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.

支耳肾综合征（BOR）是一种常染色体显性遗传病