Elastin: mutational spectrum in supravalvular aortic stenosis

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascen ding aorta which can occur sporadically, as an autosomal dominant condition , or as one component of Williams syndrome. SVAS is caused by translocation s, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. Howev er, the pathogenic mechanisms of point mutations are less clear. One hundre d patients with diagnosed SVAS and normal karyotypes were screened for muta tions in the elastin gene to further elucidate the molecular pathology of t he disorder. Mutations associated with the vascular disease were detected i n 35 patients, and included nonsense, frameshift, translation initiation an d splice site mutations. The four missense mutations identified are the fir st of this type to be associated with SVAS. Here we describe the spectrum o f mutations occurring in familial and sporadic SVAS and attempt to define t he mutational mechanisms involved in SVAS. SVAS shows variable penetrance w ithin families but the progressive nature of the disorder in some cases, ma kes identification of the molecular lesions important for future preventati ve treatments.