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中已鉴定的突变与其 在遗传性心血管疾病发展中的作用。具体地说， 识别和表征具有瓣上型的个体中的突变， 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。 升主动脉的进行性血管阻塞发生在SVAS中， 而WS患者可能在额外的时间发生血管阻塞， 部位包括肺、肾、头臂，很少有冠状动脉 脉管系统WS还与广泛的发育相关， 包括显著认知缺陷的异常。 最近发现的连锁弹性蛋白基因座的长臂， SVAS和WS患者的7号染色体（7q11.23）使 在该地区进行重点调查。迄今发现的突变 患有孤立性SVAS的患者已经定位在弹性蛋白基因内， 而WS患者迄今为止已经证明了大的缺失， 包括弹性蛋白基因，并提示有连续基因紊乱。 申请人与儿童医院的合作者一起， 波士顿，已经确定了大量的威廉姆斯综合征患者 以及患有瓣上主动脉瓣狭窄的个体/家族， 现在描述这些患者的特征，如本提案所述。下 在主要赞助商的指导下， 合作者，我们将确定突变或附近的弹性蛋白基因座， 这些人。 这些突变的位置和程度将是 定义，包括识别有助于“新的”基因， 观察到的表型。弹性蛋白基因中的特定突变将是 其功能后果的特点，以努力 定义将基因组DNA的初级改变与其相关的机制 人类阻塞性心血管疾病的最终表现，通过 改变或缺失基因产物。

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.