MOLECULAR GENETIC STUDIES OF BRANCHIO-OTO-RENAL SYNDROME

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。 不同家族间临床表现的差异提示多基因 基因座与致病有关。通过遗传连锁 分析表明，BOR基因定位于染色体8 q上。的目的 所提出的研究是将定位区域减小到0.5至lcM， 在关键区域中完成YAC重叠群以鉴定BOR基因。的 从YAC中分离随机的人类DNA序列将提供一组 紧密间隔的序列标记位点（STS），其可用于 建立一个框架图。这可以用来验证现有的 物理映射，并帮助填补连续克隆集之间的空白。 间隙将通过从已知的连续段中走出来来填充。克隆 将筛选双，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8 q的可能区域。YAC或其衍生粘粒 亚克隆可用作鉴定候选基因的资源， 通过显示，根据其与CpG岛的可能关联来确定区域 进化保守的DNA序列，或通过与组织杂交， 特异性cDNA文库和/或外显子捕获。BOR基因将会 基于其位置、组织、基因组、基因组DNA和基因组DNA， 在受影响的个体中特异性表达和一致的突变。 将需要更多的家庭将BOR区域缩小到 最小间隔新的家庭将被确定和测试的联系 与染色体8 q上的标记进行比对遗传的可能性 将使用HOMOG程序探索异质性， 家庭将通过另一轮的基因组搜索， 确定新的BOR相关基因的位置。临床差异 将分析家庭之间的关系，以确定他们在多大程度上是 与不同的连锁群相关。 BOR综合征导致鳃、听觉和肾脏异常 并造成严重的健康问题。识别 的BOR基因（S）是第一步，也是最重要的一步，以更全面的 了解该综合征的发病机制和病因。找到 该基因将为进一步研究奠定基础， 有效的治疗和遗传咨询。

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.