Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by 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 the Williams-Beuren syndrome, a complex developmental genomic disorder associated with cardiovascular, neurobehavioral, craniofacial, and metabolic abnormalities, caused by a microdeletion at 7q11.23. We report the identification of seven novel mutations within the elastin gene in 31 familial and sporadic cases of nonsyndromic SVAS. Five are frameshift mutations within the coding region of the ELN gene that result in premature stop codons (PTCs); the other two mutations abolish the donor splice site of introns 3 and 28, respectively, and are predicted to alter splicing efficiency resulting in the generation of a PTC within the same introns of the gene. In vitro analysis using minigenes and cycloheximide showed that some selected frameshift mutant alleles are substrates of nonsense-mediated mRNA decay (NMD), confirming that the functional haploinsufficiency of the ELN gene is the main pathomechanism underlying SVAS. Interestingly, molecular analysis on patient fibroblasts showed that the c.2044+5G4C mutant allele encodes for an aberrant shorter form of the elastin polypeptide that may hamper the normal assembly of elastin fibers in a dominant-negative manner.

Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm

“…“Premature stop codons in ELN may lead to nonsense-mediated mRNA decay, and thereby decreased levels of ELN and thus result in functional haploinsufficiency as it has been described for Williams syndrome.” 9,10 . Reduced elastin availability during vascular maturation results in increased cell proliferation 11 , as a result of excessive integrin β3 signaling 12 .…”

Genetic architecture of reciprocal CNVs

“…For example, two genes have been implicated in the etiology of the Williams-Beuren syndrome, each gene responsible for a different phenotypic component of del/dup patients. Haploinsufficiency of elastin (ELN) is responsible for the supravalvular aortic stenosis and other arteriopathies but not cognitive defects in patients with WBS 84,85 . Further, the identification of a small deletion including ELN and LIMK-1 in two families with partial WBS implicated LIMK-1 hemizygosity in impaired visuospatial constructive cognition 86 .…”

Epidemiology and Etiology of Congenital Heart Diseases

“…Mutation of this gene has been implicated in both Ellis-van Creveld syndrome and Weyers acrodental dysostosis, the disease locus mapped to chromosome 4p16 (Polymeropoulos et al, 1996). Ellis-van Creveld syndrome is an autosomal recessive disorder characterized by chondrodysplasia and CHD, typically a common atrium of the atrioventricular septal defect type or secundum type atrial septal defects (Ali et al, 2010;Hills et al, 2011;Tompson et al, 2007 (Micale et al, 2010;Rodriguez-Revenga et al, 2005;Arrington et al, 2006).  FBN1, fibrillin 1; This gene encodes a member of the fibrillin family.…”