ELASTIN POINT MUTATIONS CAUSE AN OBSTRUCTIVE VASCULAR-DISEASE, SUPRAVALVULAR AORTIC-STENOSIS

Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascu lar disease that affects the aorta, carotid, coronary and pulmonary ar teries, Previous molecular genetic data have led to the hypothesis tha t SVAS results from mutations in the elastin gene, ELN, In these studi es, the disease phenotype was linked to gross DNA rearrangements (35 a nd 85 kb deletions and a translocation) in three SVAS families, Howeve r, gross rearrangements of ELN have not been identified in most cases of autosomal dominant SVAS. To define the spectrum of ELN mutations re sponsible for this disorder, we refined the genomic structure of human ELN and used this information in mutational analyses. ELN point mutat ions co-segregate with the disease in four familial cases and are asso ciated with SVAS in three sporadic cases. Two of the mutations are non sense, one is a single base pair deletion and four are splice site mut ations, In one sporadic case, the mutation arose de novo, These data d emonstrate that point mutations of ELN cause autosomal dominant SVAS.