The overall goal of this proposal is to identify the nature and functional relevance of a spectrum of mutations in the elastin gene that are responsible for the pathogenesis of a heritable neonatal vascular disorder, supravalvular aortic stenosls (SVAS). SVAS is a disease characterized by the deposition of abnormal elastic fibers in the ascending aorta-that leads to narrowing of the aorta and, if left untreated, frequently leads to severe cardiac abnormalities. This disease can occur sporadically, as a familial defect, or in association with a more complex developmeiital disorder, Williams syndrome. Recent linkage data has implicated mutations in the elastin gene as being responsible for the development of familial SVAS. Prelinary data presented in this application clearly show, for the first time, that a mutation in the elastin gene is indeed responsible for the pathogenesis of SVAS. Moreover, these preliminary data also demonstrate an SVAS-like phenotype in transgenic mice with intragenic deletions of certain domains of the tropoelattin gene.
The aim of this proposal therefore is to define the nature of the elastin gene mutations in a cohort of unrelated SVAS patients with the view to establishing phenotypic correlations with different genotypes. This information will provide new insights into the molecular pathogenesis of SVAS and provide an important basis for understanding elastin and elastic fiber assembly during fetal and neonatal development.
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