MOLECULAR GENETIC STUDIES OF BRANCHIOGENIC DISORDERS

支气管疾病的分子遗传学研究

• 批准号: 6887826
• 负责人: William J Kimberling
• 金额: $ 25.2万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887826
• 关键词: Europe; Japan; United States; chromosomes; clinical research; complementary DNA; congenital oral /facial /cranial defect; cooperative study; family genetics; gene expression; gene mutation; genetic disorder; genetic mapping; genetic markers; genetic polymorphism; genetic screening; genome; genotype; hearing disorders; heterozygote; human genetic material tag; human subject; labyrinth disorder; linkage mapping; nucleic acid sequence; southern blotting

The group of autosomal dominant disorders associated with branchial anomalies are characterized by external, middle and inner ear malformations, branchial cleft sinuses, cervical fistulas, mixed hearing loss, renal anomalies and occasional other manifestations. The Branchio-oto-renal (BOR), gene on chromosome 8q, has been identified as EYA1, however, some BOR, Branchio-renal (BR) and Branchio-oto (BO) families have not shown any mutation in the EYA1 gene. Gene mapping data suggests that multiple genes are involved and that this may be partly responsible for the variable phenotypic expression seen between families. We identified one large family with branchial and hearing anomalies (BO) unlinked to the 8q region and recently mapped the gene (named BGS2) to chromosome 1q. Also, there are at least two large families found to be unlinked to both regions suggesting the presence of a third locus associated with branchiogenic disorders. More than 50 - 60 percent of our BOR families did not show a mutation in the EYA1 gene or genetic linkage to 1q or 8q. We have collected the world's largest series of BOR type families, a resource that will allow us to identify the various genes involved in BOR syndrome. We propose to determine the distribution of mutations associated with the EYA1 gene, and to analyze clinical differences between families to determine to what degree they are correlated with different linkage groups. The possibility of genetic heterogeneity will be continually explored and families unlinked to 8q and 1q will be put through another round of genome searching to determine the location of any new BOR-related genes. The critical region of BGS2 has been narrowed from 22 cM to 9 cM. New families will be ascertained and tested for linkage with the markers on chromosome 8q and 1q. Refining the region is a gradual process, however, based on the completion of human genome project it may not be necessary to decrease the resolution to a smaller interval. Strong candidate genes lying within the critical region will be tested. The BGS2 gene will be identified among the candidate genes on the basis of its genomic position, tissue specific expression and consistent disease causing mutations in affected individuals. The BOR syndrome results in craniofacial anomalies in affected individuals and poses serious health problems. Defining the spectrum of defects and mapping and cloning the BGS genes are the first and foremost steps to a more comprehensive understanding of the pathogenesis and etiology of this syndrome. Finding the genes will lay the foundation for further research concerning effective treatment and genetic counseling.

与分支异常相关的常染色体显性疾病组的特征是外耳和内耳畸形，分支裂口窦，宫颈瘘，混合听力损失，肾异常以及偶尔其他表现。 在8q染色体上的基因上的分支 - 荷属（BOR）已被鉴定为EYA1，但是，某些BOR，分支 - 肾脏（BR）和分支-Oto（BO）家族尚未在EYA1基因中显示出任何突变。 基因映射数据表明涉及多个基因，这可能部分负责家族之间看到的可变表型表达。我们确定了一个具有分支机构的大家庭，听到异常（BO）未链接到8Q区域，最近将基因（名为BGS2）映射到染色体1q。 同样，至少有两个大家庭与两个区域无关，这表明存在与枝疾病相关的第三个基因座。 超过50-60％的BOR家族没有在EYA1基因或遗传连接到1Q或8Q中显示突变。我们已经收集了世界上最大的BOR类型家庭，这将使我们能够识别涉及BOR综合征的各种基因。 我们建议确定与EYA1基因相关的突变的分布，并分析家庭之间的临床差异，以确定它们与不同的链接组相关的程度。遗传异质性的可能性将不断探索，并将通过另一轮基因组搜索来确定任何与BOR相关的新基因的位置，将其未链接到8Q和1Q的家庭。 BGS2的临界区域已从22厘米缩小到9厘米。将确定并测试新家庭与8Q和1Q染色体上的标记的联系。 然而，根据人类基因组项目的完成，精炼该区域是一个逐步的过程，可能不需要将分辨率减少到较小的间隔。 将测试位于关键区域内的强候选基因。 BGS2基因将根据候选基因的基因组位置，组织特异性表达和一致的疾病在受影响个体的突变中鉴定。 BOR综合征导致受影响个体的颅面异常，并带来严重的健康问题。 定义缺陷，映射和克隆BGS基因的范围是对该综合征的发病机理和病因的更全面的第一步。 寻找基因将为有效治疗和遗传咨询的进一步研究奠定基础。