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: 10400017
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400017
• 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; 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; Prognosis; 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）是一种高度可变的表型，影响了全球超过7000万儿童。在综合征HL中，是Usher综合征（USH），这是一种由双侧感觉神经性HL定义的神经感觉障碍，以及由于色素性视网膜炎（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，在美国患有USH的1/6000个个体的频率。已经确定了十个基因座的USH表型和基因，已鉴定出14个不同的遗传基因座。 USH基因/蛋白质决定剂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富有成果。但是，这两个感觉器官的许多基本组成部分的分子身份仍然未知，从而排除了我们对分子和细胞基础的理解以及听力和视力的精确机制。同样，已知的局部/基因突变也不解释所有已知的USH病例。这项研究的长期目标是充分了解遗传的Usher综合征的机制，并开发用于治疗和预防USH的治疗剂。拟议的研究的目的是识别和表征对残留感觉细胞的哺乳动物内耳发育，功能和长期维持必不可少的蛋白质。我们的假设是，如果突变的基因会导致死亡和失明，那么该基因的正常功能对于听力和视力是必要的。拟议研究的理由是，鉴定出严重的基因并了解其正常功能对于防止听力和视力丧失以及开发治疗剂来治疗这些障碍至关重要。该项目涉及NIH的使命，该使命是发展基本知识，这些知识可能可以翻译以减少人类残疾的伯纳斯。在我们的初步数据中，我们已经确定了两个突变基因：USH1K和USH1M，并绘制了两个对听觉和视觉功能必不可少的其他基因的染色体位置（USH1H和USH1N）。拟议的实验设计包括两个目标，其中包括确定性和临床表型成员的大家庭的临床型成员；鉴定新的USH基因，表征它们在小鼠内耳和视网膜中的表达，并确定新型USH基因对模型系统中编码蛋白的鉴定变体的影响。该项目将有利地将人类的临床评估和遗传分析与内耳和视网膜的发展和功能相关。通过推进一致的方法并产生临床上相关的基本新知识，这将是重要的，具有改善USH分子流行病学，遗传诊断和咨询的很高潜力。

项目成果

Genetic association analysis of 77,539 genomes reveals rare disease etiologies.

• DOI: 10.1038/s41591-023-02211-z
• 发表时间: 2023-03
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Greene, Daniel;Pirri, Daniela;Frudd, Karen;Sackey, Ege;Al-Owain, Mohammed;Giese, Arnaud P. J.;Ramzan, Khushnooda;Riaz, Sehar;Yamanaka, Itaru;Boeckx, Nele;Thys, Chantal;Gelb, Bruce D.;Brennan, Paul;Hartill, Verity;Harvengt, Julie;Kosho, Tomoki;Mansour, Sahar;Masuno, Mitsuo;Ohata, Takako;Stewart, Helen;Taibah, Khalid;Turner, Claire L. S.;Imtiaz, Faiqa;Riazuddin, Saima;Morisaki, Takayuki;Ostergaard, Pia;Loeys, Bart L.;Morisaki, Hiroko;Ahmed, Zubair M.;Birdsey, Graeme M.;Freson, Kathleen;Mumford, Andrew;Turro, Ernest
• 通讯作者: Turro, Ernest