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.
