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.

鳃-耳-肾综合征 (BOR) 是一种常染色体显性遗传疾病， 包括外耳、中耳和内耳畸形、鳃裂 鼻窦、颈瘘、混合性听力损失和肾脏异常。 家族之间临床表达的差异表明多基因 位点参与引起疾病。通过遗传连锁 分析显示，BOR基因定位于染色体8q。目的 拟议的研究是将定位区域减小到 0.5 至 l cmM，并且 在关键区域完成 YAC 重叠群以识别 BOR 基因。这 从 YAC 中分离出随机人类 DNA 序列将提供一组 紧密间隔的序列标记位点（STS），可用于 构建框架图。这可以用来验证现有的 物理图谱并有助于填补连续克隆组之间的空白。 间隙将通过从已知的连续段走出来填补。克隆 将筛选二、三和四重复多态性和连锁 将用于将BOR基因的位置细化到最小 染色体 8q 的可能区域。 YAC 或其衍生物粘粒 亚克隆可用作鉴定候选基因的资源 区域基于它们与 CpG 岛屿可能的关联，通过显示 进化保守的DNA序列，或通过与组织杂交 特定的 cDNA 文库和/或通过外显子捕获。 BOR 基因将是 根据其位置、组织在候选基因中进行鉴定 受影响个体中的特异性表达和一致突变。 将需要更多的家庭来将 BOR 区域缩小到 最小间隔。新家庭将被确定并测试关联性 标记位于 8q 染色体上。遗传的可能性 将使用 HOMOG 程序和 unlinked 来探索异质性 家庭将接受另一轮基因组搜索 确定新的 BOR 相关基因的位置。临床差异 将分析家庭之间的情况，以确定他们的程度 与不同的连锁群相关。 BOR 综合征导致鳃、听觉和肾脏异常 在受影响的个体中并造成严重的健康问题。鉴别 BOR 基因的研究是迈向更全面的第一步，也是最重要的一步。 了解该综合征的发病机制和病因。寻找 该基因将为进一步研究奠定基础 有效的治疗和遗传咨询。