MOLECULAR GENETIC ANALYSIS OF WILLIAMS SYNDROME/SVAS

威廉姆斯综合征/SVAS 的分子遗传学分析

• 批准号: 2519177
• 负责人: LESLIE B SMOOT
• 金额: $ 8.37万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519177
• 关键词: DNA; Williams syndrome; aortic valve stenosis; artificial chromosomes; cell transformation; cellular pathology; chromosome deletion; elastin; family genetics; gene mutation; genetic disorder; genotype; human subject; immunocytochemistry; northern blottings; nucleic acid sequence; phenotype; polymerase chain reaction; tissue /cell culture; western blottings

The goal of the proposed research is to investigate and define the relationship between identified mutations in human genomic DNA and their role in the development of heritable cardiovascular disease. Specifically, to identify and characterize mutations in individuals with supravalvar aortic stenosis (SVAS) and William's syndrome (WS), and correlate the nature of these mutations with observed phenotypes. Progressive vascular obstruction of the ascending aorta occurs in SVAS, whereas patients with WS may develop vascular obstruction at additional sites including pulmonary, renal, brachiocephalic, and rarely coronary vasculature. WS is also associated with pervasive developmental abnormalities which include significant cognitive deficits. Recent identification of linkage to the elastin locus on the long arm of chromosome seven (7q11.23) in individuals with SVAS and WS has enabled focused investigation in this region. Mutations identified to date in patients with isolated SVAS have been located within the elastin gene, whereas WS patients have thus far demonstrated large deletions which include the elastin gene and are suggestive of a contiguous gene disorder. The applicant in conjunction with collaborators at Children's Hospital, Boston, has identified a large number of patients with Williams syndrome as well as individuals/families with supravalvar aortic stenosis, and is now characterizing these patients as described in this proposal. Under the direction of the primary sponsor and in association with named collaborators we will identify mutations at or near the elastin locus in these individuals. The location and extent of these mutations will be defined, including identification of 'new' genes contributing to the observed phenotypes. Specific mutations in the elastin gene will be characterized with regard to their functional consequences in an effort to define mechanisms linking primary alterations of genomic DNA to their ultimate manifestations in human obstructive cardiovascular disease, via altered or absent gene products.

拟议研究的目标是调查和定义 人类基因组 DNA 中已发现的突变及其之间的关系 在遗传性心血管疾病的发展中的作用。具体来说， 识别和表征瓣上变异个体的突变 主动脉瓣狭窄 (SVAS) 和威廉氏综合征 (WS)，并将 这些突变的性质与观察到的表型。 升主动脉进行性血管阻塞发生在 SVAS 中， 而 WS 患者可能会在额外的时间出现血管阻塞 部位包括肺、肾、头臂，很少有冠状动脉 脉管系统。 WS 还与普遍发育有关 异常，包括显着的认知缺陷。 最近鉴定出与长臂上弹性蛋白基因座的连锁 SVAS 和 WS 患者的第七号染色体 (7q11.23) 已启用 重点调查该地区。迄今为止发现的突变 患有孤立性 SVAS 的患者已位于弹性蛋白基因内， 而 WS 患者迄今为止已表现出大量缺失， 包括弹性蛋白基因，提示存在连续基因疾病。 申请人与儿童医院的合作者一起， 波士顿已发现大量威廉姆斯综合症患者 以及患有瓣上主动脉瓣狭窄的个人/家庭，并且 现在按照本提案中的描述描述这些患者的特征。下 主要赞助商的方向并与指定的 合作者，我们将鉴定弹性蛋白基因座处或附近的突变 这些人。 这些突变的位置和程度将是 定义，包括鉴定有助于 观察到的表型。弹性蛋白基因的特定突变将是 其功能后果的特征是为了 定义将基因组 DNA 的主要改变与它们的相关性联系起来的机制 人类阻塞性心血管疾病的最终表现，通过 基因产物改变或缺失。