title: Elastin: mutational spectrum in supravalvular aortic stenosis.
abstract: Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, 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. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments.
authors.affiliation: University Department of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Metcalfe
authors.forename: A K
authors.initials: AK
authors.lastname: Rucka
authors.forename: L
authors.initials: L
authors.lastname: Smoot
authors.forename: G
authors.initials: G
authors.lastname: Hofstadler
authors.forename: G
authors.initials: G
authors.lastname: Tuzler
authors.forename: P
authors.initials: P
authors.lastname: McKeown
authors.forename: V
authors.initials: V
authors.lastname: Siu
authors.forename: A
authors.initials: A
authors.lastname: Rauch
authors.forename: J
authors.initials: J
authors.lastname: Dean
authors.forename: N
authors.initials: N
authors.lastname: Dennis
authors.forename: I
authors.initials: I
authors.lastname: Ellis
authors.forename: W
authors.initials: W
authors.lastname: Reardon
authors.forename: C
authors.initials: C
authors.lastname: Cytrynbaum
authors.forename: L
authors.initials: L
authors.lastname: Osborne
authors.forename: J R
authors.initials: JR
authors.lastname: Yates
authors.forename: A P
authors.initials: AP
authors.lastname: Read
authors.forename: D
authors.initials: D
authors.lastname: Donnai
authors.forename: M
authors.initials: M
authors.lastname: Tassabehji
mesh_terms: D017398:Alternative Splicing; D021921:Aortic Stenosis, Supravalvular / Q000235:genetics*; D018387:Codon, Initiator; D018389:Codon, Nonsense; D004247:DNA / Q000032:analysis; D004549:Elastin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011110:Polymorphism, Genetic
chemical_list: D018387:Codon, Initiator; D018389:Codon, Nonsense; D004247:DNA; D004549:Elastin