Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis

Supravalvular aortic stenosis (SVAS) is an inherited obstructive vasculardisease that affects the aorta, carotid, coronary and pulmonary arteries.Previous molecular genetic data have led to the hypothesis that SVASresults from mutations in the elastin gene, ELN. In these studies, thedisease phenotype was linked to gross DNA rearrangements (35 and 85 kbdeletions and a translocation) in three SVAS families. However, grossrearrangements of ELN have not been identified in most cases of autosomaldominant SVAS. To define the spectrum of ELN mutations responsible for thisdisorder, we refined the genomic structure of human ELN and used thisinformation in mutational analyses. ELN point mutations co-segregate withthe disease in four familial cases and are associated with SVAS in threesporadic cases. Two of the mutations are nonsense, one is a single basepair deletion and four are splice site mutations. In one sporadic case, themutation arose de novo. These data demonstrate that point mutations of ELNcause autosomal dominant SVAS.