairment; hereditary hearing loss; improved; individualized medicine; inner ear development; mechanical force; member; molecular pathology; mutant; neurosensory; new therapeutic target; novel; novel therapeutic intervention; prevent hearing loss; screening; simulation; skills; spatiotemporal; synaptic function; therapeutic development; whole genome

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.

听力损失 (HL) 是一种高度变异的表型，影响着全球超过 7000 万儿童，其中包括亚瑟综合征 (USH)，这是一种神经感觉障碍，由双侧感觉神经性 HL 和色素性视网膜炎 (RP) 引起的视力丧失所定义。亚瑟综合征分为三种临床亚型。一项分子诊断研究表明，在美国，1/6000 的个体患有亚瑟综合征，这与 14 个不同的基因位点有关。 USH 表型的基因和其中 11 个基因座的基因已被确定。USH 基因/蛋白质决定因素的遗传和功能研究在阐明内耳和视网膜感觉上皮的常见分子成分方面取得了丰硕成果。这两种感觉器官的许多重要组成部分仍然未知，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/基因突变并不能解释所有已知的 USH 病例。 -学期这项研究的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。拟议研究的目的是鉴定和表征对哺乳动物内耳发育、功能和长期发育至关重要的蛋白质。我们的假设是，如果突变基因导致耳聋和失明，那么该基因的正常功能对于听力和视力来说是必要的，这项研究的基本原理是识别致病基因并了解其基因。正常功能对于预防听力至关重要该项目致力于开发可用于减轻人类残疾负担的基础知识。在我们的初步数据中，我们已经确定了两种突变基因：USH1K 和 USH1K。 USH1M，并绘制了对听觉和视觉功能至关重要的两个额外基因的染色体位置（USH1H 和 USH1N）。拟议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，表征其在小鼠内耳和视网膜中的表达，并确定已鉴定的新 USH 基因变体对模型系统中编码蛋白质的影响。与内耳和视网膜发育和功能相关的临床评估和遗传分析通过推进协调一致的方法并产生与临床相关的基础新知识将具有重要意义，对于改善分子流行病学、遗传诊断和咨询具有很大潜力。嘘。