MOLECULAR GENETIC STUDIES OF BRANCHIO-OTO-RENAL SYNDROME

臂耳肾综合征的分子遗传学研究

• 批准号: 5209960
• 负责人: Shrawan Kumar
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5209960
• 关键词: artificial chromosomes; autosomal dominant trait; clinical research; congenital deafness; genetic polymorphism; human genetic material tag; human subject; linkage mapping; molecular cloning; molecular genetics

Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant disorder which consists of external, middle and inner ear malformations, branchial cleft sinuses, cervical fistulas, mixed hearing loss and renal anomalies. Variable clinical expression between families suggests that multiple gene loci are involved in causing the disease. Through genetic linkage analysis, the BOR gene has been localized on chromosome 8q. The purpose of the proposed study is to reduce the localization region to 0.5 to l cM and complete a YAC contig in the critical region to identify the BOR gene. The isolation of random human DNA sequences from the YACs will provide a set of closely spaced sequence tagged sites (STSs) which can be used to construct a framework map. This can be used to verify the existing physical map and help to fill the gaps between sets of contiguous clones. Gaps will be filled by walking out from known contiguous segments. Clones will be screened for di-, tri- and tetra- repeat polymorphisms and linkage will be used to refine the position of the BOR gene to the smallest possible region of chromosome 8q. YACs or their derivative cosmid subclones can be used as a resource to identify candidate genes in the region based on their possible association to CpG islands, by displaying evolutionary conserved DNA sequences, or by hybridization to tissue specific cDNA libraries and/or by exon trapping. The BOR gene will be identified among the candidate genes on the basis of its position, tissue specific expression and consistent mutation in affected individuals. Additional families will be required to narrow down the BOR region to the smallest interval. New families will be ascertained and tested for linkage with the markers on chromosome 8q. The possibility of genetic heterogeneity will be explored using the program HOMOG and unlinked families will be put through another round of genome searching to determine the location of new BOR-related genes. Clinical differences between families will be analyzed to determine to what degree they are correlated with different linkage groups. The BOR syndrome results in branchial, auditory, and renal abnormalities in affected individuals and poses serious health problems. Identification of the BOR gene(s) is the first and foremost step to a more comprehensive understanding of the pathogenesis and etiology of this syndrome. Finding the gene(s) will lay the foundation for further research concerning effective treatment and genetic counseling.

分支 - 局部肾脏综合征（BOR）是一种常染色体显性疾病，该疾病是该疾病 由外耳和内耳畸形，分支裂缝组成 鼻窦，宫颈瘘，混合听力损失和肾异常。 家族之间的可变临床表达表明多个基因 基因座参与引起疾病。通过遗传联系 分析，BOR基因已定位在8Q染色体上。目的 拟议的研究是将定位区域降低到L cm，并 在关键区域完成YAC重叠群以识别BOR基因。这 从YAC隔离随机人DNA序列将提供一个集合 可用于序列序列标记的位点（STSS）的 构建框架图。这可以用来验证现有的 物理图并有助于填补连续克隆集合之间的空白。 从已知的连续段中走出来，将填补空白。克隆 将筛选DI-，三和四重复的多态性和连接 将用于完善BOR基因对最小的位置 染色体8Q的可能区域。 YAC或他们的衍生宇宙 子克隆可以用作识别候选基因的资源 通过展示，基于它们与CPG岛的可能关联 进化保守的DNA序列，或通过与组织杂交 特定的cDNA库和/或通过外显子捕获。 BOR基因将是 在候选基因之间根据其位置鉴定 受影响个体的特定表达和一致的突变。 需要其他家庭才能将Bor地区缩小到 最小的间隔。新家庭将得到确定并测试联系 与染色体8Q上的标记。遗传的可能性 异质性将使用程序同质探索并取消链接 家庭将通过另一轮基因组进行搜索 确定新的BOR相关基因的位置。临床差异 在家庭之间将进行分析以确定他们在多大程度上 与不同的链接组相关。 BOR综合征导致分支，听觉和肾异常 在受影响的个人中，带来了严重的健康问题。鉴别 BOR基因的第一步是更全面的一步 了解该综合征的发病机理和病因。发现 该基因将奠定有关进一步研究的基础 有效的治疗和遗传咨询。