MOLECULAR GENETIC STUDIES OF BRANCHIOGENIC DISORDERS

支气管疾病的分子遗传学研究

• 批准号: 6435742
• 负责人: Shrawan Kumar
• 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/6435742
• 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.

与鳃裂异常相关的常染色体显性遗传疾病组的特征在于外耳、中耳和内耳畸形、鳃裂窦、颈瘘、混合性听力损失、肾脏异常和偶尔的其他表现。 Branchio-oto-renal（BOR）基因位于染色体8 q上，被鉴定为EYA 1基因，但在部分BOR、Branchio-renal（BR）和Branchio-oto（BO）家系中未发现EYA 1基因突变。 基因定位数据表明，多个基因参与，这可能是部分负责家庭之间看到的可变表型表达。我们发现了一个与8 q区域无关的鳃和听力异常（BO）的大家族，最近将该基因（命名为BGS 2）定位于染色体1 q。 此外，至少有两个大的家庭被发现是不连锁的两个地区，这表明存在的第三个基因座与鳃原性疾病。 超过50 - 60%的BOR家族没有显示EYA 1基因突变或与1 q或8 q的遗传连锁。我们已经收集了世界上最大的BOR型家族系列，这一资源将使我们能够识别BOR综合征中涉及的各种基因。 我们建议确定与EYA 1基因相关的突变的分布，并分析家庭之间的临床差异，以确定它们在多大程度上与不同的连锁群相关。遗传异质性的可能性将继续探索，与8 q和1 q无关的家庭将通过另一轮基因组搜索，以确定任何新的BOR相关基因的位置。BGS 2的临界区域已从22 cM缩小到9 cM。新的家庭将被确定和测试与染色体8 q和1 q上的标记的连锁。 区域的细化是一个渐进的过程，但随着人类基因组计划的完成，可能没有必要将分辨率降低到更小的区间。 将测试位于关键区域内的强候选基因。 BGS 2基因将根据其基因组位置、组织特异性表达和受影响个体中一致的致病突变在候选基因中进行鉴定。BOR综合征导致受影响个体的颅面异常，并造成严重的健康问题。 定义缺陷谱和定位并克隆BGS基因是更全面地了解该综合征的发病机制和病因的首要步骤。 找到这些基因将为进一步研究有效的治疗和遗传咨询奠定基础。