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.

与鳃异常相关的常染色体显性遗传疾病的特征是外耳、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。 位于8q染色体上的Branchio-oto-renal (BOR)基因已被鉴定为EYA1，然而，一些BOR、Branchio-renal (BR)和Branchio-oto (BO)家族的EYA1基因并未显示出任何突变。 基因图谱数据表明涉及多个基因，这可能是家族之间表型表达差异的部分原因。我们发现了一个具有与 8q 区域无关的鳃和听力异常 (BO) 的大家族，并最近将该基因（名为 BGS2）定位到了 1q 染色体。 此外，至少有两个大家族被发现与这两个区域无关，表明存在与鳃形成疾病相关的第三个基因座。 我们超过 50-60% 的 BOR 家族没有显示 EYA1 基因突变或与 1q 或 8q 的遗传连锁。我们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与 BOR 综合征相关的各种基因。 我们建议确定与 EYA1 基因相关的突变分布，并分析家族之间的临床差异，以确定它们与不同连锁群的相关程度。我们将不断探索遗传异质性的可能性，并且与 8q 和 1q 无关的家族将进行另一轮基因组搜索，以确定任何新的 BOR 相关基因的位置。 BGS2 的关键区域已从 22 cM 缩小至 9 cM。新家族将被确定并测试与染色体 8q 和 1q 上标记的连锁。 细化该区域是一个渐进的过程，然而，基于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。 BGS2 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 综合征会导致受影响个体颅面异常，并造成严重的健康问题。 定义缺陷谱以及绘制和克隆 BGS 基因是更全面地了解该综合征的发病机制和病因学的首要步骤。 寻找基因将为进一步研究有效治疗和遗传咨询奠定基础。