MOLECULAR GENETIC ANALYSIS OF WILLIAMS SYNDROME/SVAS

拟议研究的目标是调查和定义 人类基因组DNA已识别突变与其相互关系的研究 在遗传性心血管疾病的发展中的作用。具体来说， 鉴定和表征瓣膜上变异症患者的突变 主动脉瓣狭窄(SVAS)和威廉综合征(WS)，并与 这些突变的性质与观察到的表型有关。 升主动脉的进行性血管阻塞在SVAS中发生， 而WS患者可能在另一处发生血管阻塞 部位包括肺、肾、头臂和罕见的冠状动脉 脉管系统。WS也与普及性发展有关 包括严重认知缺陷在内的异常。 最近发现的与长臂上的弹性蛋白基因连锁的研究 SVAS和WS患者的七号染色体(7q11.23)已启用 在这一地区进行重点调查。迄今发现的突变在 孤立的SVAS患者被定位在弹性蛋白基因内， 鉴于WS患者到目前为止表现出大量缺失， 包括弹性蛋白基因，并提示存在毗连的基因紊乱。 申请者与儿童医院的合作者， 波士顿发现了大量威廉姆斯综合征患者 以及患有瓣膜上动脉狭窄的个人/家庭，以及 现在描述这项提案中所描述的这些患者的特征。在.之下 主要赞助人的指导，并与指定的 合作者我们将确定弹性蛋白基因座或其附近的突变 这些人。这些突变的位置和程度将是 定义，包括识别有助于 观察到的表型。弹性蛋白基因的特定突变将是 以其功能后果为特征的，以努力 确定将基因组DNA的主要改变与其 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。

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.